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Seeking new vaccines against whooping cough: The PERISCOPE project
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.
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.
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.
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.
FROM ESPID 2020
COVID-19–induced drop in first measles vaccinations sparks resurgence concerns
Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.
As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.
The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
MMR vaccination rates begin to drop with onset of COVID-19 pandemic.
From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid.
Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.
“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.
Innovative approaches are needed to encourage families to seek preventive care.
In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.
In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”
Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.
Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.
SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.
Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.
As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.
The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
MMR vaccination rates begin to drop with onset of COVID-19 pandemic.
From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid.
Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.
“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.
Innovative approaches are needed to encourage families to seek preventive care.
In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.
In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”
Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.
Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.
SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.
Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.
As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.
The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
MMR vaccination rates begin to drop with onset of COVID-19 pandemic.
From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid.
Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.
“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.
Innovative approaches are needed to encourage families to seek preventive care.
In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.
In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”
Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.
Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.
SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.
FROM PEDIATRICS
ASH guidelines for venous thromboembolism: What family physicians need to know
Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. .
These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.
How to treat uncomplicated patients
For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.
Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.
Medication-related suggestions
The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.
Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.
The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.
In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.
In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.
Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.
What the recommendations are missing
As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.
Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. .
These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.
How to treat uncomplicated patients
For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.
Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.
Medication-related suggestions
The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.
Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.
The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.
In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.
In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.
Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.
What the recommendations are missing
As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.
Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. .
These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.
How to treat uncomplicated patients
For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.
Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.
Medication-related suggestions
The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.
Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.
The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.
In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.
In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.
Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.
What the recommendations are missing
As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.
Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
The top pediatric articles of 2019
Updates in pediatric hospital medicine
The expansion of the field of pediatric hospital medicine in the past 30 years has resulted in improved health care outcomes for hospitalized children1,2 and has been accompanied by a robust increase in the amount of scholarly work related to the field.3 We performed a review of the literature published in 2019 to identify the 10 articles that had the most impact on pediatric hospital medicine, and presented the findings at HM20 Virtual, the 2020 annual conference of the Society of Hospital Medicine. Five of the selected articles are highlighted here.
STUDY 1
Wechsler ME et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med. 2019 Sep 26;381(13):1227-39.
Background
Current pediatric asthma guidelines suggest adding a long-acting beta-agonist (LABA) to inhaled corticosteroid (ICS) therapy, rather than increasing the ICS dose, for children with poorly controlled asthma. However, these data are based on trials with disproportionately few Black subjects. This study aimed to determine the best step-up therapy for Black patients whose asthma was poorly controlled on ICS monotherapy.
Study overview and results
The authors reported two parallel double-blind, randomized, controlled trials, one in children and one in adolescents and adults. The study of children included 280 subjects ranging in age from 5 to 11, with at least one Black grandparent, and with poorly controlled asthma on low-dose ICS therapy. It used a four-way crossover design in which each subject was treated with four different 14-week treatment regimens: either double (medium-dose) or quintuple (high-dose) their baseline ICS dose, with or without the addition of a LABA. A superior response was defined by the composite outcome of at least one fewer asthma exacerbation, more asthma-control days, or a 5–percentage point difference in predicted FEV1. Forty-six percent of children had improved asthma outcomes when the ICS dose was increased rather than with the addition of a LABA. In contrast, Black adolescents and Black adults had superior responses to the addition of a LABA. There was no significant interaction between the percentage of African ancestry as determined by DNA genotyping and the primary composite outcome. High-dose ICS was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years.
Limitations
Approximately 25% of children dropped out of the study, with disproportionately more children dropping out while on a high-dose ICS regimen. Additionally, the difference in the composite outcome was primarily driven by differences in FEV1, with few subjects demonstrating a difference in asthma exacerbations or asthma-control days. Although a decrease in urinary cortisol to creatinine ratio was noted in children under 8 on high-dose ICS, the study period was not long enough to determine the clinical implications of this finding.
Important findings and implications
While studies with a majority of white children have suggested a superior response from adding a LABA compared to increasing the dose of an ICS, almost half of Black children showed a superior response when the dose of an ICS was increased rather than adding a LABA. It is important to note that current guidelines are based on studies with a disproportionate majority of white subjects and may not accurately reflect optimal care for patients in other racial groups. This study underscores the need to include a diverse patient population in research studies.
STUDY 2
Chang PW, Newman TB. A simpler prediction rule for rebound hyperbilirubinemia. Pediatrics. 2019 Jul;144(1):e20183712.
Background
Hyperbilirubinemia (jaundice) is estimated to affect 50%-60% of all newborns. Rebound hyperbilirubinemia – a rise in bilirubin after cessation of phototherapy – is common and can lead to recently discharged infants being readmitted for additional therapy. Lack of clear guidelines regarding when to discharge infants with hyperbilirubinemia has likely contributed to practice variation and some trepidation regarding whether a bilirubin level is “low enough” to discontinue therapy.
Study overview and results
The authors had previously proposed a three-factor hyperbilirubinemia risk model and sought to simplify their rule further.4 They examined a retrospective cohort of 7,048 infants greater than or equal to 35 weeks’ gestation using a random split sample. The authors derived a two-factor model using the same methods and compared its performance to the three-factor model. The two-factor formula was shown to be a good fit as a logistic regression model (Hosmer-Lemeshow test 9.21; P = .33), and the AUROC (area under the receiver operating characteristic) curves for the derivation and validation cohorts were similar between the two-factor (0.877 and 0.876, respectively) and three-factor risk models (0.887 and 0.881, respectively).
Limitations
These data are limited to infants receiving their first treatment of phototherapy and have not been externally validated. An important variable, serum bilirubin at phototherapy termination, was estimated in most subjects, which may have affected the accuracy of the prediction rule. Whether infants received home phototherapy was based only on equipment orders, and some infants may have received phototherapy unbeknownst to investigators. Last, infants with rebound hyperbilirubinemia at less than 72 hours after phototherapy discontinuation may have been missed.
Important findings and implications
This prediction model provides evidence-based, concrete data that can be used in making joint decisions with families regarding discharge timing of infants with hyperbilirubinemia. It also could be beneficial when deciding appropriate follow-up time after discharge.
STUDY 3
Ramgopal S et al. Risk of serious bacterial infection in infants aged ≤60 days presenting to emergency departments with a history of fever only. J Pediatr. 2019 Jan;204:191-195. doi: 10.1016/j.jpeds.2018.08.043.
Background
Febrile infants aged 60 days and younger are at risk for serious bacterial infections (SBI) including urinary tract infections (UTI), bacteremia, and meningitis. As physical exam is a poor discriminator of SBI in this age group, providers frequently rely on laboratory values and risk factors to guide management. Infants presenting with documented fevers by caregivers but found to have no fever in the emergency department are a challenge, and there are limited data regarding SBI frequency in this population.
Study overview and results
The authors performed a secondary analysis of a prospectively gathered cohort of infants aged 60 days and younger within the Pediatric Emergency Care Applied Research Network (PECARN) who had blood, urine, and CSF data available. Notable exclusions included infants who were premature, had a focal infection, were clinically ill, had recent antibiotic use, did not have blood, urine, and CSF data available, or were lost to telephone follow-up at 7 days to ensure wellness. The study cohort included 6,014 infants, 1,233 (32%) who were febrile by history alone. Rates of overall SBI were lower in the afebrile group (8.8% vs. 12.8%). For infants 0-28 days, rates of UTI were lower for the afebrile group (9.5% vs. 14.5%), but there was no difference in the rates of bacteremia or meningitis. For infants 29-60 days, rates of UTI (6.6% vs. 9.3%) and bacteremia (.5% vs. 1.7%) were lower in the afebrile group.
Limitations
Neither the use of home antipyretics nor the method of temperature taking at home were studied. Also, as this was a secondary analysis, it is possible that not all infants who presented with history of fever only were captured, as work-up was dictated by individual treating providers who may have chosen not to work up certain afebrile infants.
Important findings and implications
Nearly one-third of infants presenting for fever evaluation are afebrile on arrival. Although overall rates of SBI were lower in the group with fever by history only, this difference is largely accounted for by differing rates of UTI. Rates of bacteremia and meningitis remained substantial between groups, particularly for infants aged 0-28 days. Because of the significant morbidity associated with these infections, it is reasonable to suggest that absence of fever on presentation alone should not alter clinical or laboratory work-up, particularly in infants 0-28 days.
STUDY 4
Humphrey-Murto S et al. The influence of prior performance information on ratings of current performance and implications for learner handover: A scoping review. Acad Med. 2019 Jul;94(7):1050-7.
Background
Learner Handover (LH) or “forward feeding” occurs when information about trainees is shared between faculty supervisors. Although this can be helpful to tailor educational experiences and build upon previous assessments, it risks stigmatizing trainees and adding bias to future feedback and assessments as the trainee never really has a “clean slate.” In this study, the authors sought to uncover the key concepts of how prior performance information (PPI) influences assessments and any implications for medical education.
Study overview and results
The authors performed a cross-disciplinary scoping review looking at over 17,000 articles published between 1980 and 2017 across the domains of psychology, sports, business, and education. Seven themes were identified with the following notable findings. Raters exposed to positive PPI scored a learner’s performance higher, and vice versa. There was a dose-response relationship with more positive and more negative PPI resulting in higher and lower assessments, respectively. General standards, such as a direction to complete all work in a timely manner, caused an assimilation effect, while specific standards, such as a direction to complete a certain task by a certain day, did not. More motivated and more experienced raters are less affected by PPI, and those who believe that people can change (incremental theorists) are less affected by PPI while those who believe personal attributes are fixed (entity theorists) are more affected.
Limitations
The heterogeneity of the studies and the fact that they were largely conducted in experimental settings may limit generalizability to medical education. Slightly less than half of the studies included a control arm. Last, most of the studies looked at the ratings of only one target performance, not multiple performances over time.
Important findings and implications
Ratings of current performance displace toward PPI direction, with negative PPI more influential than positive PPI. In a formative setting, PPI may help the assessor focus on areas of possible weakness. In contrast, for a summative assessment, PPI may be prejudicial and have an impact on the rating given to the student. Clinicians should be mindful of the information they share with future raters about learners and the potential bias on future assessments that can manifest as a result.
STUDY 5
McCann ME et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): An international, multicentre, randomised, controlled equivalence trial. The Lancet. 2019 Feb;393:664-77.
Background
Animal models and observational studies have suggested a link between early anesthesia exposure and adverse neurocognitive outcomes; however, findings have been mixed and studies are prone to confounding. This study is the first randomized controlled trial to compare neurocognitive outcomes for infants exposed to general anesthesia versus awake-regional anesthesia.
Study overview and results
In this international, multicenter, assessor-masked trial, 722 infants undergoing inguinal hernia repair were randomized to awake-regional anesthesia or single-agent sevoflurane-based general anesthesia. Infants born at greater than 26 weeks’ gestational age were eligible, while those with prior anesthesia exposure or risks for neurocognitive delay were excluded. The primary outcome was full-scale intelligence quotient (FSIQ) testing at 5 years of age on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III). Seven additional neurodevelopmental assessments and parental questionnaires regarding behavior were administered as secondary outcomes. Average anesthesia exposure was 54 minutes and no infant had exposure greater than 120 minutes. There was no significant difference in mean scores on WPPSI-III FSIQ testing, and no difference in the additional neurocognitive assessments or parent-reported outcomes used as secondary outcomes.
Limitations
This study was limited to single, short periods of single-agent anesthesia exposure in children with no additional neurologic risk factors, so caution should be used in extrapolating these data to children with medical complexity and children undergoing multiple procedures, longer surgeries, or multidrug anesthetic regimens. The study population was majority male because of the surgical pathology selected and included only children in the narrow range of postmenstrual age 60 weeks or less. While this population represents a suspected a period of high cerebral vulnerability based on animal models, the implications of anesthesia exposure at other ages are unclear.
Important findings and implications
An estimated 10% of children from developed countries are exposed to general anesthesia during the first 3 years of life. While hospitalists do not typically select the route of anesthesia, they frequently care for patients undergoing procedures and must address parental concerns regarding the safety of anesthesia exposure. Given the rigorous study methods and long-term follow up in the current study, these data should provide reassurance that, for healthy infants undergoing short, single-agent anesthetic exposure, there is no evidence of future adverse neurologic outcomes.
Dr. Russo is director of pediatrics, medical director for quality and innovation, at WellSpan Health, York, Pa. Dr. Money is a pediatric hospitalist at Primary Children’s Hospital, University of Utah School of Medicine, Salt Lake City. Dr. Steed is instructor of hospital medicine, Northwestern Memorial Hospital and Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago. The authors would like to thank Dr. Klint M. Schwenk and the Society for Hospital Medicine Pediatric Special Interest Group Executive Council.
References
1. Roberts KB, Fisher ER, and Rauch DA. The history of pediatric hospital medicine in the United States, 1996-2019. J Hosp Med. 2020 Jul;15(7):424-7.
2. Mussman GM and Conway PH. Pediatric hospitalist systems versus traditional models of care: Effect on quality and cost outcomes. J Hosp Med. 2012 Apr;7(4):350-7.
3. Wang ME, Shaughnessy EE, and Leyenaar JK. The future of pediatric hospital medicine: Challenges and opportunities. J Hosp Med. 2020 Jul;15(7):428-30.
4. Chang PW et al. A clinical prediction rule for rebound hyperbilirubinemia following inpatient phototherapy. Pediatrics. 2017;139 Mar;139(3):e20162896.
Updates in pediatric hospital medicine
Updates in pediatric hospital medicine
The expansion of the field of pediatric hospital medicine in the past 30 years has resulted in improved health care outcomes for hospitalized children1,2 and has been accompanied by a robust increase in the amount of scholarly work related to the field.3 We performed a review of the literature published in 2019 to identify the 10 articles that had the most impact on pediatric hospital medicine, and presented the findings at HM20 Virtual, the 2020 annual conference of the Society of Hospital Medicine. Five of the selected articles are highlighted here.
STUDY 1
Wechsler ME et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med. 2019 Sep 26;381(13):1227-39.
Background
Current pediatric asthma guidelines suggest adding a long-acting beta-agonist (LABA) to inhaled corticosteroid (ICS) therapy, rather than increasing the ICS dose, for children with poorly controlled asthma. However, these data are based on trials with disproportionately few Black subjects. This study aimed to determine the best step-up therapy for Black patients whose asthma was poorly controlled on ICS monotherapy.
Study overview and results
The authors reported two parallel double-blind, randomized, controlled trials, one in children and one in adolescents and adults. The study of children included 280 subjects ranging in age from 5 to 11, with at least one Black grandparent, and with poorly controlled asthma on low-dose ICS therapy. It used a four-way crossover design in which each subject was treated with four different 14-week treatment regimens: either double (medium-dose) or quintuple (high-dose) their baseline ICS dose, with or without the addition of a LABA. A superior response was defined by the composite outcome of at least one fewer asthma exacerbation, more asthma-control days, or a 5–percentage point difference in predicted FEV1. Forty-six percent of children had improved asthma outcomes when the ICS dose was increased rather than with the addition of a LABA. In contrast, Black adolescents and Black adults had superior responses to the addition of a LABA. There was no significant interaction between the percentage of African ancestry as determined by DNA genotyping and the primary composite outcome. High-dose ICS was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years.
Limitations
Approximately 25% of children dropped out of the study, with disproportionately more children dropping out while on a high-dose ICS regimen. Additionally, the difference in the composite outcome was primarily driven by differences in FEV1, with few subjects demonstrating a difference in asthma exacerbations or asthma-control days. Although a decrease in urinary cortisol to creatinine ratio was noted in children under 8 on high-dose ICS, the study period was not long enough to determine the clinical implications of this finding.
Important findings and implications
While studies with a majority of white children have suggested a superior response from adding a LABA compared to increasing the dose of an ICS, almost half of Black children showed a superior response when the dose of an ICS was increased rather than adding a LABA. It is important to note that current guidelines are based on studies with a disproportionate majority of white subjects and may not accurately reflect optimal care for patients in other racial groups. This study underscores the need to include a diverse patient population in research studies.
STUDY 2
Chang PW, Newman TB. A simpler prediction rule for rebound hyperbilirubinemia. Pediatrics. 2019 Jul;144(1):e20183712.
Background
Hyperbilirubinemia (jaundice) is estimated to affect 50%-60% of all newborns. Rebound hyperbilirubinemia – a rise in bilirubin after cessation of phototherapy – is common and can lead to recently discharged infants being readmitted for additional therapy. Lack of clear guidelines regarding when to discharge infants with hyperbilirubinemia has likely contributed to practice variation and some trepidation regarding whether a bilirubin level is “low enough” to discontinue therapy.
Study overview and results
The authors had previously proposed a three-factor hyperbilirubinemia risk model and sought to simplify their rule further.4 They examined a retrospective cohort of 7,048 infants greater than or equal to 35 weeks’ gestation using a random split sample. The authors derived a two-factor model using the same methods and compared its performance to the three-factor model. The two-factor formula was shown to be a good fit as a logistic regression model (Hosmer-Lemeshow test 9.21; P = .33), and the AUROC (area under the receiver operating characteristic) curves for the derivation and validation cohorts were similar between the two-factor (0.877 and 0.876, respectively) and three-factor risk models (0.887 and 0.881, respectively).
Limitations
These data are limited to infants receiving their first treatment of phototherapy and have not been externally validated. An important variable, serum bilirubin at phototherapy termination, was estimated in most subjects, which may have affected the accuracy of the prediction rule. Whether infants received home phototherapy was based only on equipment orders, and some infants may have received phototherapy unbeknownst to investigators. Last, infants with rebound hyperbilirubinemia at less than 72 hours after phototherapy discontinuation may have been missed.
Important findings and implications
This prediction model provides evidence-based, concrete data that can be used in making joint decisions with families regarding discharge timing of infants with hyperbilirubinemia. It also could be beneficial when deciding appropriate follow-up time after discharge.
STUDY 3
Ramgopal S et al. Risk of serious bacterial infection in infants aged ≤60 days presenting to emergency departments with a history of fever only. J Pediatr. 2019 Jan;204:191-195. doi: 10.1016/j.jpeds.2018.08.043.
Background
Febrile infants aged 60 days and younger are at risk for serious bacterial infections (SBI) including urinary tract infections (UTI), bacteremia, and meningitis. As physical exam is a poor discriminator of SBI in this age group, providers frequently rely on laboratory values and risk factors to guide management. Infants presenting with documented fevers by caregivers but found to have no fever in the emergency department are a challenge, and there are limited data regarding SBI frequency in this population.
Study overview and results
The authors performed a secondary analysis of a prospectively gathered cohort of infants aged 60 days and younger within the Pediatric Emergency Care Applied Research Network (PECARN) who had blood, urine, and CSF data available. Notable exclusions included infants who were premature, had a focal infection, were clinically ill, had recent antibiotic use, did not have blood, urine, and CSF data available, or were lost to telephone follow-up at 7 days to ensure wellness. The study cohort included 6,014 infants, 1,233 (32%) who were febrile by history alone. Rates of overall SBI were lower in the afebrile group (8.8% vs. 12.8%). For infants 0-28 days, rates of UTI were lower for the afebrile group (9.5% vs. 14.5%), but there was no difference in the rates of bacteremia or meningitis. For infants 29-60 days, rates of UTI (6.6% vs. 9.3%) and bacteremia (.5% vs. 1.7%) were lower in the afebrile group.
Limitations
Neither the use of home antipyretics nor the method of temperature taking at home were studied. Also, as this was a secondary analysis, it is possible that not all infants who presented with history of fever only were captured, as work-up was dictated by individual treating providers who may have chosen not to work up certain afebrile infants.
Important findings and implications
Nearly one-third of infants presenting for fever evaluation are afebrile on arrival. Although overall rates of SBI were lower in the group with fever by history only, this difference is largely accounted for by differing rates of UTI. Rates of bacteremia and meningitis remained substantial between groups, particularly for infants aged 0-28 days. Because of the significant morbidity associated with these infections, it is reasonable to suggest that absence of fever on presentation alone should not alter clinical or laboratory work-up, particularly in infants 0-28 days.
STUDY 4
Humphrey-Murto S et al. The influence of prior performance information on ratings of current performance and implications for learner handover: A scoping review. Acad Med. 2019 Jul;94(7):1050-7.
Background
Learner Handover (LH) or “forward feeding” occurs when information about trainees is shared between faculty supervisors. Although this can be helpful to tailor educational experiences and build upon previous assessments, it risks stigmatizing trainees and adding bias to future feedback and assessments as the trainee never really has a “clean slate.” In this study, the authors sought to uncover the key concepts of how prior performance information (PPI) influences assessments and any implications for medical education.
Study overview and results
The authors performed a cross-disciplinary scoping review looking at over 17,000 articles published between 1980 and 2017 across the domains of psychology, sports, business, and education. Seven themes were identified with the following notable findings. Raters exposed to positive PPI scored a learner’s performance higher, and vice versa. There was a dose-response relationship with more positive and more negative PPI resulting in higher and lower assessments, respectively. General standards, such as a direction to complete all work in a timely manner, caused an assimilation effect, while specific standards, such as a direction to complete a certain task by a certain day, did not. More motivated and more experienced raters are less affected by PPI, and those who believe that people can change (incremental theorists) are less affected by PPI while those who believe personal attributes are fixed (entity theorists) are more affected.
Limitations
The heterogeneity of the studies and the fact that they were largely conducted in experimental settings may limit generalizability to medical education. Slightly less than half of the studies included a control arm. Last, most of the studies looked at the ratings of only one target performance, not multiple performances over time.
Important findings and implications
Ratings of current performance displace toward PPI direction, with negative PPI more influential than positive PPI. In a formative setting, PPI may help the assessor focus on areas of possible weakness. In contrast, for a summative assessment, PPI may be prejudicial and have an impact on the rating given to the student. Clinicians should be mindful of the information they share with future raters about learners and the potential bias on future assessments that can manifest as a result.
STUDY 5
McCann ME et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): An international, multicentre, randomised, controlled equivalence trial. The Lancet. 2019 Feb;393:664-77.
Background
Animal models and observational studies have suggested a link between early anesthesia exposure and adverse neurocognitive outcomes; however, findings have been mixed and studies are prone to confounding. This study is the first randomized controlled trial to compare neurocognitive outcomes for infants exposed to general anesthesia versus awake-regional anesthesia.
Study overview and results
In this international, multicenter, assessor-masked trial, 722 infants undergoing inguinal hernia repair were randomized to awake-regional anesthesia or single-agent sevoflurane-based general anesthesia. Infants born at greater than 26 weeks’ gestational age were eligible, while those with prior anesthesia exposure or risks for neurocognitive delay were excluded. The primary outcome was full-scale intelligence quotient (FSIQ) testing at 5 years of age on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III). Seven additional neurodevelopmental assessments and parental questionnaires regarding behavior were administered as secondary outcomes. Average anesthesia exposure was 54 minutes and no infant had exposure greater than 120 minutes. There was no significant difference in mean scores on WPPSI-III FSIQ testing, and no difference in the additional neurocognitive assessments or parent-reported outcomes used as secondary outcomes.
Limitations
This study was limited to single, short periods of single-agent anesthesia exposure in children with no additional neurologic risk factors, so caution should be used in extrapolating these data to children with medical complexity and children undergoing multiple procedures, longer surgeries, or multidrug anesthetic regimens. The study population was majority male because of the surgical pathology selected and included only children in the narrow range of postmenstrual age 60 weeks or less. While this population represents a suspected a period of high cerebral vulnerability based on animal models, the implications of anesthesia exposure at other ages are unclear.
Important findings and implications
An estimated 10% of children from developed countries are exposed to general anesthesia during the first 3 years of life. While hospitalists do not typically select the route of anesthesia, they frequently care for patients undergoing procedures and must address parental concerns regarding the safety of anesthesia exposure. Given the rigorous study methods and long-term follow up in the current study, these data should provide reassurance that, for healthy infants undergoing short, single-agent anesthetic exposure, there is no evidence of future adverse neurologic outcomes.
Dr. Russo is director of pediatrics, medical director for quality and innovation, at WellSpan Health, York, Pa. Dr. Money is a pediatric hospitalist at Primary Children’s Hospital, University of Utah School of Medicine, Salt Lake City. Dr. Steed is instructor of hospital medicine, Northwestern Memorial Hospital and Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago. The authors would like to thank Dr. Klint M. Schwenk and the Society for Hospital Medicine Pediatric Special Interest Group Executive Council.
References
1. Roberts KB, Fisher ER, and Rauch DA. The history of pediatric hospital medicine in the United States, 1996-2019. J Hosp Med. 2020 Jul;15(7):424-7.
2. Mussman GM and Conway PH. Pediatric hospitalist systems versus traditional models of care: Effect on quality and cost outcomes. J Hosp Med. 2012 Apr;7(4):350-7.
3. Wang ME, Shaughnessy EE, and Leyenaar JK. The future of pediatric hospital medicine: Challenges and opportunities. J Hosp Med. 2020 Jul;15(7):428-30.
4. Chang PW et al. A clinical prediction rule for rebound hyperbilirubinemia following inpatient phototherapy. Pediatrics. 2017;139 Mar;139(3):e20162896.
The expansion of the field of pediatric hospital medicine in the past 30 years has resulted in improved health care outcomes for hospitalized children1,2 and has been accompanied by a robust increase in the amount of scholarly work related to the field.3 We performed a review of the literature published in 2019 to identify the 10 articles that had the most impact on pediatric hospital medicine, and presented the findings at HM20 Virtual, the 2020 annual conference of the Society of Hospital Medicine. Five of the selected articles are highlighted here.
STUDY 1
Wechsler ME et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med. 2019 Sep 26;381(13):1227-39.
Background
Current pediatric asthma guidelines suggest adding a long-acting beta-agonist (LABA) to inhaled corticosteroid (ICS) therapy, rather than increasing the ICS dose, for children with poorly controlled asthma. However, these data are based on trials with disproportionately few Black subjects. This study aimed to determine the best step-up therapy for Black patients whose asthma was poorly controlled on ICS monotherapy.
Study overview and results
The authors reported two parallel double-blind, randomized, controlled trials, one in children and one in adolescents and adults. The study of children included 280 subjects ranging in age from 5 to 11, with at least one Black grandparent, and with poorly controlled asthma on low-dose ICS therapy. It used a four-way crossover design in which each subject was treated with four different 14-week treatment regimens: either double (medium-dose) or quintuple (high-dose) their baseline ICS dose, with or without the addition of a LABA. A superior response was defined by the composite outcome of at least one fewer asthma exacerbation, more asthma-control days, or a 5–percentage point difference in predicted FEV1. Forty-six percent of children had improved asthma outcomes when the ICS dose was increased rather than with the addition of a LABA. In contrast, Black adolescents and Black adults had superior responses to the addition of a LABA. There was no significant interaction between the percentage of African ancestry as determined by DNA genotyping and the primary composite outcome. High-dose ICS was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years.
Limitations
Approximately 25% of children dropped out of the study, with disproportionately more children dropping out while on a high-dose ICS regimen. Additionally, the difference in the composite outcome was primarily driven by differences in FEV1, with few subjects demonstrating a difference in asthma exacerbations or asthma-control days. Although a decrease in urinary cortisol to creatinine ratio was noted in children under 8 on high-dose ICS, the study period was not long enough to determine the clinical implications of this finding.
Important findings and implications
While studies with a majority of white children have suggested a superior response from adding a LABA compared to increasing the dose of an ICS, almost half of Black children showed a superior response when the dose of an ICS was increased rather than adding a LABA. It is important to note that current guidelines are based on studies with a disproportionate majority of white subjects and may not accurately reflect optimal care for patients in other racial groups. This study underscores the need to include a diverse patient population in research studies.
STUDY 2
Chang PW, Newman TB. A simpler prediction rule for rebound hyperbilirubinemia. Pediatrics. 2019 Jul;144(1):e20183712.
Background
Hyperbilirubinemia (jaundice) is estimated to affect 50%-60% of all newborns. Rebound hyperbilirubinemia – a rise in bilirubin after cessation of phototherapy – is common and can lead to recently discharged infants being readmitted for additional therapy. Lack of clear guidelines regarding when to discharge infants with hyperbilirubinemia has likely contributed to practice variation and some trepidation regarding whether a bilirubin level is “low enough” to discontinue therapy.
Study overview and results
The authors had previously proposed a three-factor hyperbilirubinemia risk model and sought to simplify their rule further.4 They examined a retrospective cohort of 7,048 infants greater than or equal to 35 weeks’ gestation using a random split sample. The authors derived a two-factor model using the same methods and compared its performance to the three-factor model. The two-factor formula was shown to be a good fit as a logistic regression model (Hosmer-Lemeshow test 9.21; P = .33), and the AUROC (area under the receiver operating characteristic) curves for the derivation and validation cohorts were similar between the two-factor (0.877 and 0.876, respectively) and three-factor risk models (0.887 and 0.881, respectively).
Limitations
These data are limited to infants receiving their first treatment of phototherapy and have not been externally validated. An important variable, serum bilirubin at phototherapy termination, was estimated in most subjects, which may have affected the accuracy of the prediction rule. Whether infants received home phototherapy was based only on equipment orders, and some infants may have received phototherapy unbeknownst to investigators. Last, infants with rebound hyperbilirubinemia at less than 72 hours after phototherapy discontinuation may have been missed.
Important findings and implications
This prediction model provides evidence-based, concrete data that can be used in making joint decisions with families regarding discharge timing of infants with hyperbilirubinemia. It also could be beneficial when deciding appropriate follow-up time after discharge.
STUDY 3
Ramgopal S et al. Risk of serious bacterial infection in infants aged ≤60 days presenting to emergency departments with a history of fever only. J Pediatr. 2019 Jan;204:191-195. doi: 10.1016/j.jpeds.2018.08.043.
Background
Febrile infants aged 60 days and younger are at risk for serious bacterial infections (SBI) including urinary tract infections (UTI), bacteremia, and meningitis. As physical exam is a poor discriminator of SBI in this age group, providers frequently rely on laboratory values and risk factors to guide management. Infants presenting with documented fevers by caregivers but found to have no fever in the emergency department are a challenge, and there are limited data regarding SBI frequency in this population.
Study overview and results
The authors performed a secondary analysis of a prospectively gathered cohort of infants aged 60 days and younger within the Pediatric Emergency Care Applied Research Network (PECARN) who had blood, urine, and CSF data available. Notable exclusions included infants who were premature, had a focal infection, were clinically ill, had recent antibiotic use, did not have blood, urine, and CSF data available, or were lost to telephone follow-up at 7 days to ensure wellness. The study cohort included 6,014 infants, 1,233 (32%) who were febrile by history alone. Rates of overall SBI were lower in the afebrile group (8.8% vs. 12.8%). For infants 0-28 days, rates of UTI were lower for the afebrile group (9.5% vs. 14.5%), but there was no difference in the rates of bacteremia or meningitis. For infants 29-60 days, rates of UTI (6.6% vs. 9.3%) and bacteremia (.5% vs. 1.7%) were lower in the afebrile group.
Limitations
Neither the use of home antipyretics nor the method of temperature taking at home were studied. Also, as this was a secondary analysis, it is possible that not all infants who presented with history of fever only were captured, as work-up was dictated by individual treating providers who may have chosen not to work up certain afebrile infants.
Important findings and implications
Nearly one-third of infants presenting for fever evaluation are afebrile on arrival. Although overall rates of SBI were lower in the group with fever by history only, this difference is largely accounted for by differing rates of UTI. Rates of bacteremia and meningitis remained substantial between groups, particularly for infants aged 0-28 days. Because of the significant morbidity associated with these infections, it is reasonable to suggest that absence of fever on presentation alone should not alter clinical or laboratory work-up, particularly in infants 0-28 days.
STUDY 4
Humphrey-Murto S et al. The influence of prior performance information on ratings of current performance and implications for learner handover: A scoping review. Acad Med. 2019 Jul;94(7):1050-7.
Background
Learner Handover (LH) or “forward feeding” occurs when information about trainees is shared between faculty supervisors. Although this can be helpful to tailor educational experiences and build upon previous assessments, it risks stigmatizing trainees and adding bias to future feedback and assessments as the trainee never really has a “clean slate.” In this study, the authors sought to uncover the key concepts of how prior performance information (PPI) influences assessments and any implications for medical education.
Study overview and results
The authors performed a cross-disciplinary scoping review looking at over 17,000 articles published between 1980 and 2017 across the domains of psychology, sports, business, and education. Seven themes were identified with the following notable findings. Raters exposed to positive PPI scored a learner’s performance higher, and vice versa. There was a dose-response relationship with more positive and more negative PPI resulting in higher and lower assessments, respectively. General standards, such as a direction to complete all work in a timely manner, caused an assimilation effect, while specific standards, such as a direction to complete a certain task by a certain day, did not. More motivated and more experienced raters are less affected by PPI, and those who believe that people can change (incremental theorists) are less affected by PPI while those who believe personal attributes are fixed (entity theorists) are more affected.
Limitations
The heterogeneity of the studies and the fact that they were largely conducted in experimental settings may limit generalizability to medical education. Slightly less than half of the studies included a control arm. Last, most of the studies looked at the ratings of only one target performance, not multiple performances over time.
Important findings and implications
Ratings of current performance displace toward PPI direction, with negative PPI more influential than positive PPI. In a formative setting, PPI may help the assessor focus on areas of possible weakness. In contrast, for a summative assessment, PPI may be prejudicial and have an impact on the rating given to the student. Clinicians should be mindful of the information they share with future raters about learners and the potential bias on future assessments that can manifest as a result.
STUDY 5
McCann ME et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): An international, multicentre, randomised, controlled equivalence trial. The Lancet. 2019 Feb;393:664-77.
Background
Animal models and observational studies have suggested a link between early anesthesia exposure and adverse neurocognitive outcomes; however, findings have been mixed and studies are prone to confounding. This study is the first randomized controlled trial to compare neurocognitive outcomes for infants exposed to general anesthesia versus awake-regional anesthesia.
Study overview and results
In this international, multicenter, assessor-masked trial, 722 infants undergoing inguinal hernia repair were randomized to awake-regional anesthesia or single-agent sevoflurane-based general anesthesia. Infants born at greater than 26 weeks’ gestational age were eligible, while those with prior anesthesia exposure or risks for neurocognitive delay were excluded. The primary outcome was full-scale intelligence quotient (FSIQ) testing at 5 years of age on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III). Seven additional neurodevelopmental assessments and parental questionnaires regarding behavior were administered as secondary outcomes. Average anesthesia exposure was 54 minutes and no infant had exposure greater than 120 minutes. There was no significant difference in mean scores on WPPSI-III FSIQ testing, and no difference in the additional neurocognitive assessments or parent-reported outcomes used as secondary outcomes.
Limitations
This study was limited to single, short periods of single-agent anesthesia exposure in children with no additional neurologic risk factors, so caution should be used in extrapolating these data to children with medical complexity and children undergoing multiple procedures, longer surgeries, or multidrug anesthetic regimens. The study population was majority male because of the surgical pathology selected and included only children in the narrow range of postmenstrual age 60 weeks or less. While this population represents a suspected a period of high cerebral vulnerability based on animal models, the implications of anesthesia exposure at other ages are unclear.
Important findings and implications
An estimated 10% of children from developed countries are exposed to general anesthesia during the first 3 years of life. While hospitalists do not typically select the route of anesthesia, they frequently care for patients undergoing procedures and must address parental concerns regarding the safety of anesthesia exposure. Given the rigorous study methods and long-term follow up in the current study, these data should provide reassurance that, for healthy infants undergoing short, single-agent anesthetic exposure, there is no evidence of future adverse neurologic outcomes.
Dr. Russo is director of pediatrics, medical director for quality and innovation, at WellSpan Health, York, Pa. Dr. Money is a pediatric hospitalist at Primary Children’s Hospital, University of Utah School of Medicine, Salt Lake City. Dr. Steed is instructor of hospital medicine, Northwestern Memorial Hospital and Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago. The authors would like to thank Dr. Klint M. Schwenk and the Society for Hospital Medicine Pediatric Special Interest Group Executive Council.
References
1. Roberts KB, Fisher ER, and Rauch DA. The history of pediatric hospital medicine in the United States, 1996-2019. J Hosp Med. 2020 Jul;15(7):424-7.
2. Mussman GM and Conway PH. Pediatric hospitalist systems versus traditional models of care: Effect on quality and cost outcomes. J Hosp Med. 2012 Apr;7(4):350-7.
3. Wang ME, Shaughnessy EE, and Leyenaar JK. The future of pediatric hospital medicine: Challenges and opportunities. J Hosp Med. 2020 Jul;15(7):428-30.
4. Chang PW et al. A clinical prediction rule for rebound hyperbilirubinemia following inpatient phototherapy. Pediatrics. 2017;139 Mar;139(3):e20162896.
Nicotine vaping tapers off among teens
Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.
The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic.
A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.
During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.
“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”
Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.
Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.
Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).
The findings were published in JAMA Pediatrics.
Early data show progress
“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.
“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.
“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.
“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
COVID-era limitations
“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”
In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”
The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.
Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.
The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic.
A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.
During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.
“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”
Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.
Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.
Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).
The findings were published in JAMA Pediatrics.
Early data show progress
“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.
“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.
“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.
“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
COVID-era limitations
“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”
In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”
The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.
Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.
The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic.
A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.
During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.
“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”
Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.
Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.
Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).
The findings were published in JAMA Pediatrics.
Early data show progress
“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.
“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.
“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.
“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
COVID-era limitations
“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”
In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”
The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.
E-cigarette use tied to increased COPD, asthma risk
Results from a large national prospective cohort study of adults demonstrated that the use of electronic cigarettes is associated with an increased risk of asthma, chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis – independent of cigarette smoking and other combustible tobacco product use.
“Our longitudinal results are consistent with the findings of prior population studies,” researchers led by Wubin Xie, DrPH, MPH, wrote in a study published online in JAMA Network Open. “With a more refined study design assessing multiple respiratory conditions and extensive sensitivity checks to mitigate bias from reverse causation and residual confounding by cigarette smoking and other tobacco product use, our results strengthen the evidence of the potential role of e-cigarette use in pulmonary disease pathogenesis. The findings may be used to inform counseling of patients on the potential risks of e-cigarette use.”
Dr. Xie of Boston University, and colleagues used data from the Population Assessment of Tobacco and Health (PATH) study waves 1-4 to examine the association of e-cigarette use with incident respiratory conditions, including COPD, emphysema, chronic bronchitis, and asthma. An earlier analysis of PATH data found an association between e-cigarette use with a composite respiratory disease outcome, but it did not consider the timing of respiratory events over follow-up and was underpowered to evaluate specific respiratory conditions.
The current analysis included data from 21,618 U.S. adults who were surveyed in four waves of PATH between 2013 and 2018. Of these, 49% were men, 65% were non-Hispanic White, 12% were non-Hispanic Black, 16% were Hispanic, and the remainder were non-Hispanic other. Their mean pack-years was 6.7 at baseline, 26% had self-reported hypertension, and their mean body mass index was 27.8 kg/m2. The analysis was limited to data from the wave 1 cohort of adults and the prospective follow-up at waves 2-4 from public use files. It excluded adults who reported a history of a respiratory condition such as COPD, emphysema, chronic bronchitis, or asthma at wave 1 (baseline).
Two-thirds of respondents (66%) were never e-cigarette users, 12% were former e-cigarette users, and 5% were current e-cigarette users. After the researchers adjusted for cigarette and other combustible tobacco product use, demographic characteristics, and chronic health conditions, they observed an increased risk of respiratory disease among former e-cigarette users (incidence rate ratio, 1.28) and current e-cigarette users (IRR, 1.31). Among respondents with good self-reported health, the IRR for former e-cigarette users was 1.21 and the IRR for current e-cigarette users was 1.43. As for specific respiratory diseases among current e-cigarette users, the IRR was 1.33 for chronic bronchitis, 1.69 for emphysema, 1.57 for COPD, and 1.31 for asthma.
“Our findings on clinical outcome were consistent with studies assessing in vivo biomarkers of e-cigarette exposure in animal subjects, human participants, and population studies,” the authors wrote. “Studies have documented that exclusive e-cigarette use may be associated with higher exposure to harmful and potentially harmful constituents, compared with tobacco nonuse. The potential mechanisms of the association of e-cigarette exposure with pulmonary diseases include pulmonary inflammation, increased oxidative stress, and inhibited immune response. Animal studies have generated substantial evidence on e-cigarette exposure and emphysematous lung destruction, loss of pulmonary capillaries, reduced small airway function, and airway hyperresponsiveness, suggesting the plausibility of e-cigarettes causing chronic lung diseases.”
They acknowledged certain limitations of the study, including its reliance on self-reported measures of e-cigarette and other tobacco product use and its reliance on self-reported diagnoses of respiratory diseases.
The study was supported by grants from the National Heart, Lung, and Blood Institute; the Food and Drug Administration Center for Tobacco Products; and the American Lung Association Public Policy Research Award. Dr. Xie reported having no financial disclosures. His coauthors reported having received research grants and personal fees from a variety of sources.
SOURCE: Xie W et al. JAMA Netw Open. 2020 Nov 12. doi: 10.1001/jamanetworkopen.2020.20816
Results from a large national prospective cohort study of adults demonstrated that the use of electronic cigarettes is associated with an increased risk of asthma, chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis – independent of cigarette smoking and other combustible tobacco product use.
“Our longitudinal results are consistent with the findings of prior population studies,” researchers led by Wubin Xie, DrPH, MPH, wrote in a study published online in JAMA Network Open. “With a more refined study design assessing multiple respiratory conditions and extensive sensitivity checks to mitigate bias from reverse causation and residual confounding by cigarette smoking and other tobacco product use, our results strengthen the evidence of the potential role of e-cigarette use in pulmonary disease pathogenesis. The findings may be used to inform counseling of patients on the potential risks of e-cigarette use.”
Dr. Xie of Boston University, and colleagues used data from the Population Assessment of Tobacco and Health (PATH) study waves 1-4 to examine the association of e-cigarette use with incident respiratory conditions, including COPD, emphysema, chronic bronchitis, and asthma. An earlier analysis of PATH data found an association between e-cigarette use with a composite respiratory disease outcome, but it did not consider the timing of respiratory events over follow-up and was underpowered to evaluate specific respiratory conditions.
The current analysis included data from 21,618 U.S. adults who were surveyed in four waves of PATH between 2013 and 2018. Of these, 49% were men, 65% were non-Hispanic White, 12% were non-Hispanic Black, 16% were Hispanic, and the remainder were non-Hispanic other. Their mean pack-years was 6.7 at baseline, 26% had self-reported hypertension, and their mean body mass index was 27.8 kg/m2. The analysis was limited to data from the wave 1 cohort of adults and the prospective follow-up at waves 2-4 from public use files. It excluded adults who reported a history of a respiratory condition such as COPD, emphysema, chronic bronchitis, or asthma at wave 1 (baseline).
Two-thirds of respondents (66%) were never e-cigarette users, 12% were former e-cigarette users, and 5% were current e-cigarette users. After the researchers adjusted for cigarette and other combustible tobacco product use, demographic characteristics, and chronic health conditions, they observed an increased risk of respiratory disease among former e-cigarette users (incidence rate ratio, 1.28) and current e-cigarette users (IRR, 1.31). Among respondents with good self-reported health, the IRR for former e-cigarette users was 1.21 and the IRR for current e-cigarette users was 1.43. As for specific respiratory diseases among current e-cigarette users, the IRR was 1.33 for chronic bronchitis, 1.69 for emphysema, 1.57 for COPD, and 1.31 for asthma.
“Our findings on clinical outcome were consistent with studies assessing in vivo biomarkers of e-cigarette exposure in animal subjects, human participants, and population studies,” the authors wrote. “Studies have documented that exclusive e-cigarette use may be associated with higher exposure to harmful and potentially harmful constituents, compared with tobacco nonuse. The potential mechanisms of the association of e-cigarette exposure with pulmonary diseases include pulmonary inflammation, increased oxidative stress, and inhibited immune response. Animal studies have generated substantial evidence on e-cigarette exposure and emphysematous lung destruction, loss of pulmonary capillaries, reduced small airway function, and airway hyperresponsiveness, suggesting the plausibility of e-cigarettes causing chronic lung diseases.”
They acknowledged certain limitations of the study, including its reliance on self-reported measures of e-cigarette and other tobacco product use and its reliance on self-reported diagnoses of respiratory diseases.
The study was supported by grants from the National Heart, Lung, and Blood Institute; the Food and Drug Administration Center for Tobacco Products; and the American Lung Association Public Policy Research Award. Dr. Xie reported having no financial disclosures. His coauthors reported having received research grants and personal fees from a variety of sources.
SOURCE: Xie W et al. JAMA Netw Open. 2020 Nov 12. doi: 10.1001/jamanetworkopen.2020.20816
Results from a large national prospective cohort study of adults demonstrated that the use of electronic cigarettes is associated with an increased risk of asthma, chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis – independent of cigarette smoking and other combustible tobacco product use.
“Our longitudinal results are consistent with the findings of prior population studies,” researchers led by Wubin Xie, DrPH, MPH, wrote in a study published online in JAMA Network Open. “With a more refined study design assessing multiple respiratory conditions and extensive sensitivity checks to mitigate bias from reverse causation and residual confounding by cigarette smoking and other tobacco product use, our results strengthen the evidence of the potential role of e-cigarette use in pulmonary disease pathogenesis. The findings may be used to inform counseling of patients on the potential risks of e-cigarette use.”
Dr. Xie of Boston University, and colleagues used data from the Population Assessment of Tobacco and Health (PATH) study waves 1-4 to examine the association of e-cigarette use with incident respiratory conditions, including COPD, emphysema, chronic bronchitis, and asthma. An earlier analysis of PATH data found an association between e-cigarette use with a composite respiratory disease outcome, but it did not consider the timing of respiratory events over follow-up and was underpowered to evaluate specific respiratory conditions.
The current analysis included data from 21,618 U.S. adults who were surveyed in four waves of PATH between 2013 and 2018. Of these, 49% were men, 65% were non-Hispanic White, 12% were non-Hispanic Black, 16% were Hispanic, and the remainder were non-Hispanic other. Their mean pack-years was 6.7 at baseline, 26% had self-reported hypertension, and their mean body mass index was 27.8 kg/m2. The analysis was limited to data from the wave 1 cohort of adults and the prospective follow-up at waves 2-4 from public use files. It excluded adults who reported a history of a respiratory condition such as COPD, emphysema, chronic bronchitis, or asthma at wave 1 (baseline).
Two-thirds of respondents (66%) were never e-cigarette users, 12% were former e-cigarette users, and 5% were current e-cigarette users. After the researchers adjusted for cigarette and other combustible tobacco product use, demographic characteristics, and chronic health conditions, they observed an increased risk of respiratory disease among former e-cigarette users (incidence rate ratio, 1.28) and current e-cigarette users (IRR, 1.31). Among respondents with good self-reported health, the IRR for former e-cigarette users was 1.21 and the IRR for current e-cigarette users was 1.43. As for specific respiratory diseases among current e-cigarette users, the IRR was 1.33 for chronic bronchitis, 1.69 for emphysema, 1.57 for COPD, and 1.31 for asthma.
“Our findings on clinical outcome were consistent with studies assessing in vivo biomarkers of e-cigarette exposure in animal subjects, human participants, and population studies,” the authors wrote. “Studies have documented that exclusive e-cigarette use may be associated with higher exposure to harmful and potentially harmful constituents, compared with tobacco nonuse. The potential mechanisms of the association of e-cigarette exposure with pulmonary diseases include pulmonary inflammation, increased oxidative stress, and inhibited immune response. Animal studies have generated substantial evidence on e-cigarette exposure and emphysematous lung destruction, loss of pulmonary capillaries, reduced small airway function, and airway hyperresponsiveness, suggesting the plausibility of e-cigarettes causing chronic lung diseases.”
They acknowledged certain limitations of the study, including its reliance on self-reported measures of e-cigarette and other tobacco product use and its reliance on self-reported diagnoses of respiratory diseases.
The study was supported by grants from the National Heart, Lung, and Blood Institute; the Food and Drug Administration Center for Tobacco Products; and the American Lung Association Public Policy Research Award. Dr. Xie reported having no financial disclosures. His coauthors reported having received research grants and personal fees from a variety of sources.
SOURCE: Xie W et al. JAMA Netw Open. 2020 Nov 12. doi: 10.1001/jamanetworkopen.2020.20816
FROM JAMA NETWORK OPEN
To vape or not to vape: Is that really a question?
All pediatricians are relieved that the rates of children smoking cigarettes has dropped steadily since 2011. This decline seems to be associated with education on the dangers of cigarettes and fewer parents smoking. Perhaps less modeling of cigarette use in movies (although it increased again from 2010 to 2019) and lawsuits against advertisements targeting children also has helped.
“Whew,” we may have said, “we can relax our efforts to convince children to avoid smoking.” But, as is commonly true in medicine, the next threat was right around the corner – in this case vaping or e-cigarettes, also called vapes, e-hookahs, vape pens, tank systems, mods, and electronic nicotine delivery systems. And the size of the problem is huge – over 20% of high school students report using e-cigarettes – and immediate, as vaping can kill in the short term as well as causing long-term harm.
“E-cigarette, or vaping, product use–associated Lung Injury” – EVALI for short – has killed 68 vapers and hospitalized thousands. EVALI is thought to be caused by a vitamin E acetate additive used when vaping marijuana, particularly from informal sources like friends, family, or in-person or online dealers.
Vaping increases the risk of severe COVID-19 disease
While EVALI deaths dropped in months after being explained, the COVID-19 epidemic is now a much greater threat to vapers. Vaping increases risk of severe COVID-19 disease because of its immediate paralysis of lung cilia. Sharing vape devices and touching one’s lips while using also increase the risk of virus transmission. Vaping and smoking increase the number of ACE2 receptors to which the SARS-CoV-2 virus attaches causing the characteristic cell damage, and suppresses macrophages and neutrophils, resulting in more smokers testing positive, being twice as likely to develop a severe illness and get hospitalized because of pneumonia from COVID-19, and being less likely to recover. Unfortunately, addressing this new threat to the immediate and long-term health of our patients appears to be more complicated than for addressing smoking tobacco. First of all, vaping is much more difficult to detect than smelly cigarettes sending smoke signals from behind the garage or in the school bathrooms. Many, if not most, adults do not recognize the vaping devices when they see them, as many are tiny and some look like computer thumb drives. The aerosol emitted when in use, while containing dangerous toxins, has less odor than tobacco smoke. Vaping equipment and ads have been designed to attract youth, including linking them to sports and music events. Vaping has been advertised as a way to wean off nicotine addiction, a claim that has some scientific evidence in adults, but at a lower dose of nicotine. Warning children about the dangers of marijuana vaping has been made less credible by the rapid expansion of legalization of marijuana around the United States, eliciting “I told you it was fine” reactions from youth. And the person vaping does not know what or how much of the psychoactive components are being delivered into their bodies. One Juul pod, for example, has the equivalent in nicotine of an entire pack of 20 cigarettes. They are highly addictive, especially to the developing brain, such that youth who vape are more likely to become addicted and to smoke cigarettes in the future.
Help from federal regulation has been weak
While all 50 states ban sales to youth, adults can still buy. Food and Drug Administration limitations on kid-friendly ads, and use of sweet, fruity, and mint flavorings that are most preferred by children, apply only to new producers. The FDA does not yet regulate content of vaping solutions.
So we pediatricians are on the front line for this new threat to prevent vaping or convince youth to cut down or quit. The first step in addressing vaping is being knowledgeable about its many known and emerging health risks. It may seem obvious that the dangers of vaping microscopic particles depends on the contents. Water vapor alone is not dangerous; in fact, we prescribe it in nebulizers. Unfortunately, the contents of different vaping products vary and are not well defined in different vape products. The process of using an electric current to vaporize a substance can make it more toxic than the precursor, and teens have little idea about the substances they are inhaling. The psychoactive components vary from nicotine to tetrahydrocannabinol in varying amounts. These have the well known effects of stimulation or a high, but also the potential adverse effects of poor concentration, agitation, and even psychosis. Most e-cigarettes contain nicotine, which is highly addictive and can harm adolescent brain development, which continues into the early- to mid-20s. About two-thirds of Juul users aged 15-24 years did not know that it always contains nicotine, as do 99% of all vape solutions (Centers for Disease Control and Prevention, 2020). Earlier use of nicotine is more highly associated with later addiction to tobacco products that cause lung damage, acid reflux, insulin resistance, harm to the testes, harm to fetuses, cancer, and heart disease.
E-cigarette aerosols also contain dozens of other harmful substances besides nicotine ranging from acetone, propylene glycol, and metals to formaldehyde and ethyl benzene. These same chemicals are part of familiar toxic substances such as antifreeze, paint thinner, and pesticides. These cause ear, eye and throat irritation, and impairments in the cardiovascular system reducing athletic ability – at the least. Some flavorings in vape fluids also are toxic. Even the residual left on furniture and floors is harmful to those coming in contact, including pets.
How to encourage teens not to vaping
Trying to scare youth about health hazards is not generally effective in stopping risk behaviors since adolescence is a time of perceived singularity (it does not apply to me) and even a sense of immortality. Teens also see peers who vape as being unaffected and decide on using based on this small personal sample instead of valid statistics.
But teens do pay some attention to peer models or influencers saying why they do not use. One source of such testimony you can refer to is videos of inspiring athletes, musicians, and other “cool” young adults found on the naturalhigh.org website. You may know other examples of community teens desisting you can reference.
Parent rules, and less so advice, against smoking have been shown to be effective in deterring youth cigarette smoking. Because parents are less aware of vaping and its dangers, another step we can take is educating parents in our practices about vaping, its variable forms, its effects, and dangers, supplying authoritative materials, and advising them to talk with their children. Other steps the American Academy of Pediatrics recommends regarding smoking is for parents to be a role model of not using or try to quit, designate the house and car as smoking free, avoid children viewing smoking in media, tell their children about the side effects, and encourage their children who use to quit. Parents also can encourage schools to teach and have rules about smoking and vaping (e.g., med.stanford.edu/tobaccopreventiontoolkit.html).
Another approach we have been using is to not only screen for all substance use, but also to gather information about the teen’s strengths, activities, and life goals both to enhance rapport and to reference during motivational interviewing as reasons to avoid, reduce, or quit vaping. Motivational interviewing has been shown to help patients make healthier lifestyle choices by nonjudgmentally exploring their pros and cons in a conversation that takes into account readiness to change. This fits well with the stage of developing autonomy when teens want above all to make their own decisions. The cons of using can be discussed as including the effects and side effects of vaping interfering with their favored activities and moving towards their identified goals. Praising abstinence and asking them to show you how they could decline offers to vape are valuable reinforcement you can provide.
Finally, we all know that teens hate being manipulated. Vaping education we provide can make it clear that youth are being tricked by companies – most being large cigarette producers who know the dangers of vaping – into getting addicted so these companies can get rich on their money.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].
All pediatricians are relieved that the rates of children smoking cigarettes has dropped steadily since 2011. This decline seems to be associated with education on the dangers of cigarettes and fewer parents smoking. Perhaps less modeling of cigarette use in movies (although it increased again from 2010 to 2019) and lawsuits against advertisements targeting children also has helped.
“Whew,” we may have said, “we can relax our efforts to convince children to avoid smoking.” But, as is commonly true in medicine, the next threat was right around the corner – in this case vaping or e-cigarettes, also called vapes, e-hookahs, vape pens, tank systems, mods, and electronic nicotine delivery systems. And the size of the problem is huge – over 20% of high school students report using e-cigarettes – and immediate, as vaping can kill in the short term as well as causing long-term harm.
“E-cigarette, or vaping, product use–associated Lung Injury” – EVALI for short – has killed 68 vapers and hospitalized thousands. EVALI is thought to be caused by a vitamin E acetate additive used when vaping marijuana, particularly from informal sources like friends, family, or in-person or online dealers.
Vaping increases the risk of severe COVID-19 disease
While EVALI deaths dropped in months after being explained, the COVID-19 epidemic is now a much greater threat to vapers. Vaping increases risk of severe COVID-19 disease because of its immediate paralysis of lung cilia. Sharing vape devices and touching one’s lips while using also increase the risk of virus transmission. Vaping and smoking increase the number of ACE2 receptors to which the SARS-CoV-2 virus attaches causing the characteristic cell damage, and suppresses macrophages and neutrophils, resulting in more smokers testing positive, being twice as likely to develop a severe illness and get hospitalized because of pneumonia from COVID-19, and being less likely to recover. Unfortunately, addressing this new threat to the immediate and long-term health of our patients appears to be more complicated than for addressing smoking tobacco. First of all, vaping is much more difficult to detect than smelly cigarettes sending smoke signals from behind the garage or in the school bathrooms. Many, if not most, adults do not recognize the vaping devices when they see them, as many are tiny and some look like computer thumb drives. The aerosol emitted when in use, while containing dangerous toxins, has less odor than tobacco smoke. Vaping equipment and ads have been designed to attract youth, including linking them to sports and music events. Vaping has been advertised as a way to wean off nicotine addiction, a claim that has some scientific evidence in adults, but at a lower dose of nicotine. Warning children about the dangers of marijuana vaping has been made less credible by the rapid expansion of legalization of marijuana around the United States, eliciting “I told you it was fine” reactions from youth. And the person vaping does not know what or how much of the psychoactive components are being delivered into their bodies. One Juul pod, for example, has the equivalent in nicotine of an entire pack of 20 cigarettes. They are highly addictive, especially to the developing brain, such that youth who vape are more likely to become addicted and to smoke cigarettes in the future.
Help from federal regulation has been weak
While all 50 states ban sales to youth, adults can still buy. Food and Drug Administration limitations on kid-friendly ads, and use of sweet, fruity, and mint flavorings that are most preferred by children, apply only to new producers. The FDA does not yet regulate content of vaping solutions.
So we pediatricians are on the front line for this new threat to prevent vaping or convince youth to cut down or quit. The first step in addressing vaping is being knowledgeable about its many known and emerging health risks. It may seem obvious that the dangers of vaping microscopic particles depends on the contents. Water vapor alone is not dangerous; in fact, we prescribe it in nebulizers. Unfortunately, the contents of different vaping products vary and are not well defined in different vape products. The process of using an electric current to vaporize a substance can make it more toxic than the precursor, and teens have little idea about the substances they are inhaling. The psychoactive components vary from nicotine to tetrahydrocannabinol in varying amounts. These have the well known effects of stimulation or a high, but also the potential adverse effects of poor concentration, agitation, and even psychosis. Most e-cigarettes contain nicotine, which is highly addictive and can harm adolescent brain development, which continues into the early- to mid-20s. About two-thirds of Juul users aged 15-24 years did not know that it always contains nicotine, as do 99% of all vape solutions (Centers for Disease Control and Prevention, 2020). Earlier use of nicotine is more highly associated with later addiction to tobacco products that cause lung damage, acid reflux, insulin resistance, harm to the testes, harm to fetuses, cancer, and heart disease.
E-cigarette aerosols also contain dozens of other harmful substances besides nicotine ranging from acetone, propylene glycol, and metals to formaldehyde and ethyl benzene. These same chemicals are part of familiar toxic substances such as antifreeze, paint thinner, and pesticides. These cause ear, eye and throat irritation, and impairments in the cardiovascular system reducing athletic ability – at the least. Some flavorings in vape fluids also are toxic. Even the residual left on furniture and floors is harmful to those coming in contact, including pets.
How to encourage teens not to vaping
Trying to scare youth about health hazards is not generally effective in stopping risk behaviors since adolescence is a time of perceived singularity (it does not apply to me) and even a sense of immortality. Teens also see peers who vape as being unaffected and decide on using based on this small personal sample instead of valid statistics.
But teens do pay some attention to peer models or influencers saying why they do not use. One source of such testimony you can refer to is videos of inspiring athletes, musicians, and other “cool” young adults found on the naturalhigh.org website. You may know other examples of community teens desisting you can reference.
Parent rules, and less so advice, against smoking have been shown to be effective in deterring youth cigarette smoking. Because parents are less aware of vaping and its dangers, another step we can take is educating parents in our practices about vaping, its variable forms, its effects, and dangers, supplying authoritative materials, and advising them to talk with their children. Other steps the American Academy of Pediatrics recommends regarding smoking is for parents to be a role model of not using or try to quit, designate the house and car as smoking free, avoid children viewing smoking in media, tell their children about the side effects, and encourage their children who use to quit. Parents also can encourage schools to teach and have rules about smoking and vaping (e.g., med.stanford.edu/tobaccopreventiontoolkit.html).
Another approach we have been using is to not only screen for all substance use, but also to gather information about the teen’s strengths, activities, and life goals both to enhance rapport and to reference during motivational interviewing as reasons to avoid, reduce, or quit vaping. Motivational interviewing has been shown to help patients make healthier lifestyle choices by nonjudgmentally exploring their pros and cons in a conversation that takes into account readiness to change. This fits well with the stage of developing autonomy when teens want above all to make their own decisions. The cons of using can be discussed as including the effects and side effects of vaping interfering with their favored activities and moving towards their identified goals. Praising abstinence and asking them to show you how they could decline offers to vape are valuable reinforcement you can provide.
Finally, we all know that teens hate being manipulated. Vaping education we provide can make it clear that youth are being tricked by companies – most being large cigarette producers who know the dangers of vaping – into getting addicted so these companies can get rich on their money.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].
All pediatricians are relieved that the rates of children smoking cigarettes has dropped steadily since 2011. This decline seems to be associated with education on the dangers of cigarettes and fewer parents smoking. Perhaps less modeling of cigarette use in movies (although it increased again from 2010 to 2019) and lawsuits against advertisements targeting children also has helped.
“Whew,” we may have said, “we can relax our efforts to convince children to avoid smoking.” But, as is commonly true in medicine, the next threat was right around the corner – in this case vaping or e-cigarettes, also called vapes, e-hookahs, vape pens, tank systems, mods, and electronic nicotine delivery systems. And the size of the problem is huge – over 20% of high school students report using e-cigarettes – and immediate, as vaping can kill in the short term as well as causing long-term harm.
“E-cigarette, or vaping, product use–associated Lung Injury” – EVALI for short – has killed 68 vapers and hospitalized thousands. EVALI is thought to be caused by a vitamin E acetate additive used when vaping marijuana, particularly from informal sources like friends, family, or in-person or online dealers.
Vaping increases the risk of severe COVID-19 disease
While EVALI deaths dropped in months after being explained, the COVID-19 epidemic is now a much greater threat to vapers. Vaping increases risk of severe COVID-19 disease because of its immediate paralysis of lung cilia. Sharing vape devices and touching one’s lips while using also increase the risk of virus transmission. Vaping and smoking increase the number of ACE2 receptors to which the SARS-CoV-2 virus attaches causing the characteristic cell damage, and suppresses macrophages and neutrophils, resulting in more smokers testing positive, being twice as likely to develop a severe illness and get hospitalized because of pneumonia from COVID-19, and being less likely to recover. Unfortunately, addressing this new threat to the immediate and long-term health of our patients appears to be more complicated than for addressing smoking tobacco. First of all, vaping is much more difficult to detect than smelly cigarettes sending smoke signals from behind the garage or in the school bathrooms. Many, if not most, adults do not recognize the vaping devices when they see them, as many are tiny and some look like computer thumb drives. The aerosol emitted when in use, while containing dangerous toxins, has less odor than tobacco smoke. Vaping equipment and ads have been designed to attract youth, including linking them to sports and music events. Vaping has been advertised as a way to wean off nicotine addiction, a claim that has some scientific evidence in adults, but at a lower dose of nicotine. Warning children about the dangers of marijuana vaping has been made less credible by the rapid expansion of legalization of marijuana around the United States, eliciting “I told you it was fine” reactions from youth. And the person vaping does not know what or how much of the psychoactive components are being delivered into their bodies. One Juul pod, for example, has the equivalent in nicotine of an entire pack of 20 cigarettes. They are highly addictive, especially to the developing brain, such that youth who vape are more likely to become addicted and to smoke cigarettes in the future.
Help from federal regulation has been weak
While all 50 states ban sales to youth, adults can still buy. Food and Drug Administration limitations on kid-friendly ads, and use of sweet, fruity, and mint flavorings that are most preferred by children, apply only to new producers. The FDA does not yet regulate content of vaping solutions.
So we pediatricians are on the front line for this new threat to prevent vaping or convince youth to cut down or quit. The first step in addressing vaping is being knowledgeable about its many known and emerging health risks. It may seem obvious that the dangers of vaping microscopic particles depends on the contents. Water vapor alone is not dangerous; in fact, we prescribe it in nebulizers. Unfortunately, the contents of different vaping products vary and are not well defined in different vape products. The process of using an electric current to vaporize a substance can make it more toxic than the precursor, and teens have little idea about the substances they are inhaling. The psychoactive components vary from nicotine to tetrahydrocannabinol in varying amounts. These have the well known effects of stimulation or a high, but also the potential adverse effects of poor concentration, agitation, and even psychosis. Most e-cigarettes contain nicotine, which is highly addictive and can harm adolescent brain development, which continues into the early- to mid-20s. About two-thirds of Juul users aged 15-24 years did not know that it always contains nicotine, as do 99% of all vape solutions (Centers for Disease Control and Prevention, 2020). Earlier use of nicotine is more highly associated with later addiction to tobacco products that cause lung damage, acid reflux, insulin resistance, harm to the testes, harm to fetuses, cancer, and heart disease.
E-cigarette aerosols also contain dozens of other harmful substances besides nicotine ranging from acetone, propylene glycol, and metals to formaldehyde and ethyl benzene. These same chemicals are part of familiar toxic substances such as antifreeze, paint thinner, and pesticides. These cause ear, eye and throat irritation, and impairments in the cardiovascular system reducing athletic ability – at the least. Some flavorings in vape fluids also are toxic. Even the residual left on furniture and floors is harmful to those coming in contact, including pets.
How to encourage teens not to vaping
Trying to scare youth about health hazards is not generally effective in stopping risk behaviors since adolescence is a time of perceived singularity (it does not apply to me) and even a sense of immortality. Teens also see peers who vape as being unaffected and decide on using based on this small personal sample instead of valid statistics.
But teens do pay some attention to peer models or influencers saying why they do not use. One source of such testimony you can refer to is videos of inspiring athletes, musicians, and other “cool” young adults found on the naturalhigh.org website. You may know other examples of community teens desisting you can reference.
Parent rules, and less so advice, against smoking have been shown to be effective in deterring youth cigarette smoking. Because parents are less aware of vaping and its dangers, another step we can take is educating parents in our practices about vaping, its variable forms, its effects, and dangers, supplying authoritative materials, and advising them to talk with their children. Other steps the American Academy of Pediatrics recommends regarding smoking is for parents to be a role model of not using or try to quit, designate the house and car as smoking free, avoid children viewing smoking in media, tell their children about the side effects, and encourage their children who use to quit. Parents also can encourage schools to teach and have rules about smoking and vaping (e.g., med.stanford.edu/tobaccopreventiontoolkit.html).
Another approach we have been using is to not only screen for all substance use, but also to gather information about the teen’s strengths, activities, and life goals both to enhance rapport and to reference during motivational interviewing as reasons to avoid, reduce, or quit vaping. Motivational interviewing has been shown to help patients make healthier lifestyle choices by nonjudgmentally exploring their pros and cons in a conversation that takes into account readiness to change. This fits well with the stage of developing autonomy when teens want above all to make their own decisions. The cons of using can be discussed as including the effects and side effects of vaping interfering with their favored activities and moving towards their identified goals. Praising abstinence and asking them to show you how they could decline offers to vape are valuable reinforcement you can provide.
Finally, we all know that teens hate being manipulated. Vaping education we provide can make it clear that youth are being tricked by companies – most being large cigarette producers who know the dangers of vaping – into getting addicted so these companies can get rich on their money.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].
Asthma guidelines update FeNO, intermittent ICS use
The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.
“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.
Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.
The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.
“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.
According to Dr. Schatz, the most important updated recommendations are:
- Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
- Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
- Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.
Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”
In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.
Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.
Recommendations (strength of recommendation/certainty of evidence) include:
- Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
- Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
- Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
- Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
- Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
- Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
- For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
- Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
- For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
- A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
- A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
- If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
- In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
- Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
- Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
- Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).
One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”
The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”
Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.
SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.
The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.
“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.
Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.
The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.
“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.
According to Dr. Schatz, the most important updated recommendations are:
- Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
- Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
- Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.
Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”
In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.
Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.
Recommendations (strength of recommendation/certainty of evidence) include:
- Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
- Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
- Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
- Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
- Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
- Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
- For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
- Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
- For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
- A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
- A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
- If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
- In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
- Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
- Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
- Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).
One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”
The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”
Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.
SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.
The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.
“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.
Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.
The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.
“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.
According to Dr. Schatz, the most important updated recommendations are:
- Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
- Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
- Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.
Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”
In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.
Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.
Recommendations (strength of recommendation/certainty of evidence) include:
- Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
- Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
- Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
- Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
- Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
- Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
- For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
- Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
- For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
- A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
- A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
- If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
- In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
- Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
- Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
- Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).
One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”
The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”
Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.
SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.
FROM THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Understanding messenger RNA and other SARS-CoV-2 vaccines
In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.
These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.1 Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.
The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.2
A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”3 Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
Early efficacy results have been surprising
Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.
Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.
Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
Could mRNA COVID-19 vaccines be dangerous in the long term?
These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.
What about availability?
Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.
Timelines and testing other vaccines
Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.
Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.
AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.
Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.
Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.
Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.
After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.
Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.
However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].
References
1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.
2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.
3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).
4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.
5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.
6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.
In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.
These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.1 Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.
The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.2
A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”3 Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
Early efficacy results have been surprising
Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.
Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.
Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
Could mRNA COVID-19 vaccines be dangerous in the long term?
These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.
What about availability?
Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.
Timelines and testing other vaccines
Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.
Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.
AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.
Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.
Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.
Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.
After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.
Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.
However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].
References
1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.
2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.
3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).
4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.
5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.
6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.
In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.
These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.1 Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.
The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.2
A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”3 Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
Early efficacy results have been surprising
Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.
Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.
Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
Could mRNA COVID-19 vaccines be dangerous in the long term?
These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.
What about availability?
Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.
Timelines and testing other vaccines
Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.
Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.
AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.
Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.
Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.
Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.
After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.
Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.
However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].
References
1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.
2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.
3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).
4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.
5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.
6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.
How to identify and treat common bites and stings
Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).
Insects and arachnids:Background and epidemiology
Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).1
The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.2 In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%3; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.4
Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).5 Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.5
Arthropod bites are common in the United States; almost one-half are caused by spiders.7 Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.8
Risk factors
Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.
Continue to: There are also risk factors...
There are also risk factors for a systemic sting reaction:
- A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.9
- Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.10
- Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.11
Presentation: Signs and symptomsvary with severity
Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction12:
- A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.13
- A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.14 This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.16
- Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.17 In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,2 and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.18
- The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.19
Bees and wasps
Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).2
Continue to: Bee and wasp sting...
Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.20,21
Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.22
For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.
Centipedes and spiders
Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.23 Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.23
Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.25 Most spiders found in the United States cannot bite through human skin.26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.26,27
The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.29,30
Continue to: In contrast...
In contrast, the body of a black widow spider is black; females exhibit a distinctive red or yellow hourglass marking on their ventral aspect.28,31 The pinprick sensation of a bite leads to symptoms that can include erythema, swelling, pain, stiffness, chills, fever, nausea, and stomach pain.30,32
Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.
Fleas
Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).33 Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.35-37
Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.34,35
Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.33,38
Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.39 Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.33,38
Continue to: The Centers for Disease Control and Prevention...
The Centers for Disease Control and Prevention provide a general introduction to getting rid of fleas for pet owners.40 For specific guidance on flea-eradication strategies and specific flea-control products, advise patients to seek the advice of their veterinarian.
Flies and biting midges
Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.43
Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”44 are tiny (1-3 mm long) blood-sucking flies.45 Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.44 The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.
Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.44,45
Mosquitoes
Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.
The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.46 Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.46,47
Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.
Continue to: Management
Management. Advise patients to reduce their risk by using insect repellent, sleeping under mosquito netting, and wearing a long-sleeve shirt and long pants when traveling to endemic areas or when a local outbreak occurs.48
Ticks
Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.29 Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).49
Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.
Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.50
Diagnosis and the utilityof special testing
The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.18,51
Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.11,12
Continue to: Allergen-specific IgE antibody testing.
Allergen-specific IgE antibody testing. These serum assays—typically, radioallergosorbent testing (RAST)—are less sensitive than venom skin tests. RAST is useful when venom skin testing cannot be performed or when skin testing is negative in a patient who has had a severe allergic reaction to an insect bite or sting. Serum IgE-specific antibody testing is preferred over venom skin testing in patients who are at high risk of anaphylaxis.52,53
Providing reliefand advanced care
Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.54 For painful lesions, an oral analgesic can be prescribed.
For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H1- and H2-receptor antagonists can be used concomitantly.54,55
Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.54-56
Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.27,28,31
VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.57 The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.58
Continue to: After VIT is complete...
After VIT is complete, counsel patients that a mild systemic reaction is still possible after an insect bite or sting. More prolonged, even lifetime, treatment should be considered for patients who have58,59
- a history of severe, life-threatening allergic reactions to bites and stings
- honey bee sting allergy
- mast-cell disease
- a history of anaphylaxis while receiving VIT.
Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.58,59
Managing anaphylaxis
This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O2 and intravenous fluids is recommended for hemodynamically unstable patients.60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.56
After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.17,56
Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.14,17
CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; [email protected].
1. Numbers of insects (species and individuals). Smithsonian BugInfo Web site. www.si.edu/spotlight/buginfo/bugnos. Accessed November 25, 2020.
2. Antonicelli L, Bilò MB, Bonifazi F. Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol. 2002;2:341-346.
3. Jack jumper ant allergy. Australasian Society of Clinical Immunology and Allergy (ASCIA) Web site. Updated October 19, 2019. www.allergy.org.au/patients/insect-allergy-bites-and-stings/jack-jumper-ant-allergy. Accessed November 25, 2020.
4. Kemp SF, deShazo RD, Moffit JE, et al. Expanding habitat of the imported fire ant (Solenopsis invicta): a public health concern. J Allergy Clin Immunol. 2000;105:683-691.
5. Goodnight ML. Arachnid. In: Encyclopædia Britannica. 2012. www.britannica.com/animal/arachnid. Accessed November 25, 2020.
6. Despommier DD, Gwadz RW, Hotez PJ. Arachnids. In: Despommier DD, Gwadz RW, Hotez PJ. Parasitic Diseases. 3rd ed. Springer-Verlag; 1995:268-283.
7. Diaz JH, Leblanc KE. Common spider bites. Am Fam Physician. 2007;75:869-873.
8. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52:1032-1283.
9. Pucci S, Antonicelli L, Bilò MB, et al. Shortness of interval between two stings as risk factor for developing Hymenoptera venom allergy. Allergy.1994;49:894-896.
10. Müller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343-347.
11. Müller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol. 2007;7:337-341.
12. Golden DBK. Stinging insect allergy. Am Fam Physician. 2003;67:2541-2546.
13. Golden DBK, Demain T, Freeman T, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118:28-54.
14. Bilò BM, Rueff F, Mosbech H, et al; EAACI Interest Group on Insect Venom Hypersensitivity. Diagnosis of Hymenoptera venom allergy. Allergy. 2005;60:1339-1349.
15. Reisman RE. Insect stings. N Engl J Med. 1994;331:523-527.
16. Pucci S, D’Alò S, De Pasquale T, et al. Risk of anaphylaxis in patients with large local reactions to hymenoptera stings: a retrospective and prospective study. Clin Mol Allergy. 2015;13:21.
17. Golden DBK. Large local reactions to insect stings. J Allergy Clin Immunol Pract. 2015;3:331-334.
18. Clark S, Camargo CA Jr. Emergency treatment and prevention of insect-sting anaphylaxis. Curr Opin Allergy Clin Immunol. 2006;6:279-283.
19. Stinging insect allergy. In: Volcheck GW. Clinical Allergy: Diagnosis and Management. Humana Press; 2009:465-479.
20. Järvinen KM, Celestin J. Anaphylaxis avoidance and management: educating patients and their caregivers. J Asthma Allergy. 2014;7:95-104.
21. Institute for Quality and Efficiency in Health Care (IQWiG). Insect venom allergies: overview. InformedHealth.org. Updated May 7, 2020. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0096282/. Accessed November 25, 2020.
22. Casale TB, Burks AW. Clinical practice. Hymenoptera-sting hypersensitivity. N Engl J Med. 2014;370:1432-1439.
23. Shelley RM. Centipedes and millipedes with emphasis on North American fauna. Kansas School Naturalist. 1999;45:1-16. https://sites.google.com/g.emporia.edu/ksn/ksn-home/vol-45-no-3-centipedes-and-millipedes-with-emphasis-on-n-america-fauna#h.p_JEf3uDlTg0jw. Accessed November 25, 2020.
24. Ogg B. Centipedes and millipedes. Nebraska Extension in Lancaster County Web site. https://lancaster.unl.edu/pest/resources/CentipedeMillipede012.shtml. Accessed November 25, 2020.
25. Cushing PE. Spiders (Arachnida: Araneae). In: Capinera JL, ed. Encyclopedia of Entomology. Springer, Dordrecht; 2008:226.
26. Diaz JH, Leblanc KE. Common spider bites. Am Fam Physician. 2007;75:869-873.
27. The National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. Venomous spiders. www.cdc.gov/niosh/topics/spiders/. Accessed November 25, 2020.
28. Starr S. What you need to know to prevent a poisonous spider bite. AAP News. 2013;34:42. www.aappublications.org/content/aapnews/34/9/42.5.full.pdf. Accessed November 25, 2020.
29. Spider bites. Mayo Clinic Web site. www.mayoclinic.org/diseases-conditions/spider-bites/symptoms-causes/syc-20352371. Accessed November 25, 2020.
30. Barish RA, Arnold T. Spider bites. In: Merck Manual (Professional Version). Merck Sharp & Dohme Corp.; 2016. www.merckmanuals.com/professional/injuries-poisoning/bites-and-stings/spider-bites. Accessed November 25, 2020.
31. Juckett G. Arthropod bites. Am Fam Physician. 2013;88:841-847.
32. Clark RF, Wethern-Kestner S, Vance MV, et al. Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases. Ann Emerg Med. 1992;21:782-787.
33. Koehler PG, Pereira RM, Diclaro JW II. Fleas. Publication ENY-025. University of Florida IFAS Extension. Revised January 2012. https://edis.ifas.ufl.edu/ig087. Accessed November 25, 2020.
34. Bitam I, Dittmar K, Parola P, et al. Fleas and flea-borne diseases. Int J Infect Dis. 2010;14:e667-e676.
35. Leulmi H, Socolovschi C, Laudisoit A, et al. Detection of Rickettsia felis, Rickettsia typhi, Bartonella species and Yersinia pestis in fleas (Siphonaptera) from Africa. PLoS Negl Trop Dis. 2014;8:e3152.
36. Naimer SA, Cohen AD, Mumcuoglu KY, et al. Household papular urticaria. Isr Med Assoc J. 2002;4(11 suppl):911-913.
37. Golomb MR, Golomb HS. What’s eating you? Cat flea (Ctenocephalides felis). Cutis. 2010;85:10-11.
38. Dryden MW. Flea and tick control in the 21st century: challenges and opportunities. Vet Dermatol. 2009;20:435-440.
39. Dryden MW. Fleas in dogs and cats. Merck Sharp & Dohme Corporation: Merck Manual Veterinary Manual. Updated December 2014. www.merckvetmanual.com/integumentary-system/fleas-and-flea-allergy-dermatitis/fleas-in-dogs-and-cats. Accessed November 25, 2020.
40. Centers for Disease Control and Prevention. Getting rid of fleas. www.cdc.gov/fleas/getting_rid.html. Accessed November 25, 2020.
41. Chattopadhyay P, Goyary D, Dhiman S, et al. Immunomodulating effects and hypersensitivity reactions caused by Northeast Indian black fly salivary gland extract. J Immunotoxicol. 2014;11:126-132.
42. Hrabak TM, Dice JP. Use of immunotherapy in the management of presumed anaphylaxis to the deer fly. Ann Allergy Asthma Immunol. 2003;90:351-354.
43. Royden A, Wedley A, Merga JY, et al. A role for flies (Diptera) in the transmission of Campylobacter to broilers? Epidemiol Infect. 2016;144:3326-3334.
44. Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med. 2002;347:13-18.
45. Carpenter S, Groschup MH, Garros C, et al. Culicoides biting midges, arboviruses and public health in Europe. Antiviral Res. 2013;100:102-113.
46. Peng Z, Yang M, Simons FE. Immunologic mechanisms in mosquito allergy: correlation of skin reactions with specific IgE and IgG anti-bodies and lymphocyte proliferation response to mosquito antigens. Ann Allergy Asthma Immunol. 1996;77:238-244.
47. Simons FE, Peng Z. Skeeter syndrome. J Allergy Clin Immunol. 1999;104:705-707.
48. Centers for Disease Control and Prevention. Travelers’ health. Clinician resources. wwwnc.cdc.gov/travel/page/clinician-information-center. Accessed November 25, 2020.
49. Gauci M, Loh RK, Stone BF, et al. Allergic reactions to the Australian paralysis tick, Ixodes holocyclus: diagnostic evaluation by skin test and radioimmunoassay. Clin Exp Allergy. 1989;19:279-283.
50. Centers for Disease Control and Prevention. Ticks. Removing a tick. www.cdc.gov/ticks/removing_a_tick.html. Accessed November 25, 2020.
51. Golden DB, Kagey-Sobotka A, Norman PS, et al. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol. 2001;107:897-901.
52. Arzt L, Bokanovic D, Schrautzer C, et al. Immunological differences between insect venom-allergic patients with and without immunotherapy and asymptomatically sensitized subjects. Allergy. 2018;73:1223-1231.
53. Heddle R, Golden DBK. Allergy to insect stings and bites. World Allergy Organization Web site. Updated August 2015. www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/allergy-to-insect-stings-and-bites. Accessed November 25, 2020.
54. RuëffF, Przybilla B, Müller U, et al. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy. 1996;51:216-225.
55. Management of simple insect bites: where’s the evidence? Drug Ther Bull. 2012;50:45-48.
56. Tracy JM. Insect allergy. Mt Sinai J Med. 2011;78:773-783.
57. Golden DBK. Insect sting allergy and venom immunotherapy: a model and a mystery. J Allergy Clin Immunol. 2005;115:439-447.
58. Winther L, Arnved J, Malling H-J, et al. Side-effects of allergen-specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy. 2006;36:254-260.
59. Mellerup MT, Hahn GW, Poulsen LK, et al. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment. Clin Exp Allergy. 2000;30:1423-1429.
60. Anaphylaxis and insect stings and bites. Med Lett Drugs Ther. 2017;59:e79-e82.
61. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47:373-380.
62. Pflipsen MC, Vega Colon KM. Anaphylaxis: recognition and management. Am Fam Physician. 2020;102:355-362. Accessed November 25, 2020.
Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).
Insects and arachnids:Background and epidemiology
Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).1
The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.2 In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%3; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.4
Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).5 Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.5
Arthropod bites are common in the United States; almost one-half are caused by spiders.7 Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.8
Risk factors
Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.
Continue to: There are also risk factors...
There are also risk factors for a systemic sting reaction:
- A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.9
- Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.10
- Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.11
Presentation: Signs and symptomsvary with severity
Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction12:
- A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.13
- A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.14 This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.16
- Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.17 In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,2 and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.18
- The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.19
Bees and wasps
Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).2
Continue to: Bee and wasp sting...
Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.20,21
Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.22
For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.
Centipedes and spiders
Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.23 Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.23
Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.25 Most spiders found in the United States cannot bite through human skin.26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.26,27
The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.29,30
Continue to: In contrast...
In contrast, the body of a black widow spider is black; females exhibit a distinctive red or yellow hourglass marking on their ventral aspect.28,31 The pinprick sensation of a bite leads to symptoms that can include erythema, swelling, pain, stiffness, chills, fever, nausea, and stomach pain.30,32
Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.
Fleas
Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).33 Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.35-37
Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.34,35
Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.33,38
Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.39 Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.33,38
Continue to: The Centers for Disease Control and Prevention...
The Centers for Disease Control and Prevention provide a general introduction to getting rid of fleas for pet owners.40 For specific guidance on flea-eradication strategies and specific flea-control products, advise patients to seek the advice of their veterinarian.
Flies and biting midges
Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.43
Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”44 are tiny (1-3 mm long) blood-sucking flies.45 Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.44 The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.
Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.44,45
Mosquitoes
Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.
The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.46 Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.46,47
Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.
Continue to: Management
Management. Advise patients to reduce their risk by using insect repellent, sleeping under mosquito netting, and wearing a long-sleeve shirt and long pants when traveling to endemic areas or when a local outbreak occurs.48
Ticks
Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.29 Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).49
Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.
Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.50
Diagnosis and the utilityof special testing
The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.18,51
Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.11,12
Continue to: Allergen-specific IgE antibody testing.
Allergen-specific IgE antibody testing. These serum assays—typically, radioallergosorbent testing (RAST)—are less sensitive than venom skin tests. RAST is useful when venom skin testing cannot be performed or when skin testing is negative in a patient who has had a severe allergic reaction to an insect bite or sting. Serum IgE-specific antibody testing is preferred over venom skin testing in patients who are at high risk of anaphylaxis.52,53
Providing reliefand advanced care
Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.54 For painful lesions, an oral analgesic can be prescribed.
For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H1- and H2-receptor antagonists can be used concomitantly.54,55
Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.54-56
Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.27,28,31
VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.57 The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.58
Continue to: After VIT is complete...
After VIT is complete, counsel patients that a mild systemic reaction is still possible after an insect bite or sting. More prolonged, even lifetime, treatment should be considered for patients who have58,59
- a history of severe, life-threatening allergic reactions to bites and stings
- honey bee sting allergy
- mast-cell disease
- a history of anaphylaxis while receiving VIT.
Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.58,59
Managing anaphylaxis
This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O2 and intravenous fluids is recommended for hemodynamically unstable patients.60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.56
After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.17,56
Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.14,17
CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; [email protected].
Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).
Insects and arachnids:Background and epidemiology
Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).1
The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.2 In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%3; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.4
Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).5 Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.5
Arthropod bites are common in the United States; almost one-half are caused by spiders.7 Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.8
Risk factors
Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.
Continue to: There are also risk factors...
There are also risk factors for a systemic sting reaction:
- A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.9
- Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.10
- Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.11
Presentation: Signs and symptomsvary with severity
Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction12:
- A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.13
- A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.14 This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.16
- Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.17 In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,2 and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.18
- The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.19
Bees and wasps
Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).2
Continue to: Bee and wasp sting...
Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.20,21
Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.22
For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.
Centipedes and spiders
Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.23 Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.23
Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.25 Most spiders found in the United States cannot bite through human skin.26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.26,27
The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.29,30
Continue to: In contrast...
In contrast, the body of a black widow spider is black; females exhibit a distinctive red or yellow hourglass marking on their ventral aspect.28,31 The pinprick sensation of a bite leads to symptoms that can include erythema, swelling, pain, stiffness, chills, fever, nausea, and stomach pain.30,32
Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.
Fleas
Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).33 Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.35-37
Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.34,35
Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.33,38
Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.39 Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.33,38
Continue to: The Centers for Disease Control and Prevention...
The Centers for Disease Control and Prevention provide a general introduction to getting rid of fleas for pet owners.40 For specific guidance on flea-eradication strategies and specific flea-control products, advise patients to seek the advice of their veterinarian.
Flies and biting midges
Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.43
Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”44 are tiny (1-3 mm long) blood-sucking flies.45 Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.44 The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.
Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.44,45
Mosquitoes
Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.
The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.46 Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.46,47
Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.
Continue to: Management
Management. Advise patients to reduce their risk by using insect repellent, sleeping under mosquito netting, and wearing a long-sleeve shirt and long pants when traveling to endemic areas or when a local outbreak occurs.48
Ticks
Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.29 Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).49
Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.
Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.50
Diagnosis and the utilityof special testing
The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.18,51
Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.11,12
Continue to: Allergen-specific IgE antibody testing.
Allergen-specific IgE antibody testing. These serum assays—typically, radioallergosorbent testing (RAST)—are less sensitive than venom skin tests. RAST is useful when venom skin testing cannot be performed or when skin testing is negative in a patient who has had a severe allergic reaction to an insect bite or sting. Serum IgE-specific antibody testing is preferred over venom skin testing in patients who are at high risk of anaphylaxis.52,53
Providing reliefand advanced care
Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.54 For painful lesions, an oral analgesic can be prescribed.
For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H1- and H2-receptor antagonists can be used concomitantly.54,55
Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.54-56
Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.27,28,31
VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.57 The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.58
Continue to: After VIT is complete...
After VIT is complete, counsel patients that a mild systemic reaction is still possible after an insect bite or sting. More prolonged, even lifetime, treatment should be considered for patients who have58,59
- a history of severe, life-threatening allergic reactions to bites and stings
- honey bee sting allergy
- mast-cell disease
- a history of anaphylaxis while receiving VIT.
Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.58,59
Managing anaphylaxis
This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O2 and intravenous fluids is recommended for hemodynamically unstable patients.60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.56
After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.17,56
Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.14,17
CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; [email protected].
1. Numbers of insects (species and individuals). Smithsonian BugInfo Web site. www.si.edu/spotlight/buginfo/bugnos. Accessed November 25, 2020.
2. Antonicelli L, Bilò MB, Bonifazi F. Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol. 2002;2:341-346.
3. Jack jumper ant allergy. Australasian Society of Clinical Immunology and Allergy (ASCIA) Web site. Updated October 19, 2019. www.allergy.org.au/patients/insect-allergy-bites-and-stings/jack-jumper-ant-allergy. Accessed November 25, 2020.
4. Kemp SF, deShazo RD, Moffit JE, et al. Expanding habitat of the imported fire ant (Solenopsis invicta): a public health concern. J Allergy Clin Immunol. 2000;105:683-691.
5. Goodnight ML. Arachnid. In: Encyclopædia Britannica. 2012. www.britannica.com/animal/arachnid. Accessed November 25, 2020.
6. Despommier DD, Gwadz RW, Hotez PJ. Arachnids. In: Despommier DD, Gwadz RW, Hotez PJ. Parasitic Diseases. 3rd ed. Springer-Verlag; 1995:268-283.
7. Diaz JH, Leblanc KE. Common spider bites. Am Fam Physician. 2007;75:869-873.
8. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52:1032-1283.
9. Pucci S, Antonicelli L, Bilò MB, et al. Shortness of interval between two stings as risk factor for developing Hymenoptera venom allergy. Allergy.1994;49:894-896.
10. Müller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343-347.
11. Müller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol. 2007;7:337-341.
12. Golden DBK. Stinging insect allergy. Am Fam Physician. 2003;67:2541-2546.
13. Golden DBK, Demain T, Freeman T, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118:28-54.
14. Bilò BM, Rueff F, Mosbech H, et al; EAACI Interest Group on Insect Venom Hypersensitivity. Diagnosis of Hymenoptera venom allergy. Allergy. 2005;60:1339-1349.
15. Reisman RE. Insect stings. N Engl J Med. 1994;331:523-527.
16. Pucci S, D’Alò S, De Pasquale T, et al. Risk of anaphylaxis in patients with large local reactions to hymenoptera stings: a retrospective and prospective study. Clin Mol Allergy. 2015;13:21.
17. Golden DBK. Large local reactions to insect stings. J Allergy Clin Immunol Pract. 2015;3:331-334.
18. Clark S, Camargo CA Jr. Emergency treatment and prevention of insect-sting anaphylaxis. Curr Opin Allergy Clin Immunol. 2006;6:279-283.
19. Stinging insect allergy. In: Volcheck GW. Clinical Allergy: Diagnosis and Management. Humana Press; 2009:465-479.
20. Järvinen KM, Celestin J. Anaphylaxis avoidance and management: educating patients and their caregivers. J Asthma Allergy. 2014;7:95-104.
21. Institute for Quality and Efficiency in Health Care (IQWiG). Insect venom allergies: overview. InformedHealth.org. Updated May 7, 2020. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0096282/. Accessed November 25, 2020.
22. Casale TB, Burks AW. Clinical practice. Hymenoptera-sting hypersensitivity. N Engl J Med. 2014;370:1432-1439.
23. Shelley RM. Centipedes and millipedes with emphasis on North American fauna. Kansas School Naturalist. 1999;45:1-16. https://sites.google.com/g.emporia.edu/ksn/ksn-home/vol-45-no-3-centipedes-and-millipedes-with-emphasis-on-n-america-fauna#h.p_JEf3uDlTg0jw. Accessed November 25, 2020.
24. Ogg B. Centipedes and millipedes. Nebraska Extension in Lancaster County Web site. https://lancaster.unl.edu/pest/resources/CentipedeMillipede012.shtml. Accessed November 25, 2020.
25. Cushing PE. Spiders (Arachnida: Araneae). In: Capinera JL, ed. Encyclopedia of Entomology. Springer, Dordrecht; 2008:226.
26. Diaz JH, Leblanc KE. Common spider bites. Am Fam Physician. 2007;75:869-873.
27. The National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. Venomous spiders. www.cdc.gov/niosh/topics/spiders/. Accessed November 25, 2020.
28. Starr S. What you need to know to prevent a poisonous spider bite. AAP News. 2013;34:42. www.aappublications.org/content/aapnews/34/9/42.5.full.pdf. Accessed November 25, 2020.
29. Spider bites. Mayo Clinic Web site. www.mayoclinic.org/diseases-conditions/spider-bites/symptoms-causes/syc-20352371. Accessed November 25, 2020.
30. Barish RA, Arnold T. Spider bites. In: Merck Manual (Professional Version). Merck Sharp & Dohme Corp.; 2016. www.merckmanuals.com/professional/injuries-poisoning/bites-and-stings/spider-bites. Accessed November 25, 2020.
31. Juckett G. Arthropod bites. Am Fam Physician. 2013;88:841-847.
32. Clark RF, Wethern-Kestner S, Vance MV, et al. Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases. Ann Emerg Med. 1992;21:782-787.
33. Koehler PG, Pereira RM, Diclaro JW II. Fleas. Publication ENY-025. University of Florida IFAS Extension. Revised January 2012. https://edis.ifas.ufl.edu/ig087. Accessed November 25, 2020.
34. Bitam I, Dittmar K, Parola P, et al. Fleas and flea-borne diseases. Int J Infect Dis. 2010;14:e667-e676.
35. Leulmi H, Socolovschi C, Laudisoit A, et al. Detection of Rickettsia felis, Rickettsia typhi, Bartonella species and Yersinia pestis in fleas (Siphonaptera) from Africa. PLoS Negl Trop Dis. 2014;8:e3152.
36. Naimer SA, Cohen AD, Mumcuoglu KY, et al. Household papular urticaria. Isr Med Assoc J. 2002;4(11 suppl):911-913.
37. Golomb MR, Golomb HS. What’s eating you? Cat flea (Ctenocephalides felis). Cutis. 2010;85:10-11.
38. Dryden MW. Flea and tick control in the 21st century: challenges and opportunities. Vet Dermatol. 2009;20:435-440.
39. Dryden MW. Fleas in dogs and cats. Merck Sharp & Dohme Corporation: Merck Manual Veterinary Manual. Updated December 2014. www.merckvetmanual.com/integumentary-system/fleas-and-flea-allergy-dermatitis/fleas-in-dogs-and-cats. Accessed November 25, 2020.
40. Centers for Disease Control and Prevention. Getting rid of fleas. www.cdc.gov/fleas/getting_rid.html. Accessed November 25, 2020.
41. Chattopadhyay P, Goyary D, Dhiman S, et al. Immunomodulating effects and hypersensitivity reactions caused by Northeast Indian black fly salivary gland extract. J Immunotoxicol. 2014;11:126-132.
42. Hrabak TM, Dice JP. Use of immunotherapy in the management of presumed anaphylaxis to the deer fly. Ann Allergy Asthma Immunol. 2003;90:351-354.
43. Royden A, Wedley A, Merga JY, et al. A role for flies (Diptera) in the transmission of Campylobacter to broilers? Epidemiol Infect. 2016;144:3326-3334.
44. Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med. 2002;347:13-18.
45. Carpenter S, Groschup MH, Garros C, et al. Culicoides biting midges, arboviruses and public health in Europe. Antiviral Res. 2013;100:102-113.
46. Peng Z, Yang M, Simons FE. Immunologic mechanisms in mosquito allergy: correlation of skin reactions with specific IgE and IgG anti-bodies and lymphocyte proliferation response to mosquito antigens. Ann Allergy Asthma Immunol. 1996;77:238-244.
47. Simons FE, Peng Z. Skeeter syndrome. J Allergy Clin Immunol. 1999;104:705-707.
48. Centers for Disease Control and Prevention. Travelers’ health. Clinician resources. wwwnc.cdc.gov/travel/page/clinician-information-center. Accessed November 25, 2020.
49. Gauci M, Loh RK, Stone BF, et al. Allergic reactions to the Australian paralysis tick, Ixodes holocyclus: diagnostic evaluation by skin test and radioimmunoassay. Clin Exp Allergy. 1989;19:279-283.
50. Centers for Disease Control and Prevention. Ticks. Removing a tick. www.cdc.gov/ticks/removing_a_tick.html. Accessed November 25, 2020.
51. Golden DB, Kagey-Sobotka A, Norman PS, et al. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol. 2001;107:897-901.
52. Arzt L, Bokanovic D, Schrautzer C, et al. Immunological differences between insect venom-allergic patients with and without immunotherapy and asymptomatically sensitized subjects. Allergy. 2018;73:1223-1231.
53. Heddle R, Golden DBK. Allergy to insect stings and bites. World Allergy Organization Web site. Updated August 2015. www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/allergy-to-insect-stings-and-bites. Accessed November 25, 2020.
54. RuëffF, Przybilla B, Müller U, et al. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy. 1996;51:216-225.
55. Management of simple insect bites: where’s the evidence? Drug Ther Bull. 2012;50:45-48.
56. Tracy JM. Insect allergy. Mt Sinai J Med. 2011;78:773-783.
57. Golden DBK. Insect sting allergy and venom immunotherapy: a model and a mystery. J Allergy Clin Immunol. 2005;115:439-447.
58. Winther L, Arnved J, Malling H-J, et al. Side-effects of allergen-specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy. 2006;36:254-260.
59. Mellerup MT, Hahn GW, Poulsen LK, et al. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment. Clin Exp Allergy. 2000;30:1423-1429.
60. Anaphylaxis and insect stings and bites. Med Lett Drugs Ther. 2017;59:e79-e82.
61. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47:373-380.
62. Pflipsen MC, Vega Colon KM. Anaphylaxis: recognition and management. Am Fam Physician. 2020;102:355-362. Accessed November 25, 2020.
1. Numbers of insects (species and individuals). Smithsonian BugInfo Web site. www.si.edu/spotlight/buginfo/bugnos. Accessed November 25, 2020.
2. Antonicelli L, Bilò MB, Bonifazi F. Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol. 2002;2:341-346.
3. Jack jumper ant allergy. Australasian Society of Clinical Immunology and Allergy (ASCIA) Web site. Updated October 19, 2019. www.allergy.org.au/patients/insect-allergy-bites-and-stings/jack-jumper-ant-allergy. Accessed November 25, 2020.
4. Kemp SF, deShazo RD, Moffit JE, et al. Expanding habitat of the imported fire ant (Solenopsis invicta): a public health concern. J Allergy Clin Immunol. 2000;105:683-691.
5. Goodnight ML. Arachnid. In: Encyclopædia Britannica. 2012. www.britannica.com/animal/arachnid. Accessed November 25, 2020.
6. Despommier DD, Gwadz RW, Hotez PJ. Arachnids. In: Despommier DD, Gwadz RW, Hotez PJ. Parasitic Diseases. 3rd ed. Springer-Verlag; 1995:268-283.
7. Diaz JH, Leblanc KE. Common spider bites. Am Fam Physician. 2007;75:869-873.
8. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52:1032-1283.
9. Pucci S, Antonicelli L, Bilò MB, et al. Shortness of interval between two stings as risk factor for developing Hymenoptera venom allergy. Allergy.1994;49:894-896.
10. Müller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol. 2005;5:343-347.
11. Müller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol. 2007;7:337-341.
12. Golden DBK. Stinging insect allergy. Am Fam Physician. 2003;67:2541-2546.
13. Golden DBK, Demain T, Freeman T, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118:28-54.
14. Bilò BM, Rueff F, Mosbech H, et al; EAACI Interest Group on Insect Venom Hypersensitivity. Diagnosis of Hymenoptera venom allergy. Allergy. 2005;60:1339-1349.
15. Reisman RE. Insect stings. N Engl J Med. 1994;331:523-527.
16. Pucci S, D’Alò S, De Pasquale T, et al. Risk of anaphylaxis in patients with large local reactions to hymenoptera stings: a retrospective and prospective study. Clin Mol Allergy. 2015;13:21.
17. Golden DBK. Large local reactions to insect stings. J Allergy Clin Immunol Pract. 2015;3:331-334.
18. Clark S, Camargo CA Jr. Emergency treatment and prevention of insect-sting anaphylaxis. Curr Opin Allergy Clin Immunol. 2006;6:279-283.
19. Stinging insect allergy. In: Volcheck GW. Clinical Allergy: Diagnosis and Management. Humana Press; 2009:465-479.
20. Järvinen KM, Celestin J. Anaphylaxis avoidance and management: educating patients and their caregivers. J Asthma Allergy. 2014;7:95-104.
21. Institute for Quality and Efficiency in Health Care (IQWiG). Insect venom allergies: overview. InformedHealth.org. Updated May 7, 2020. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0096282/. Accessed November 25, 2020.
22. Casale TB, Burks AW. Clinical practice. Hymenoptera-sting hypersensitivity. N Engl J Med. 2014;370:1432-1439.
23. Shelley RM. Centipedes and millipedes with emphasis on North American fauna. Kansas School Naturalist. 1999;45:1-16. https://sites.google.com/g.emporia.edu/ksn/ksn-home/vol-45-no-3-centipedes-and-millipedes-with-emphasis-on-n-america-fauna#h.p_JEf3uDlTg0jw. Accessed November 25, 2020.
24. Ogg B. Centipedes and millipedes. Nebraska Extension in Lancaster County Web site. https://lancaster.unl.edu/pest/resources/CentipedeMillipede012.shtml. Accessed November 25, 2020.
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PRACTICE RECOMMENDATIONS
❯ Recommend that patients use an insect repellent, such as an over-the-counter formulation that contains DEET, picaridin, or PMD (a chemical constituent of Eucalyptus citriodora oil) to prevent flea bites. C
❯ Prescribe nonsedating oral antihistamines as first-line symptomatic treatment of mild-to-moderate pruritus secondary to an insect bite. C
❯ When indicated, refer patients for venom immunotherapy, which is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis and death. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
