TBD Meeting (3776-20)

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure. An analysis of adult and pediatric encounters suggests that a variety of techniques can be employed to alter expectations and reduce antibiotic prescribing.

At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.

It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.

In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.

In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:

• Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
• Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
• Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).

Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).

But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.

Wavebreakmedia/Thinkstock

When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.

How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
 

Try a 3-prong communication plan

To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:

• Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
• Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
• Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.

Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.

In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
 

Questions answered

A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:

• Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
• Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
• Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
• Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
• Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
• Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
• Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
• Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.

When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”

Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”

Dr. Stivers stated that she has nothing to disclose.

Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure. An analysis of adult and pediatric encounters suggests that a variety of techniques can be employed to alter expectations and reduce antibiotic prescribing.

At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.

It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.

In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.

In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:

• Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
• Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
• Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).

Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).

But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.

Wavebreakmedia/Thinkstock

When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.

How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
 

Try a 3-prong communication plan

To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:

• Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
• Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
• Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.

Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.

In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
 

Questions answered

A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:

• Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
• Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
• Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
• Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
• Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
• Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
• Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
• Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.

When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”

Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”

Dr. Stivers stated that she has nothing to disclose.

Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure. An analysis of adult and pediatric encounters suggests that a variety of techniques can be employed to alter expectations and reduce antibiotic prescribing.

At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.

It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.

In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.

In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:

• Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
• Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
• Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).

Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).

But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.

Wavebreakmedia/Thinkstock

When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.

How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
 

Try a 3-prong communication plan

To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:

• Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
• Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
• Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.

Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.

In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
 

Questions answered

A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:

• Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
• Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
• Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
• Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
• Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
• Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
• Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
• Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.

When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”

Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”

Dr. Stivers stated that she has nothing to disclose.

A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.

Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.

Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.

Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.

Vladimir Voronin/Fotolia

Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).

Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).

Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”

He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”

For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.

Dr. Kopsidas had no relevant financial disclosures.

A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.

Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.

Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.

Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.

Vladimir Voronin/Fotolia

Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).

Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).

Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”

He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”

For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.

Dr. Kopsidas had no relevant financial disclosures.

A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.

Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.

Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.

Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.

Vladimir Voronin/Fotolia

Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).

Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).

Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”

He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”

For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.

Dr. Kopsidas had no relevant financial disclosures.

Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and CDI should be considered early in cancer patients who develop gastrointestinal symptoms, Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.

Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.

Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.

Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.

CDC/Jennifer Hulsey

Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.

Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.

In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?

Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.

Dr. Murphy had no financial conflicts of interest to declare.

Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and CDI should be considered early in cancer patients who develop gastrointestinal symptoms, Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.

Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.

Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.

Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.

CDC/Jennifer Hulsey

Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.

Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.

In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?

Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.

Dr. Murphy had no financial conflicts of interest to declare.

Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and CDI should be considered early in cancer patients who develop gastrointestinal symptoms, Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.

Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.

Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.

Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.

CDC/Jennifer Hulsey

Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.

Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.

In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?

Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.

Dr. Murphy had no financial conflicts of interest to declare.

The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.

Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
 

International guidelines differ on the subject

The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.

Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.

Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
 

There are diagnostic aids for GAS infection

It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.

Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
 

When are antibiotics warranted?

It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.

LightFieldStudios/Getty Images

Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.

But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.

Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.

Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.

Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.

As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.

Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”

The presenters had no financial conflicts of interest to declare.

The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.

Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
 

International guidelines differ on the subject

The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.

Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.

Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
 

There are diagnostic aids for GAS infection

It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.

Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
 

When are antibiotics warranted?

It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.

LightFieldStudios/Getty Images

Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.

But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.

Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.

Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.

Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.

As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.

Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”

The presenters had no financial conflicts of interest to declare.

The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.

Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
 

International guidelines differ on the subject

The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.

Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.

Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
 

There are diagnostic aids for GAS infection

It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.

Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
 

When are antibiotics warranted?

It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.

LightFieldStudios/Getty Images

Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.

But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.

Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.

Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.

Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.

As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.

Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”

The presenters had no financial conflicts of interest to declare.

Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.

Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”

Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.

The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.

As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.

The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.

“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.

Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.

“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.

These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”

Dr. Danino had nothing to disclose.

Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.

Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”

Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.

The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.

As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.

The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.

“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.

Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.

“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.

These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”

Dr. Danino had nothing to disclose.

Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.

Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”

Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.

The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.

As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.

The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.

“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.

Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.

“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.

These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”

Dr. Danino had nothing to disclose.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.