Immunology

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

An epidemiologic study of children aged 2 months to 5.5 years using data from the French national birth cohort (ELFE) reveals an increased risk of food allergies linked to a delayed introduction of major allergenic foods. These findings were published in Allergy.

Launched in April 2011, the French ELFE study aims to monitor children from birth to adulthood to better understand the factors from the intrauterine period to adolescence that affect their development, health, social skills, and school career. Thanks to this cohort, a team of scientists has reviewed the relationship between complementary feeding practices and allergies in French children.

The study focused on 6,662 children who had no signs of an allergic reaction before 2 months of age. Data on feeding practices were collected monthly from ages 3 months to 10 months. Their age at complementary feeding introduction was calculated, and a food diversity score was determined at 8 and 10 months. The number of major allergenic foods (out of eggs, fish, wheat, and dairy products) not introduced at 8 and 10 months was also determined. Allergic diseases (food allergy, eczema, asthma, and rhinoconjunctivitis) were reported by parents at 2 months and at 1, 2, 3.5, and 5.5 years.

Initially, scientists determined that just 62% of children began complementary feeding in the recommended age window, which is between ages 4 months and 6 months. They then closely studied the link between delayed introduction of major allergenic foods and the risk of food allergies. They saw that for 1 in 10 children, at least two major allergens, from eggs, fish, wheat, and dairy products, had still not been introduced into the diet of infants by the age of 10 months. Now, these children have a risk of developing a food allergy before the age of 5.5 years that is two times greater than that of children in whom the four major allergens were introduced before the age of 10 months.

These findings therefore confirm the importance of not delaying the introduction of major food allergens to prevent the occurrence of childhood allergic diseases. They provide convincing arguments in support of new recommendations made by the French pediatric and allergy societies as well as those issued by Public Health France.
 

ELFE: The first cohort to follow children from birth to adulthood

ELFE is the first longitudinal nationwide French study dedicated to monitoring children from birth to adulthood. More than 18,000 children born in metropolitan France in 2011 were included in this study, which represents 1 in 50 children born in 2011. From the time that researchers first met the families in the maternity ward, the parents who agreed to participate in this great scientific adventure have been questioned at regular intervals to better understand how environment, family members, and living conditions affect the development, health, and socialization of children.

This article was translated from the Medscape French Edition. A version of this article first appeared on Medscape.com.

An epidemiologic study of children aged 2 months to 5.5 years using data from the French national birth cohort (ELFE) reveals an increased risk of food allergies linked to a delayed introduction of major allergenic foods. These findings were published in Allergy.

Launched in April 2011, the French ELFE study aims to monitor children from birth to adulthood to better understand the factors from the intrauterine period to adolescence that affect their development, health, social skills, and school career. Thanks to this cohort, a team of scientists has reviewed the relationship between complementary feeding practices and allergies in French children.

The study focused on 6,662 children who had no signs of an allergic reaction before 2 months of age. Data on feeding practices were collected monthly from ages 3 months to 10 months. Their age at complementary feeding introduction was calculated, and a food diversity score was determined at 8 and 10 months. The number of major allergenic foods (out of eggs, fish, wheat, and dairy products) not introduced at 8 and 10 months was also determined. Allergic diseases (food allergy, eczema, asthma, and rhinoconjunctivitis) were reported by parents at 2 months and at 1, 2, 3.5, and 5.5 years.

Initially, scientists determined that just 62% of children began complementary feeding in the recommended age window, which is between ages 4 months and 6 months. They then closely studied the link between delayed introduction of major allergenic foods and the risk of food allergies. They saw that for 1 in 10 children, at least two major allergens, from eggs, fish, wheat, and dairy products, had still not been introduced into the diet of infants by the age of 10 months. Now, these children have a risk of developing a food allergy before the age of 5.5 years that is two times greater than that of children in whom the four major allergens were introduced before the age of 10 months.

These findings therefore confirm the importance of not delaying the introduction of major food allergens to prevent the occurrence of childhood allergic diseases. They provide convincing arguments in support of new recommendations made by the French pediatric and allergy societies as well as those issued by Public Health France.
 

ELFE: The first cohort to follow children from birth to adulthood

ELFE is the first longitudinal nationwide French study dedicated to monitoring children from birth to adulthood. More than 18,000 children born in metropolitan France in 2011 were included in this study, which represents 1 in 50 children born in 2011. From the time that researchers first met the families in the maternity ward, the parents who agreed to participate in this great scientific adventure have been questioned at regular intervals to better understand how environment, family members, and living conditions affect the development, health, and socialization of children.

This article was translated from the Medscape French Edition. A version of this article first appeared on Medscape.com.

An epidemiologic study of children aged 2 months to 5.5 years using data from the French national birth cohort (ELFE) reveals an increased risk of food allergies linked to a delayed introduction of major allergenic foods. These findings were published in Allergy.

Launched in April 2011, the French ELFE study aims to monitor children from birth to adulthood to better understand the factors from the intrauterine period to adolescence that affect their development, health, social skills, and school career. Thanks to this cohort, a team of scientists has reviewed the relationship between complementary feeding practices and allergies in French children.

The study focused on 6,662 children who had no signs of an allergic reaction before 2 months of age. Data on feeding practices were collected monthly from ages 3 months to 10 months. Their age at complementary feeding introduction was calculated, and a food diversity score was determined at 8 and 10 months. The number of major allergenic foods (out of eggs, fish, wheat, and dairy products) not introduced at 8 and 10 months was also determined. Allergic diseases (food allergy, eczema, asthma, and rhinoconjunctivitis) were reported by parents at 2 months and at 1, 2, 3.5, and 5.5 years.

Initially, scientists determined that just 62% of children began complementary feeding in the recommended age window, which is between ages 4 months and 6 months. They then closely studied the link between delayed introduction of major allergenic foods and the risk of food allergies. They saw that for 1 in 10 children, at least two major allergens, from eggs, fish, wheat, and dairy products, had still not been introduced into the diet of infants by the age of 10 months. Now, these children have a risk of developing a food allergy before the age of 5.5 years that is two times greater than that of children in whom the four major allergens were introduced before the age of 10 months.

These findings therefore confirm the importance of not delaying the introduction of major food allergens to prevent the occurrence of childhood allergic diseases. They provide convincing arguments in support of new recommendations made by the French pediatric and allergy societies as well as those issued by Public Health France.
 

ELFE: The first cohort to follow children from birth to adulthood

ELFE is the first longitudinal nationwide French study dedicated to monitoring children from birth to adulthood. More than 18,000 children born in metropolitan France in 2011 were included in this study, which represents 1 in 50 children born in 2011. From the time that researchers first met the families in the maternity ward, the parents who agreed to participate in this great scientific adventure have been questioned at regular intervals to better understand how environment, family members, and living conditions affect the development, health, and socialization of children.

This article was translated from the Medscape French Edition. A version of this article first appeared on Medscape.com.

Last month, I described a 28-year-old patient with a history of injection drug use who presented with pain in his left forearm. His history showed that, within the past 2 years, he’d been seen for cutaneous infections multiple times as an outpatient and in the emergency department. His records indicated that he was diagnosed with a penicillin allergy as a child when he developed a rash after receiving amoxicillin. I believed the next course of action should be to test for a penicillin allergy with an oral amoxicillin challenge.
 

Thank you for your excellent questions regarding this case. Great to hear the enthusiasm for testing for penicillin allergy!

One question focused on the course of action in the case of a mild or moderate IgE-mediated reaction after a single dose test with amoxicillin. Treatment for these reactions should include an antihistamine. I would reserve intravenous antihistamines for more severe cases, which also require treatment with a course of corticosteroids. However, the risk for a moderate to severe reaction to amoxicillin on retesting is quite low.

Clinicians need to exercise caution in the use of systemic corticosteroids. These drugs can be lifesaving, but even short courses of corticosteroids are associated with potentially serious adverse events. In a review of adverse events associated with short-course systemic corticosteroids among children, the rate of vomiting was 5.4%; behavioral change, 4.7%; and sleep disturbance, 4.3%. One child died after contracting herpes zoster, more than one-third of children developed elevated blood pressure, and 81.1% had evidence of suppression of the hypothalamic-pituitary-adrenal axis.

Among adults, short courses of systemic corticosteroids are associated with acute increases in the risks for gastrointestinal bleeding and hypertension. Cumulative exposure to short courses of corticosteroids over time results in higher risks for obesity, type 2 diabetes, and osteoporosis.

Another question prompted by this young man’s case focused on the durability of IgE reactions against penicillin. The IgE response to penicillin does indeed wane over time; 80% of patients with a previous true penicillin allergy can tolerate the antibiotic after 10 years. Thus, about 95% of patients with a remote history of penicillin allergy are tolerant of penicillin, and testing can be performed using the algorithm described.

Clinicians should avoid applying current guidelines for the evaluation of patients with penicillin allergy to other common drug allergies. The overall prevalence of sulfonamide allergy is 3%-8%, and the vast majority of these reactions follow treatment with trimethoprim-sulfamethoxazole. Sulfa allergy is even more common among persons living with HIV infection. The natural history of sulfa allergy is not as well established as penicillin allergy. Allergy testing is encouraged in these cases. Graded oral challenge testing is best reserved for patients who are unlikely to have a true sulfa allergy based on their history.

A version of this article first appeared on Medscape.com.

Last month, I described a 28-year-old patient with a history of injection drug use who presented with pain in his left forearm. His history showed that, within the past 2 years, he’d been seen for cutaneous infections multiple times as an outpatient and in the emergency department. His records indicated that he was diagnosed with a penicillin allergy as a child when he developed a rash after receiving amoxicillin. I believed the next course of action should be to test for a penicillin allergy with an oral amoxicillin challenge.
 

Thank you for your excellent questions regarding this case. Great to hear the enthusiasm for testing for penicillin allergy!

One question focused on the course of action in the case of a mild or moderate IgE-mediated reaction after a single dose test with amoxicillin. Treatment for these reactions should include an antihistamine. I would reserve intravenous antihistamines for more severe cases, which also require treatment with a course of corticosteroids. However, the risk for a moderate to severe reaction to amoxicillin on retesting is quite low.

Clinicians need to exercise caution in the use of systemic corticosteroids. These drugs can be lifesaving, but even short courses of corticosteroids are associated with potentially serious adverse events. In a review of adverse events associated with short-course systemic corticosteroids among children, the rate of vomiting was 5.4%; behavioral change, 4.7%; and sleep disturbance, 4.3%. One child died after contracting herpes zoster, more than one-third of children developed elevated blood pressure, and 81.1% had evidence of suppression of the hypothalamic-pituitary-adrenal axis.

Among adults, short courses of systemic corticosteroids are associated with acute increases in the risks for gastrointestinal bleeding and hypertension. Cumulative exposure to short courses of corticosteroids over time results in higher risks for obesity, type 2 diabetes, and osteoporosis.

Another question prompted by this young man’s case focused on the durability of IgE reactions against penicillin. The IgE response to penicillin does indeed wane over time; 80% of patients with a previous true penicillin allergy can tolerate the antibiotic after 10 years. Thus, about 95% of patients with a remote history of penicillin allergy are tolerant of penicillin, and testing can be performed using the algorithm described.

Clinicians should avoid applying current guidelines for the evaluation of patients with penicillin allergy to other common drug allergies. The overall prevalence of sulfonamide allergy is 3%-8%, and the vast majority of these reactions follow treatment with trimethoprim-sulfamethoxazole. Sulfa allergy is even more common among persons living with HIV infection. The natural history of sulfa allergy is not as well established as penicillin allergy. Allergy testing is encouraged in these cases. Graded oral challenge testing is best reserved for patients who are unlikely to have a true sulfa allergy based on their history.

A version of this article first appeared on Medscape.com.

Last month, I described a 28-year-old patient with a history of injection drug use who presented with pain in his left forearm. His history showed that, within the past 2 years, he’d been seen for cutaneous infections multiple times as an outpatient and in the emergency department. His records indicated that he was diagnosed with a penicillin allergy as a child when he developed a rash after receiving amoxicillin. I believed the next course of action should be to test for a penicillin allergy with an oral amoxicillin challenge.
 

Thank you for your excellent questions regarding this case. Great to hear the enthusiasm for testing for penicillin allergy!

One question focused on the course of action in the case of a mild or moderate IgE-mediated reaction after a single dose test with amoxicillin. Treatment for these reactions should include an antihistamine. I would reserve intravenous antihistamines for more severe cases, which also require treatment with a course of corticosteroids. However, the risk for a moderate to severe reaction to amoxicillin on retesting is quite low.

Clinicians need to exercise caution in the use of systemic corticosteroids. These drugs can be lifesaving, but even short courses of corticosteroids are associated with potentially serious adverse events. In a review of adverse events associated with short-course systemic corticosteroids among children, the rate of vomiting was 5.4%; behavioral change, 4.7%; and sleep disturbance, 4.3%. One child died after contracting herpes zoster, more than one-third of children developed elevated blood pressure, and 81.1% had evidence of suppression of the hypothalamic-pituitary-adrenal axis.

Among adults, short courses of systemic corticosteroids are associated with acute increases in the risks for gastrointestinal bleeding and hypertension. Cumulative exposure to short courses of corticosteroids over time results in higher risks for obesity, type 2 diabetes, and osteoporosis.

Another question prompted by this young man’s case focused on the durability of IgE reactions against penicillin. The IgE response to penicillin does indeed wane over time; 80% of patients with a previous true penicillin allergy can tolerate the antibiotic after 10 years. Thus, about 95% of patients with a remote history of penicillin allergy are tolerant of penicillin, and testing can be performed using the algorithm described.

Clinicians should avoid applying current guidelines for the evaluation of patients with penicillin allergy to other common drug allergies. The overall prevalence of sulfonamide allergy is 3%-8%, and the vast majority of these reactions follow treatment with trimethoprim-sulfamethoxazole. Sulfa allergy is even more common among persons living with HIV infection. The natural history of sulfa allergy is not as well established as penicillin allergy. Allergy testing is encouraged in these cases. Graded oral challenge testing is best reserved for patients who are unlikely to have a true sulfa allergy based on their history.

A version of this article first appeared on Medscape.com.

The combination of a patient-specific mRNA-based cancer vaccine (mRNA-4157/V940, Moderna and Merck) and the immune checkpoint inhibitor pembrolizumab significantly improved recurrence-free survival for patients with high-risk melanoma compared with pembrolizumab alone, according to the latest data from the KEYNOTE-942 trial.

This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.

The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.

“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.

“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.

Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
 

A promising personalized vaccine

The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.

Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”

The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.

The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.

“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.

In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.

Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).

Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.

In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.

The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.

Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).

The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).

The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.

Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.

The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”

Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.

KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
 

A version of this article first appeared on Medscape.com.

The combination of a patient-specific mRNA-based cancer vaccine (mRNA-4157/V940, Moderna and Merck) and the immune checkpoint inhibitor pembrolizumab significantly improved recurrence-free survival for patients with high-risk melanoma compared with pembrolizumab alone, according to the latest data from the KEYNOTE-942 trial.

This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.

The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.

“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.

“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.

Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
 

A promising personalized vaccine

The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.

Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”

The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.

The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.

“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.

In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.

Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).

Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.

In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.

The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.

Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).

The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).

The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.

Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.

The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”

Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.

KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
 

A version of this article first appeared on Medscape.com.

The combination of a patient-specific mRNA-based cancer vaccine (mRNA-4157/V940, Moderna and Merck) and the immune checkpoint inhibitor pembrolizumab significantly improved recurrence-free survival for patients with high-risk melanoma compared with pembrolizumab alone, according to the latest data from the KEYNOTE-942 trial.

This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.

The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.

“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.

“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.

Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
 

A promising personalized vaccine

The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.

Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”

The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.

The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.

“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.

In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.

Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).

Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.

In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.

The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.

Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).

The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).

The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.

Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.

The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”

Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.

KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
 

A version of this article first appeared on Medscape.com.

You are seeing a 28-year-old man for a same-day appointment. He has a history of opioid use disorder and chronic hepatitis C virus infection. He has been using injections of heroin and fentanyl for more than 6 years, and you can see in his medical record that he has had four outpatient appointments for cutaneous infections along with three emergency department visits for same in the past 2 years. His chief complaint today is pain over his left forearm for the past 3 days. He does not report fever or other constitutional symptoms.

Examination of the left forearm reveals 8 cm of erythema with induration and calor but no fluctuance. The area is moderately tender to palpation. He has no other abnormal findings on exam.

What’s your course of action?
 

Dr. Vega’s take

You want to treat this patient with antibiotics and close follow-up, and you note that he has a history of penicillin allergy. A note in his record states that he had a rash after receiving amoxicillin as a child.

Sometimes, we have to take the most expedient action in health care. But most of the time, we should do the right thing, even if it’s harder. I would gather more history of this reaction to penicillin and consider an oral challenge, hoping that the work that we put in to testing him for penicillin allergy pays dividends for him now and for years to come.

Penicillin allergy is very commonly listed in patient health records. In a retrospective analysis of the charts of 11,761 patients seen at a single U.S. urban outpatient system in 2012, 11.5% had documentation of penicillin allergy. Rash was the most common manifestation listed for allergy (37% of cases), followed by unknown symptoms (20%), hives (19%), swelling/angioedema (12%), and anaphylaxis (7%). Women were nearly twice as likely as men were to report a history of penicillin allergy, and patients of Asian descent had half the reported prevalence of penicillin allergy, compared with White patients.

Only 6% of the patients reporting penicillin allergy in this study had been referred to an allergy specialist. Given the consequences of true penicillin allergy, this rate is far too low. Patients with a history of penicillin allergy have higher risks for mortality from coexisting hematologic malignancies and penicillin-sensitive infections such as Staphylococcus species. They more frequently develop resistance to multiple antimicrobials and have longer average lengths of stay in the hospital.

Getting a good history for penicillin allergy can be challenging. Approximately three-quarters of penicillin allergies are diagnosed prior to age 3 years. Some children with a family history of penicillin allergy are mislabeled as having an active allergy, even though family history is not a significant contributor to penicillin allergy. Most rashes blamed on penicillin among children are actually not immunoglobulin (Ig) E–mediated and instead represent viral exanthems.

In response to these challenges, at the end of 2022, the American Academy of Allergy, Asthma & Immunology along with the American College of Allergy, Asthma and Immunology published new recommendations for the management of drug allergy. These recommendations provide an algorithm for the active reassessment of penicillin allergy. Like other recommendations in recent years, they call for a proactive approach in questioning the potential clinical consequences of the penicillin allergy listed in the health record.

First, the guidelines recommend against needing any testing for previous adverse reactions to penicillin, such as headache, nausea/vomiting, or diarrhea, that are not IgE-mediated. However, patients who have experienced these adverse reactions may still be reticent to take penicillin. For them and for adults with a history of mild to moderate reactions to penicillin more than 5 years ago, a single oral challenge test with amoxicillin is practical and can be used to exclude penicillin allergy.
 

The oral amoxicillin challenge

After patients take a treatment dose of oral amoxicillin, they should be observed for 1 hour for any objective reaction. The clinical setting should be able to support patients in the rare case of a more severe reaction to penicillin. Subjective symptoms such as pruritus without objective findings such as rash may be considered a successful challenge, and penicillin may be taken off the list of allergies. The treating team can bill CPT codes for drug challenge testing.

Some research has supported multidose testing with amoxicillin to assess for late reactions to a penicillin oral challenge, but the current guidelines recommend against this approach based on the very limited yield in finding additional cases of true allergy with extra doses of antibiotics. One method to address this issue is to have patients advise the practice if symptoms develop within 10 days of the oral challenge, with photos or prompt clinical evaluation to assess for an IgE-mediated reaction.

Many patients, and certainly some clinicians, will have significant trepidation regarding an oral challenge, despite the low risk for complications. For these patients, as well as children with a history of penicillin allergy and patients with a history of anaphylaxis to penicillin or probable IgE-mediated reaction to penicillin in the past several years, skin testing is recommended. Lower-risk patients might feel reassured to complete an oral challenge test after a negative skin test.

Penicillin skin testing is more reliable than a radioallergosorbent test or an enzyme-linked immunoassay and carries a high specificity. However, skin testing requires the specialized care of an allergy clinic, and this resource is limited in many communities.

Many patients will have negative oral challenge or skin testing for penicillin allergy, but there are still some critical responsibilities for the clinician after testing is complete. First, the label of penicillin allergy should be expunged from all available health records. Second, the clinician should communicate clearly and with empathy to the patient that they can take penicillin-based antibiotics safely and with confidence. Repeat testing is unnecessary unless new symptoms develop.

Given the millions of U.S. residents with penicillin allergy documented in the health record but limited resources for allergy testing, we all need to be engaged in proactively delabeling this allergy from patients who can take penicillin antibiotics without problems. But the application of this policy to clinical practice is challenging on several levels, from patient and clinician fear to practical constraints on time.

Dr. Vega is health sciences clinical professor, family medicine, University of California, Irvine. He has disclosed ties with McNeil Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

You are seeing a 28-year-old man for a same-day appointment. He has a history of opioid use disorder and chronic hepatitis C virus infection. He has been using injections of heroin and fentanyl for more than 6 years, and you can see in his medical record that he has had four outpatient appointments for cutaneous infections along with three emergency department visits for same in the past 2 years. His chief complaint today is pain over his left forearm for the past 3 days. He does not report fever or other constitutional symptoms.

Examination of the left forearm reveals 8 cm of erythema with induration and calor but no fluctuance. The area is moderately tender to palpation. He has no other abnormal findings on exam.

What’s your course of action?
 

Dr. Vega’s take

You want to treat this patient with antibiotics and close follow-up, and you note that he has a history of penicillin allergy. A note in his record states that he had a rash after receiving amoxicillin as a child.

Sometimes, we have to take the most expedient action in health care. But most of the time, we should do the right thing, even if it’s harder. I would gather more history of this reaction to penicillin and consider an oral challenge, hoping that the work that we put in to testing him for penicillin allergy pays dividends for him now and for years to come.

Penicillin allergy is very commonly listed in patient health records. In a retrospective analysis of the charts of 11,761 patients seen at a single U.S. urban outpatient system in 2012, 11.5% had documentation of penicillin allergy. Rash was the most common manifestation listed for allergy (37% of cases), followed by unknown symptoms (20%), hives (19%), swelling/angioedema (12%), and anaphylaxis (7%). Women were nearly twice as likely as men were to report a history of penicillin allergy, and patients of Asian descent had half the reported prevalence of penicillin allergy, compared with White patients.

Only 6% of the patients reporting penicillin allergy in this study had been referred to an allergy specialist. Given the consequences of true penicillin allergy, this rate is far too low. Patients with a history of penicillin allergy have higher risks for mortality from coexisting hematologic malignancies and penicillin-sensitive infections such as Staphylococcus species. They more frequently develop resistance to multiple antimicrobials and have longer average lengths of stay in the hospital.

Getting a good history for penicillin allergy can be challenging. Approximately three-quarters of penicillin allergies are diagnosed prior to age 3 years. Some children with a family history of penicillin allergy are mislabeled as having an active allergy, even though family history is not a significant contributor to penicillin allergy. Most rashes blamed on penicillin among children are actually not immunoglobulin (Ig) E–mediated and instead represent viral exanthems.

In response to these challenges, at the end of 2022, the American Academy of Allergy, Asthma & Immunology along with the American College of Allergy, Asthma and Immunology published new recommendations for the management of drug allergy. These recommendations provide an algorithm for the active reassessment of penicillin allergy. Like other recommendations in recent years, they call for a proactive approach in questioning the potential clinical consequences of the penicillin allergy listed in the health record.

First, the guidelines recommend against needing any testing for previous adverse reactions to penicillin, such as headache, nausea/vomiting, or diarrhea, that are not IgE-mediated. However, patients who have experienced these adverse reactions may still be reticent to take penicillin. For them and for adults with a history of mild to moderate reactions to penicillin more than 5 years ago, a single oral challenge test with amoxicillin is practical and can be used to exclude penicillin allergy.
 

The oral amoxicillin challenge

After patients take a treatment dose of oral amoxicillin, they should be observed for 1 hour for any objective reaction. The clinical setting should be able to support patients in the rare case of a more severe reaction to penicillin. Subjective symptoms such as pruritus without objective findings such as rash may be considered a successful challenge, and penicillin may be taken off the list of allergies. The treating team can bill CPT codes for drug challenge testing.

Some research has supported multidose testing with amoxicillin to assess for late reactions to a penicillin oral challenge, but the current guidelines recommend against this approach based on the very limited yield in finding additional cases of true allergy with extra doses of antibiotics. One method to address this issue is to have patients advise the practice if symptoms develop within 10 days of the oral challenge, with photos or prompt clinical evaluation to assess for an IgE-mediated reaction.

Many patients, and certainly some clinicians, will have significant trepidation regarding an oral challenge, despite the low risk for complications. For these patients, as well as children with a history of penicillin allergy and patients with a history of anaphylaxis to penicillin or probable IgE-mediated reaction to penicillin in the past several years, skin testing is recommended. Lower-risk patients might feel reassured to complete an oral challenge test after a negative skin test.

Penicillin skin testing is more reliable than a radioallergosorbent test or an enzyme-linked immunoassay and carries a high specificity. However, skin testing requires the specialized care of an allergy clinic, and this resource is limited in many communities.

Many patients will have negative oral challenge or skin testing for penicillin allergy, but there are still some critical responsibilities for the clinician after testing is complete. First, the label of penicillin allergy should be expunged from all available health records. Second, the clinician should communicate clearly and with empathy to the patient that they can take penicillin-based antibiotics safely and with confidence. Repeat testing is unnecessary unless new symptoms develop.

Given the millions of U.S. residents with penicillin allergy documented in the health record but limited resources for allergy testing, we all need to be engaged in proactively delabeling this allergy from patients who can take penicillin antibiotics without problems. But the application of this policy to clinical practice is challenging on several levels, from patient and clinician fear to practical constraints on time.

Dr. Vega is health sciences clinical professor, family medicine, University of California, Irvine. He has disclosed ties with McNeil Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

You are seeing a 28-year-old man for a same-day appointment. He has a history of opioid use disorder and chronic hepatitis C virus infection. He has been using injections of heroin and fentanyl for more than 6 years, and you can see in his medical record that he has had four outpatient appointments for cutaneous infections along with three emergency department visits for same in the past 2 years. His chief complaint today is pain over his left forearm for the past 3 days. He does not report fever or other constitutional symptoms.

Examination of the left forearm reveals 8 cm of erythema with induration and calor but no fluctuance. The area is moderately tender to palpation. He has no other abnormal findings on exam.

What’s your course of action?
 

Dr. Vega’s take

You want to treat this patient with antibiotics and close follow-up, and you note that he has a history of penicillin allergy. A note in his record states that he had a rash after receiving amoxicillin as a child.

Sometimes, we have to take the most expedient action in health care. But most of the time, we should do the right thing, even if it’s harder. I would gather more history of this reaction to penicillin and consider an oral challenge, hoping that the work that we put in to testing him for penicillin allergy pays dividends for him now and for years to come.

Penicillin allergy is very commonly listed in patient health records. In a retrospective analysis of the charts of 11,761 patients seen at a single U.S. urban outpatient system in 2012, 11.5% had documentation of penicillin allergy. Rash was the most common manifestation listed for allergy (37% of cases), followed by unknown symptoms (20%), hives (19%), swelling/angioedema (12%), and anaphylaxis (7%). Women were nearly twice as likely as men were to report a history of penicillin allergy, and patients of Asian descent had half the reported prevalence of penicillin allergy, compared with White patients.

Only 6% of the patients reporting penicillin allergy in this study had been referred to an allergy specialist. Given the consequences of true penicillin allergy, this rate is far too low. Patients with a history of penicillin allergy have higher risks for mortality from coexisting hematologic malignancies and penicillin-sensitive infections such as Staphylococcus species. They more frequently develop resistance to multiple antimicrobials and have longer average lengths of stay in the hospital.

Getting a good history for penicillin allergy can be challenging. Approximately three-quarters of penicillin allergies are diagnosed prior to age 3 years. Some children with a family history of penicillin allergy are mislabeled as having an active allergy, even though family history is not a significant contributor to penicillin allergy. Most rashes blamed on penicillin among children are actually not immunoglobulin (Ig) E–mediated and instead represent viral exanthems.

In response to these challenges, at the end of 2022, the American Academy of Allergy, Asthma & Immunology along with the American College of Allergy, Asthma and Immunology published new recommendations for the management of drug allergy. These recommendations provide an algorithm for the active reassessment of penicillin allergy. Like other recommendations in recent years, they call for a proactive approach in questioning the potential clinical consequences of the penicillin allergy listed in the health record.

First, the guidelines recommend against needing any testing for previous adverse reactions to penicillin, such as headache, nausea/vomiting, or diarrhea, that are not IgE-mediated. However, patients who have experienced these adverse reactions may still be reticent to take penicillin. For them and for adults with a history of mild to moderate reactions to penicillin more than 5 years ago, a single oral challenge test with amoxicillin is practical and can be used to exclude penicillin allergy.
 

The oral amoxicillin challenge

After patients take a treatment dose of oral amoxicillin, they should be observed for 1 hour for any objective reaction. The clinical setting should be able to support patients in the rare case of a more severe reaction to penicillin. Subjective symptoms such as pruritus without objective findings such as rash may be considered a successful challenge, and penicillin may be taken off the list of allergies. The treating team can bill CPT codes for drug challenge testing.

Some research has supported multidose testing with amoxicillin to assess for late reactions to a penicillin oral challenge, but the current guidelines recommend against this approach based on the very limited yield in finding additional cases of true allergy with extra doses of antibiotics. One method to address this issue is to have patients advise the practice if symptoms develop within 10 days of the oral challenge, with photos or prompt clinical evaluation to assess for an IgE-mediated reaction.

Many patients, and certainly some clinicians, will have significant trepidation regarding an oral challenge, despite the low risk for complications. For these patients, as well as children with a history of penicillin allergy and patients with a history of anaphylaxis to penicillin or probable IgE-mediated reaction to penicillin in the past several years, skin testing is recommended. Lower-risk patients might feel reassured to complete an oral challenge test after a negative skin test.

Penicillin skin testing is more reliable than a radioallergosorbent test or an enzyme-linked immunoassay and carries a high specificity. However, skin testing requires the specialized care of an allergy clinic, and this resource is limited in many communities.

Many patients will have negative oral challenge or skin testing for penicillin allergy, but there are still some critical responsibilities for the clinician after testing is complete. First, the label of penicillin allergy should be expunged from all available health records. Second, the clinician should communicate clearly and with empathy to the patient that they can take penicillin-based antibiotics safely and with confidence. Repeat testing is unnecessary unless new symptoms develop.

Given the millions of U.S. residents with penicillin allergy documented in the health record but limited resources for allergy testing, we all need to be engaged in proactively delabeling this allergy from patients who can take penicillin antibiotics without problems. But the application of this policy to clinical practice is challenging on several levels, from patient and clinician fear to practical constraints on time.

Dr. Vega is health sciences clinical professor, family medicine, University of California, Irvine. He has disclosed ties with McNeil Pharmaceuticals.

A version of this article originally appeared on Medscape.com.

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study² of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies³ have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study² of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies³ have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study² of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies³ have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University’s Grossman School of Medicine in New York City.

We’ve had an organ shortage for many decades now. We can do more transplants than we have organs made available. We try very hard to get organ donation from those who die. That’s a commendable thing to do. I think doctors should always be discussing the opportunity to donate organs upon death, even in primary care settings.

It’s good to find out what people’s attitudes are. Let them learn about organ donation as something they can think about. Let them talk about it with family and friends and partners so that they know their wishes.

However, despite these efforts to encourage organ donation, we still have far fewer organs than we could use to transplant people, many people die on waiting lists because there are no organs to give them, and we’re in a situation where demand for organ transplant is actually increasing.

There is more capacity to do transplants both in the United States and elsewhere, and more people are living longer, so organ failure starts to become more common before, let’s say, terminal illness is really there. Now, we have more people who might benefit from organ transplant in an aging population.

One place to turn to help reduce the shortage of organs is to living donation. At least insofar as kidneys go, kidney donation from living persons has become a prominent source of organs for those who need kidneys – most of whom are surviving on dialysis, by the way, at a very high cost and often with a quality of life that they don’t find particularly easy to accept.

Transplant is far preferred, even though they have to take immunosuppression to keep those organ transplants going, and that has its own risks and side effects. They still get more mobility. They still are able to have a broader diet. They enjoy life far more than they do having to show up for dialysis three times a week for a couple of hours, every week, for every week that they live.

There is an interest in living kidney donation. One battle has been that, well, maybe we could get more kidneys if we just paid people to sell us their kidneys. That has been resisted, and I’ve been resistant to that idea, too, because I worry that it leads to exploitation.

The people who sell their kidneys are poor. They’re often in debt. They feel coerced by their circumstances, so they make a kidney sale. This happens in countries like India, where there are markets underground, and you see that it’s the poorest of the poor who do this, and they don’t really work their way out of debt. They just wind up without a kidney, help relieve their debt a little bit, and pretty soon, because they don’t have a job or an income except that sale of a kidney, they’re not much better off than they were before they started.

Also, people who sell kidneys for money are more likely not to admit to their own health problems, raising risks about the quality of organs. Then, of course, it puts doctors in a position to take out an organ for pay, even though it doesn’t benefit you, so that you can sell it. This raises some questions about whether that’s consistent with medical ethics.

A different idea has emerged. New York State Governor Kathy Hochul just signed legislation that allows living donors to be compensated for legitimate costs. That’s a little different matter. You’re not buying the organ, but you’re saying that if you experience health care problems due to complications from a donation, if you need money for transportation, if you lost money because you did this altruistically and you had to take time off from work and had expenses for a babysitter, restaurants, or other things, the state is going to try to create funds that will compensate you.

That, I think we should agree, is not a bad idea. You’re in a situation there where you don’t want to make people who are heroic, altruistic, and trying to help others by donating a kidney end up financially worse off.

I think there’s a difference between making someone financially whole after the decision to make a kidney available and creating a market where the poorest of the poor come forward to just sell because they see no other choice in terms of how to get rid of debts. I see these situations as not ethically equivalent, so I support efforts to try to compensate people who are our heroes. I don’t think we should ask them to financially suffer.

We’ll watch to see what happens as the New York state law comes into effect. By the way, New York is one of the states that really lags in the supply of organs for transplant, so this measure is particularly important for that state. Many other states should be considering this legislation as well.

It’s one thing to reward, if you will, donors by making sure they don’t suffer financial loss. It’s a very different thing to say, let’s have a free market and we’ll pay whoever it is that’s willing to sell us a kidney to do so. The former seems to me to be humane and just, whereas the latter risks exploitation.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University’s Grossman School of Medicine in New York City.

We’ve had an organ shortage for many decades now. We can do more transplants than we have organs made available. We try very hard to get organ donation from those who die. That’s a commendable thing to do. I think doctors should always be discussing the opportunity to donate organs upon death, even in primary care settings.

It’s good to find out what people’s attitudes are. Let them learn about organ donation as something they can think about. Let them talk about it with family and friends and partners so that they know their wishes.

However, despite these efforts to encourage organ donation, we still have far fewer organs than we could use to transplant people, many people die on waiting lists because there are no organs to give them, and we’re in a situation where demand for organ transplant is actually increasing.

There is more capacity to do transplants both in the United States and elsewhere, and more people are living longer, so organ failure starts to become more common before, let’s say, terminal illness is really there. Now, we have more people who might benefit from organ transplant in an aging population.

One place to turn to help reduce the shortage of organs is to living donation. At least insofar as kidneys go, kidney donation from living persons has become a prominent source of organs for those who need kidneys – most of whom are surviving on dialysis, by the way, at a very high cost and often with a quality of life that they don’t find particularly easy to accept.

Transplant is far preferred, even though they have to take immunosuppression to keep those organ transplants going, and that has its own risks and side effects. They still get more mobility. They still are able to have a broader diet. They enjoy life far more than they do having to show up for dialysis three times a week for a couple of hours, every week, for every week that they live.

There is an interest in living kidney donation. One battle has been that, well, maybe we could get more kidneys if we just paid people to sell us their kidneys. That has been resisted, and I’ve been resistant to that idea, too, because I worry that it leads to exploitation.

The people who sell their kidneys are poor. They’re often in debt. They feel coerced by their circumstances, so they make a kidney sale. This happens in countries like India, where there are markets underground, and you see that it’s the poorest of the poor who do this, and they don’t really work their way out of debt. They just wind up without a kidney, help relieve their debt a little bit, and pretty soon, because they don’t have a job or an income except that sale of a kidney, they’re not much better off than they were before they started.

Also, people who sell kidneys for money are more likely not to admit to their own health problems, raising risks about the quality of organs. Then, of course, it puts doctors in a position to take out an organ for pay, even though it doesn’t benefit you, so that you can sell it. This raises some questions about whether that’s consistent with medical ethics.

A different idea has emerged. New York State Governor Kathy Hochul just signed legislation that allows living donors to be compensated for legitimate costs. That’s a little different matter. You’re not buying the organ, but you’re saying that if you experience health care problems due to complications from a donation, if you need money for transportation, if you lost money because you did this altruistically and you had to take time off from work and had expenses for a babysitter, restaurants, or other things, the state is going to try to create funds that will compensate you.

That, I think we should agree, is not a bad idea. You’re in a situation there where you don’t want to make people who are heroic, altruistic, and trying to help others by donating a kidney end up financially worse off.

I think there’s a difference between making someone financially whole after the decision to make a kidney available and creating a market where the poorest of the poor come forward to just sell because they see no other choice in terms of how to get rid of debts. I see these situations as not ethically equivalent, so I support efforts to try to compensate people who are our heroes. I don’t think we should ask them to financially suffer.

We’ll watch to see what happens as the New York state law comes into effect. By the way, New York is one of the states that really lags in the supply of organs for transplant, so this measure is particularly important for that state. Many other states should be considering this legislation as well.

It’s one thing to reward, if you will, donors by making sure they don’t suffer financial loss. It’s a very different thing to say, let’s have a free market and we’ll pay whoever it is that’s willing to sell us a kidney to do so. The former seems to me to be humane and just, whereas the latter risks exploitation.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University’s Grossman School of Medicine in New York City.

We’ve had an organ shortage for many decades now. We can do more transplants than we have organs made available. We try very hard to get organ donation from those who die. That’s a commendable thing to do. I think doctors should always be discussing the opportunity to donate organs upon death, even in primary care settings.

It’s good to find out what people’s attitudes are. Let them learn about organ donation as something they can think about. Let them talk about it with family and friends and partners so that they know their wishes.

However, despite these efforts to encourage organ donation, we still have far fewer organs than we could use to transplant people, many people die on waiting lists because there are no organs to give them, and we’re in a situation where demand for organ transplant is actually increasing.

There is more capacity to do transplants both in the United States and elsewhere, and more people are living longer, so organ failure starts to become more common before, let’s say, terminal illness is really there. Now, we have more people who might benefit from organ transplant in an aging population.

One place to turn to help reduce the shortage of organs is to living donation. At least insofar as kidneys go, kidney donation from living persons has become a prominent source of organs for those who need kidneys – most of whom are surviving on dialysis, by the way, at a very high cost and often with a quality of life that they don’t find particularly easy to accept.

Transplant is far preferred, even though they have to take immunosuppression to keep those organ transplants going, and that has its own risks and side effects. They still get more mobility. They still are able to have a broader diet. They enjoy life far more than they do having to show up for dialysis three times a week for a couple of hours, every week, for every week that they live.

There is an interest in living kidney donation. One battle has been that, well, maybe we could get more kidneys if we just paid people to sell us their kidneys. That has been resisted, and I’ve been resistant to that idea, too, because I worry that it leads to exploitation.

The people who sell their kidneys are poor. They’re often in debt. They feel coerced by their circumstances, so they make a kidney sale. This happens in countries like India, where there are markets underground, and you see that it’s the poorest of the poor who do this, and they don’t really work their way out of debt. They just wind up without a kidney, help relieve their debt a little bit, and pretty soon, because they don’t have a job or an income except that sale of a kidney, they’re not much better off than they were before they started.

Also, people who sell kidneys for money are more likely not to admit to their own health problems, raising risks about the quality of organs. Then, of course, it puts doctors in a position to take out an organ for pay, even though it doesn’t benefit you, so that you can sell it. This raises some questions about whether that’s consistent with medical ethics.

A different idea has emerged. New York State Governor Kathy Hochul just signed legislation that allows living donors to be compensated for legitimate costs. That’s a little different matter. You’re not buying the organ, but you’re saying that if you experience health care problems due to complications from a donation, if you need money for transportation, if you lost money because you did this altruistically and you had to take time off from work and had expenses for a babysitter, restaurants, or other things, the state is going to try to create funds that will compensate you.

That, I think we should agree, is not a bad idea. You’re in a situation there where you don’t want to make people who are heroic, altruistic, and trying to help others by donating a kidney end up financially worse off.

I think there’s a difference between making someone financially whole after the decision to make a kidney available and creating a market where the poorest of the poor come forward to just sell because they see no other choice in terms of how to get rid of debts. I see these situations as not ethically equivalent, so I support efforts to try to compensate people who are our heroes. I don’t think we should ask them to financially suffer.

We’ll watch to see what happens as the New York state law comes into effect. By the way, New York is one of the states that really lags in the supply of organs for transplant, so this measure is particularly important for that state. Many other states should be considering this legislation as well.

It’s one thing to reward, if you will, donors by making sure they don’t suffer financial loss. It’s a very different thing to say, let’s have a free market and we’ll pay whoever it is that’s willing to sell us a kidney to do so. The former seems to me to be humane and just, whereas the latter risks exploitation.
 

A version of this article first appeared on Medscape.com.

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m².

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m².

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m².

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.