Pulmonology

Background: COPD is a highly morbid disease, and there is a need for a better understanding of the true prevalence. Little is known regarding overdiagnosis of COPD. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), airflow limitation by spirometry is a key criteria for diagnosis.

Overdiagnosis of COPD was noted to be more prevalent in high-income countries than they were in low- to middle-income countries (4.9% versus 1.9% of the participants sampled).

The self-reporting of the diagnosis of COPD is a limitation of the study because it may have artificially inflated the rate of false positives.

Bottom line: Patient-reported diagnoses of COPD should be taken with a degree of caution because of high rates of overdiagnosis and overtreatment.

Citation: Sator L et al. Overdiagnosis of COPD in subjects with unobstructed spirometry. Chest. 2019 Aug;156(2):277-88.

Dr. Gordon is a hospitalist at Maine Medical Center in Portland.

Background: COPD is a highly morbid disease, and there is a need for a better understanding of the true prevalence. Little is known regarding overdiagnosis of COPD. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), airflow limitation by spirometry is a key criteria for diagnosis.

Overdiagnosis of COPD was noted to be more prevalent in high-income countries than they were in low- to middle-income countries (4.9% versus 1.9% of the participants sampled).

The self-reporting of the diagnosis of COPD is a limitation of the study because it may have artificially inflated the rate of false positives.

Bottom line: Patient-reported diagnoses of COPD should be taken with a degree of caution because of high rates of overdiagnosis and overtreatment.

Citation: Sator L et al. Overdiagnosis of COPD in subjects with unobstructed spirometry. Chest. 2019 Aug;156(2):277-88.

Dr. Gordon is a hospitalist at Maine Medical Center in Portland.

Background: COPD is a highly morbid disease, and there is a need for a better understanding of the true prevalence. Little is known regarding overdiagnosis of COPD. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), airflow limitation by spirometry is a key criteria for diagnosis.

Overdiagnosis of COPD was noted to be more prevalent in high-income countries than they were in low- to middle-income countries (4.9% versus 1.9% of the participants sampled).

The self-reporting of the diagnosis of COPD is a limitation of the study because it may have artificially inflated the rate of false positives.

Bottom line: Patient-reported diagnoses of COPD should be taken with a degree of caution because of high rates of overdiagnosis and overtreatment.

Citation: Sator L et al. Overdiagnosis of COPD in subjects with unobstructed spirometry. Chest. 2019 Aug;156(2):277-88.

Dr. Gordon is a hospitalist at Maine Medical Center in Portland.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Background: Corticosteroids in the setting of an acute exacerbation of improve COPD symptoms but do not affect the decline in lung function, rate of repeat exacerbations after a month, or mortality. There is concern regarding the cumulative adverse effects over time. Limited prior research suggests that a patient’s blood eosinophil count may be useful for determining the necessity of steroids for treatment of exacerbation.

The primary outcome of days alive and out of the hospital within 14 days after recruitment was similar between groups (9 days; P = .34), along with the secondary outcome of treatment failure (26%; P = .90). Importantly, the cumulative steroid dose in the eosinophilia-guided group was lower than that of the control group at days 5, 30, and 90 (P less than or equal to .0002). Additionally, the control arm had worsening of baseline diabetes within 30 days and was more likely to require antibiotics for infections within 90 days.

Although not statistically significant, a trend was noted toward increased readmission for COPD exacerbations or death at 30 days in the eosinophilia-guided group (25% vs. 17% of control; P = .10). Future work will need to further study this trend.

Bottom line: Eosinophilia-guided treatment of COPD exacerbations reduced the cumulative exposure of steroid therapy, thereby decreasing side effects, although further study of safety profile is warranted.

Citation: Sivapalan P et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): A multicenter, randomized, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019 Aug;7(8): 699-709.

Dr. Dupuis is a hospitalist at Maine Medical Center in Portland.

Background: Corticosteroids in the setting of an acute exacerbation of improve COPD symptoms but do not affect the decline in lung function, rate of repeat exacerbations after a month, or mortality. There is concern regarding the cumulative adverse effects over time. Limited prior research suggests that a patient’s blood eosinophil count may be useful for determining the necessity of steroids for treatment of exacerbation.

The primary outcome of days alive and out of the hospital within 14 days after recruitment was similar between groups (9 days; P = .34), along with the secondary outcome of treatment failure (26%; P = .90). Importantly, the cumulative steroid dose in the eosinophilia-guided group was lower than that of the control group at days 5, 30, and 90 (P less than or equal to .0002). Additionally, the control arm had worsening of baseline diabetes within 30 days and was more likely to require antibiotics for infections within 90 days.

Although not statistically significant, a trend was noted toward increased readmission for COPD exacerbations or death at 30 days in the eosinophilia-guided group (25% vs. 17% of control; P = .10). Future work will need to further study this trend.

Bottom line: Eosinophilia-guided treatment of COPD exacerbations reduced the cumulative exposure of steroid therapy, thereby decreasing side effects, although further study of safety profile is warranted.

Citation: Sivapalan P et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): A multicenter, randomized, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019 Aug;7(8): 699-709.

Dr. Dupuis is a hospitalist at Maine Medical Center in Portland.

Background: Corticosteroids in the setting of an acute exacerbation of improve COPD symptoms but do not affect the decline in lung function, rate of repeat exacerbations after a month, or mortality. There is concern regarding the cumulative adverse effects over time. Limited prior research suggests that a patient’s blood eosinophil count may be useful for determining the necessity of steroids for treatment of exacerbation.

The primary outcome of days alive and out of the hospital within 14 days after recruitment was similar between groups (9 days; P = .34), along with the secondary outcome of treatment failure (26%; P = .90). Importantly, the cumulative steroid dose in the eosinophilia-guided group was lower than that of the control group at days 5, 30, and 90 (P less than or equal to .0002). Additionally, the control arm had worsening of baseline diabetes within 30 days and was more likely to require antibiotics for infections within 90 days.

Although not statistically significant, a trend was noted toward increased readmission for COPD exacerbations or death at 30 days in the eosinophilia-guided group (25% vs. 17% of control; P = .10). Future work will need to further study this trend.

Bottom line: Eosinophilia-guided treatment of COPD exacerbations reduced the cumulative exposure of steroid therapy, thereby decreasing side effects, although further study of safety profile is warranted.

Citation: Sivapalan P et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): A multicenter, randomized, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019 Aug;7(8): 699-709.

Dr. Dupuis is a hospitalist at Maine Medical Center in Portland.

Cloth masks should not be considered equivalent to medical masks for the prevention of COVID-19 in clinical settings, according to an evidence review published Jan. 11 in Annals of Family Medicine.

Nevertheless, cloth masks may provide some degree of protection, filtration studies indicate. If clinicians use cloth masks, they should take into account the fit, material, and number of layers, the review authors wrote.

And if cloth masks are used as a last resort, such as during shortages of personal protective equipment (PPE), additional measures may help, such as pairing cloth masks with plastic face shields.

“We recommend frequent cloth mask changes to reduce the risk of moisture retention and washing according to hospital laundry standards to decrease the risk of ineffective cleaning,” review author Ariel Kiyomi Daoud, a researcher at the University of Colorado at Denver, Aurora, and colleagues wrote.

The investigators identified and analyzed nine studies related to cloth masks’ ability to prevent respiratory viral infections among health care clinicians. The studies generally were not specific to SARS-CoV-2. They focused on four nonrandomized trials, three laboratory efficacy studies, one single-case experiment, and one randomized controlled trial.
 

Filtration and fit

“Seven publications addressed the filtration efficacy of commercial cloth masks or materials used to create homemade masks ... in a laboratory setting,” the researchers wrote. These studies found that cloth materials prevent some level of penetration, but generally have “lesser filtration efficiency and greater variability than medical masks” do.

One study found that the materials with the greatest filtration efficacy – vacuum bags and tea towels – had low airflow, which limits their use.

Two studies found that additional layers may increase the viral filtration efficacy of cloth masks.

Several studies that assessed mask fit and airflow found that cloth masks “have worse fit and a greater level of particle leakage, compared to medical masks,” the authors reported. Most studies did not examine cloth masks’ ability to protect wearers from respiratory droplets or contact, which the World Health Organization consider the primary means of SARS-CoV-2 spread, with aerosols playing a smaller role. “Thus, we must interpret these results with caution in the context of COVID-19,” the authors wrote. “For a primary care clinician without access to medical masks, our qualitative synthesis of the literature suggests that it is better to wear a cloth mask than no mask,” as long as other protective measures are considered along with cloth mask use.

Generally consistent guidance

Agencies and researchers have shared similar recommendations about the use of cloth masks in health care settings.

“Health care workers are at the frontline and they need to be protected,” said Abrar Ahmad Chughtai, MBBS, MPH, PhD, an epidemiologist at University of New South Wales, Sydney, in an interview. “Many studies show that respirators are more effective, compared to medical masks, and medical masks are more effective, compared to cloth masks. So ideally, all frontline health care workers should use respirators. If respirators are not available, then medical masks should be used. Cloth masks are not as effective as medical masks and ideally should not be used in health care settings.”

Dr. Chughtai has written about cloth masks for protection against SARS-CoV-2 and was an investigator for a 2015 randomized trial that compared medical masks and cloth masks in health care workers.

In that trial, which was considered in the review, greater rates of influenza-like illness occurred in the cloth mask arm, compared with the medical mask arm.

“Studies show that three or more layers of cloth may reduce the spread of droplets and aerosols from the wearers,” Dr. Chughtai said. “So, cloth masks may be used in community settings to prevent spread of infections from the sick, particularly asymptomatic, people.”

In addition, cloth masks “may be used by health care workers as a last resort, if no other option is available,” he said. In that case, they should have at least three layers, fit to the face, and be washed regularly.
 

Not considered PPE

According to routine infection prevention and control recommendations for health care personnel from the Centers for Disease Control and Prevention, face masks – often referred to as surgical masks or procedure masks – should be worn by workers “at all times while they are in the healthcare facility, including in break rooms or other spaces where they might encounter coworkers.”

Unlike cloth masks, face masks offer “protection for the wearer against exposure to splashes and sprays of infectious material from others,” as well as source control, the agency says. Health care personnel “should remove their respirator or face mask, perform hand hygiene, and put on their cloth mask when leaving the facility at the end of their shift,” according to the CDC.

“Cloth masks are NOT PPE and should not be worn for the care of patients with suspected or confirmed COVID-19 or other situations where use of a respirator or face mask is recommended,” the agency notes.

When respirators or face masks are unavailable, health care personnel “might use cloth masks as a last resort for care of patients with suspected or confirmed diagnosis for which face mask or respirator use is normally recommended,” according to CDC guidance.

In that scenario, cloth masks “should ideally be used in combination with a face shield that covers the entire front (that extends to the chin or below) and sides of the face,” the CDC says.
 

Limited data for comparisons

A Dec. 29, 2020, update in Annals of Internal Medicine about masks for prevention of respiratory virus infections highlighted two recent studies in the United States that reported on mask use in health care settings. A study of more than 16,000 health care workers and first responders found that those who used an N95 or surgical mask all of the time were less likely to have SARS-CoV-2 antibodies, compared with workers who did not wear masks all the time. The adjusted odds ratio with consistent N95 use was 0.83, and the aOR with consistent surgical mask use was 0.86.

In the second study, which included more than 20,000 asymptomatic health care workers, risk for infection was reduced with any mask use versus no mask use (OR, 0.58). An N95 mask was associated with decreased risk versus a surgical mask (OR, 0.76). The studies had methodological limitations, however, and “evidence for various comparisons about mask use in health care settings and risk for SARS-CoV-2 remains insufficient,” the authors of the update wrote.

The Annals of Family Medicine review authors had no relevant disclosures. Dr. Chughtai has tested filtration of 3M masks and worked with CleanSpace Technology to research fit testing of respirators, and the 2015 randomized trial was funded by an Australian Research Council Linkage Grant with 3M as a partner on the grant. The Dec. 29, 2020, update was of a review that originally was supported by grants from the Agency for Healthcare Research Quality.

jremaly@mdedge.com

SOURCE: Daoud AK et al. Ann Fam Med. 2020 Jan 11. doi: 10.1370/afm.2640.

Cloth masks should not be considered equivalent to medical masks for the prevention of COVID-19 in clinical settings, according to an evidence review published Jan. 11 in Annals of Family Medicine.

Nevertheless, cloth masks may provide some degree of protection, filtration studies indicate. If clinicians use cloth masks, they should take into account the fit, material, and number of layers, the review authors wrote.

And if cloth masks are used as a last resort, such as during shortages of personal protective equipment (PPE), additional measures may help, such as pairing cloth masks with plastic face shields.

“We recommend frequent cloth mask changes to reduce the risk of moisture retention and washing according to hospital laundry standards to decrease the risk of ineffective cleaning,” review author Ariel Kiyomi Daoud, a researcher at the University of Colorado at Denver, Aurora, and colleagues wrote.

The investigators identified and analyzed nine studies related to cloth masks’ ability to prevent respiratory viral infections among health care clinicians. The studies generally were not specific to SARS-CoV-2. They focused on four nonrandomized trials, three laboratory efficacy studies, one single-case experiment, and one randomized controlled trial.
 

Filtration and fit

“Seven publications addressed the filtration efficacy of commercial cloth masks or materials used to create homemade masks ... in a laboratory setting,” the researchers wrote. These studies found that cloth materials prevent some level of penetration, but generally have “lesser filtration efficiency and greater variability than medical masks” do.

One study found that the materials with the greatest filtration efficacy – vacuum bags and tea towels – had low airflow, which limits their use.

Two studies found that additional layers may increase the viral filtration efficacy of cloth masks.

Several studies that assessed mask fit and airflow found that cloth masks “have worse fit and a greater level of particle leakage, compared to medical masks,” the authors reported. Most studies did not examine cloth masks’ ability to protect wearers from respiratory droplets or contact, which the World Health Organization consider the primary means of SARS-CoV-2 spread, with aerosols playing a smaller role. “Thus, we must interpret these results with caution in the context of COVID-19,” the authors wrote. “For a primary care clinician without access to medical masks, our qualitative synthesis of the literature suggests that it is better to wear a cloth mask than no mask,” as long as other protective measures are considered along with cloth mask use.

Generally consistent guidance

Agencies and researchers have shared similar recommendations about the use of cloth masks in health care settings.

“Health care workers are at the frontline and they need to be protected,” said Abrar Ahmad Chughtai, MBBS, MPH, PhD, an epidemiologist at University of New South Wales, Sydney, in an interview. “Many studies show that respirators are more effective, compared to medical masks, and medical masks are more effective, compared to cloth masks. So ideally, all frontline health care workers should use respirators. If respirators are not available, then medical masks should be used. Cloth masks are not as effective as medical masks and ideally should not be used in health care settings.”

Dr. Chughtai has written about cloth masks for protection against SARS-CoV-2 and was an investigator for a 2015 randomized trial that compared medical masks and cloth masks in health care workers.

In that trial, which was considered in the review, greater rates of influenza-like illness occurred in the cloth mask arm, compared with the medical mask arm.

“Studies show that three or more layers of cloth may reduce the spread of droplets and aerosols from the wearers,” Dr. Chughtai said. “So, cloth masks may be used in community settings to prevent spread of infections from the sick, particularly asymptomatic, people.”

In addition, cloth masks “may be used by health care workers as a last resort, if no other option is available,” he said. In that case, they should have at least three layers, fit to the face, and be washed regularly.
 

Not considered PPE

According to routine infection prevention and control recommendations for health care personnel from the Centers for Disease Control and Prevention, face masks – often referred to as surgical masks or procedure masks – should be worn by workers “at all times while they are in the healthcare facility, including in break rooms or other spaces where they might encounter coworkers.”

Unlike cloth masks, face masks offer “protection for the wearer against exposure to splashes and sprays of infectious material from others,” as well as source control, the agency says. Health care personnel “should remove their respirator or face mask, perform hand hygiene, and put on their cloth mask when leaving the facility at the end of their shift,” according to the CDC.

“Cloth masks are NOT PPE and should not be worn for the care of patients with suspected or confirmed COVID-19 or other situations where use of a respirator or face mask is recommended,” the agency notes.

When respirators or face masks are unavailable, health care personnel “might use cloth masks as a last resort for care of patients with suspected or confirmed diagnosis for which face mask or respirator use is normally recommended,” according to CDC guidance.

In that scenario, cloth masks “should ideally be used in combination with a face shield that covers the entire front (that extends to the chin or below) and sides of the face,” the CDC says.
 

Limited data for comparisons

A Dec. 29, 2020, update in Annals of Internal Medicine about masks for prevention of respiratory virus infections highlighted two recent studies in the United States that reported on mask use in health care settings. A study of more than 16,000 health care workers and first responders found that those who used an N95 or surgical mask all of the time were less likely to have SARS-CoV-2 antibodies, compared with workers who did not wear masks all the time. The adjusted odds ratio with consistent N95 use was 0.83, and the aOR with consistent surgical mask use was 0.86.

In the second study, which included more than 20,000 asymptomatic health care workers, risk for infection was reduced with any mask use versus no mask use (OR, 0.58). An N95 mask was associated with decreased risk versus a surgical mask (OR, 0.76). The studies had methodological limitations, however, and “evidence for various comparisons about mask use in health care settings and risk for SARS-CoV-2 remains insufficient,” the authors of the update wrote.

The Annals of Family Medicine review authors had no relevant disclosures. Dr. Chughtai has tested filtration of 3M masks and worked with CleanSpace Technology to research fit testing of respirators, and the 2015 randomized trial was funded by an Australian Research Council Linkage Grant with 3M as a partner on the grant. The Dec. 29, 2020, update was of a review that originally was supported by grants from the Agency for Healthcare Research Quality.

jremaly@mdedge.com

SOURCE: Daoud AK et al. Ann Fam Med. 2020 Jan 11. doi: 10.1370/afm.2640.

Cloth masks should not be considered equivalent to medical masks for the prevention of COVID-19 in clinical settings, according to an evidence review published Jan. 11 in Annals of Family Medicine.

Nevertheless, cloth masks may provide some degree of protection, filtration studies indicate. If clinicians use cloth masks, they should take into account the fit, material, and number of layers, the review authors wrote.

And if cloth masks are used as a last resort, such as during shortages of personal protective equipment (PPE), additional measures may help, such as pairing cloth masks with plastic face shields.

“We recommend frequent cloth mask changes to reduce the risk of moisture retention and washing according to hospital laundry standards to decrease the risk of ineffective cleaning,” review author Ariel Kiyomi Daoud, a researcher at the University of Colorado at Denver, Aurora, and colleagues wrote.

The investigators identified and analyzed nine studies related to cloth masks’ ability to prevent respiratory viral infections among health care clinicians. The studies generally were not specific to SARS-CoV-2. They focused on four nonrandomized trials, three laboratory efficacy studies, one single-case experiment, and one randomized controlled trial.
 

Filtration and fit

“Seven publications addressed the filtration efficacy of commercial cloth masks or materials used to create homemade masks ... in a laboratory setting,” the researchers wrote. These studies found that cloth materials prevent some level of penetration, but generally have “lesser filtration efficiency and greater variability than medical masks” do.

One study found that the materials with the greatest filtration efficacy – vacuum bags and tea towels – had low airflow, which limits their use.

Two studies found that additional layers may increase the viral filtration efficacy of cloth masks.

Several studies that assessed mask fit and airflow found that cloth masks “have worse fit and a greater level of particle leakage, compared to medical masks,” the authors reported. Most studies did not examine cloth masks’ ability to protect wearers from respiratory droplets or contact, which the World Health Organization consider the primary means of SARS-CoV-2 spread, with aerosols playing a smaller role. “Thus, we must interpret these results with caution in the context of COVID-19,” the authors wrote. “For a primary care clinician without access to medical masks, our qualitative synthesis of the literature suggests that it is better to wear a cloth mask than no mask,” as long as other protective measures are considered along with cloth mask use.

Generally consistent guidance

Agencies and researchers have shared similar recommendations about the use of cloth masks in health care settings.

“Health care workers are at the frontline and they need to be protected,” said Abrar Ahmad Chughtai, MBBS, MPH, PhD, an epidemiologist at University of New South Wales, Sydney, in an interview. “Many studies show that respirators are more effective, compared to medical masks, and medical masks are more effective, compared to cloth masks. So ideally, all frontline health care workers should use respirators. If respirators are not available, then medical masks should be used. Cloth masks are not as effective as medical masks and ideally should not be used in health care settings.”

Dr. Chughtai has written about cloth masks for protection against SARS-CoV-2 and was an investigator for a 2015 randomized trial that compared medical masks and cloth masks in health care workers.

In that trial, which was considered in the review, greater rates of influenza-like illness occurred in the cloth mask arm, compared with the medical mask arm.

“Studies show that three or more layers of cloth may reduce the spread of droplets and aerosols from the wearers,” Dr. Chughtai said. “So, cloth masks may be used in community settings to prevent spread of infections from the sick, particularly asymptomatic, people.”

In addition, cloth masks “may be used by health care workers as a last resort, if no other option is available,” he said. In that case, they should have at least three layers, fit to the face, and be washed regularly.
 

Not considered PPE

According to routine infection prevention and control recommendations for health care personnel from the Centers for Disease Control and Prevention, face masks – often referred to as surgical masks or procedure masks – should be worn by workers “at all times while they are in the healthcare facility, including in break rooms or other spaces where they might encounter coworkers.”

Unlike cloth masks, face masks offer “protection for the wearer against exposure to splashes and sprays of infectious material from others,” as well as source control, the agency says. Health care personnel “should remove their respirator or face mask, perform hand hygiene, and put on their cloth mask when leaving the facility at the end of their shift,” according to the CDC.

“Cloth masks are NOT PPE and should not be worn for the care of patients with suspected or confirmed COVID-19 or other situations where use of a respirator or face mask is recommended,” the agency notes.

When respirators or face masks are unavailable, health care personnel “might use cloth masks as a last resort for care of patients with suspected or confirmed diagnosis for which face mask or respirator use is normally recommended,” according to CDC guidance.

In that scenario, cloth masks “should ideally be used in combination with a face shield that covers the entire front (that extends to the chin or below) and sides of the face,” the CDC says.
 

Limited data for comparisons

A Dec. 29, 2020, update in Annals of Internal Medicine about masks for prevention of respiratory virus infections highlighted two recent studies in the United States that reported on mask use in health care settings. A study of more than 16,000 health care workers and first responders found that those who used an N95 or surgical mask all of the time were less likely to have SARS-CoV-2 antibodies, compared with workers who did not wear masks all the time. The adjusted odds ratio with consistent N95 use was 0.83, and the aOR with consistent surgical mask use was 0.86.

In the second study, which included more than 20,000 asymptomatic health care workers, risk for infection was reduced with any mask use versus no mask use (OR, 0.58). An N95 mask was associated with decreased risk versus a surgical mask (OR, 0.76). The studies had methodological limitations, however, and “evidence for various comparisons about mask use in health care settings and risk for SARS-CoV-2 remains insufficient,” the authors of the update wrote.

The Annals of Family Medicine review authors had no relevant disclosures. Dr. Chughtai has tested filtration of 3M masks and worked with CleanSpace Technology to research fit testing of respirators, and the 2015 randomized trial was funded by an Australian Research Council Linkage Grant with 3M as a partner on the grant. The Dec. 29, 2020, update was of a review that originally was supported by grants from the Agency for Healthcare Research Quality.

jremaly@mdedge.com

SOURCE: Daoud AK et al. Ann Fam Med. 2020 Jan 11. doi: 10.1370/afm.2640.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Among children with moderate or severe persistent asthma, monitoring daily inhaler use with sensors and a mobile application may improve asthma symptom control and caregiver quality of life, a randomized trial suggests.

But the intervention also may lead to more ED visits and increased hospitalization rates.

“We improved asthma symptom control but did not reduce health care use,” Ruchi S. Gupta, MD, MPH, and colleagues, wrote in a study published in Pediatrics.

The monitoring system alerted clinicians when a patient used a short-acting beta-agonist more than four times in a day. It could be that the “alerts enabled providers to detect asthma exacerbation virtually and refer for clinically appropriate care that included directing children to the ED,” the authors suggested. It also is possible that the intervention led caregivers to be more vigilant about symptoms and more empowered to seek care.
 

Adherence to preventive regimens

Many patients with asthma need to use preventive medications such as daily inhaled corticosteroids to control symptoms. Researchers have developed sensor-based inhaler monitoring interventions to improve treatment adherence, but the effectiveness of these interventions in improving asthma outcomes in urban and minority populations is unclear.

To assess the effectiveness of a clinically integrated, sensor-based inhaler monitoring intervention on improving asthma symptom control and related outcomes in children, Dr. Gupta, of Northwestern University and Ann & Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted a randomized, unblinded study, known as the Improving Technology-Assisted Recording of Asthma Control in Children (iTRACC) trial. They included 252 children: 127 in the control group and 125 in the intervention group.

Patients in the intervention group received Propeller Health’s Food and Drug Administration–cleared inhaler sensors for inhaled corticosteroids and short-acting beta-agonists. Caregivers could use a mobile application and clinicians could use a Web portal to track patients’ medication use. The app featured personalized insights, educational content, encouragement, surveys, and care team services.

Researchers recruited caregivers and children from five Chicago clinics for the study, which was conducted between 2016 and 2018. They included children aged 4-17 years who had a prescription for daily inhaled corticosteroids for at least 1 year before enrollment. In addition, participants had at least 1 exacerbation requiring oral corticosteroids in the previous year. They excluded children with other respiratory conditions. They also excluded participants who did not speak English because the app was available only in English.

“Sensors monitored inhaled medication use, capturing the date, time, and number of uses, and transmitted this information via Bluetooth to a paired smartphone and the provider portal in real-time,” the authors said.

Clinicians were alerted to call participants if a patient missed inhaled corticosteroid doses for 4 continuous days or used more than 4 short-acting beta-agonist doses per day. Clinicians could help guide asthma management, schedule an appointment, refill medications, and address technical difficulties with the sensors.

The intervention and control groups had similar baseline characteristics. About one-third of the patients were female, and the mean age was 9.3 years. In the control group, 28% identified as Hispanic, and 33% identified as non-Hispanic Black. In the intervention group, 40% identified as Hispanic, and 23% identified as non-Hispanic Black. About 59% reported Medicaid insurance. The intervention and control arms completed electronic surveys at 1, 3, 6, 9, and 12 months.

Average Asthma Control Test score increased from 19 to 22 in the intervention group, compared with an increase from 19 to 20 in the control group. Adjusted rates of emergency department visits and hospitalizations were greater in the intervention group (incidence rate ratios, 2.2 and 3.4, respectively). A measure of caregiver quality of life was greater in the intervention group, although the difference was not significant.

During the trial, more caregivers in the intervention group reported asthma attacks for which steroids were prescribed by a medical office (73% vs. 35%).

Some participants had to manually enter the number of daily puffs into the app because their inhalers were incompatible with the sensors. In addition, some data were missing because of incomplete or missing survey responses and sensor failure over time. “The number of intervention participants with actively transmitting sensors decreased from 102 at baseline to 56 at 12 months,” Dr. Gupta and associates noted.
 

Important area of research

“One interesting finding of this study is the increase in health care use in the intervention group to nearly twice as many emergency department (ED) visits and three times as many hospitalizations as the control group over 12 months,” Rachelle R. Ramsey, PhD, and Theresa W. Guilbert, MD, MS, of the University of Cincinnati, wrote in a related commentary. “Although it is plausible that, as the authors suggest, greater asthma knowledge and monitoring may have led to increased vigilance of asthma symptoms, it seems that this would have only led to an increase in ED visits but not hospitalizations.”

The mixture of objective electronic monitoring and subjective self-reported adherence may complicate interpretation of the results, they added.

“Overall, this article underscores the feasibility and importance of sensor-based electronic monitoring of adherence in pediatric asthma and encourages future research in this area,” Dr. Ramsey and Dr. Guilbert said.

The trial was supported by the UnitedHealth Group. Dr. Gupta has received grants from the National Institutes of Health, Rho, and other organizations, and has served as a medical consultant and adviser for a variety of companies. Dr. Ramsey is supported by the NIH. Dr. Guilbert reported fees from the American Board of Pediatrics, the Pediatric Pulmonary Subboard, and some pharmaceutical companies, plus grants from the NIH, grants and personal fees from Sanofi, Regeneron, and AstraZeneca, and royalties from UpToDate.

jremaly@mdedge.com

SOURCE: Gupta RS et al. Pediatrics. 2020 Dec 22. doi: 10.1542/peds.2020-1330.

Among children with moderate or severe persistent asthma, monitoring daily inhaler use with sensors and a mobile application may improve asthma symptom control and caregiver quality of life, a randomized trial suggests.

But the intervention also may lead to more ED visits and increased hospitalization rates.

“We improved asthma symptom control but did not reduce health care use,” Ruchi S. Gupta, MD, MPH, and colleagues, wrote in a study published in Pediatrics.

The monitoring system alerted clinicians when a patient used a short-acting beta-agonist more than four times in a day. It could be that the “alerts enabled providers to detect asthma exacerbation virtually and refer for clinically appropriate care that included directing children to the ED,” the authors suggested. It also is possible that the intervention led caregivers to be more vigilant about symptoms and more empowered to seek care.
 

Adherence to preventive regimens

Many patients with asthma need to use preventive medications such as daily inhaled corticosteroids to control symptoms. Researchers have developed sensor-based inhaler monitoring interventions to improve treatment adherence, but the effectiveness of these interventions in improving asthma outcomes in urban and minority populations is unclear.

To assess the effectiveness of a clinically integrated, sensor-based inhaler monitoring intervention on improving asthma symptom control and related outcomes in children, Dr. Gupta, of Northwestern University and Ann & Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted a randomized, unblinded study, known as the Improving Technology-Assisted Recording of Asthma Control in Children (iTRACC) trial. They included 252 children: 127 in the control group and 125 in the intervention group.

Patients in the intervention group received Propeller Health’s Food and Drug Administration–cleared inhaler sensors for inhaled corticosteroids and short-acting beta-agonists. Caregivers could use a mobile application and clinicians could use a Web portal to track patients’ medication use. The app featured personalized insights, educational content, encouragement, surveys, and care team services.

Researchers recruited caregivers and children from five Chicago clinics for the study, which was conducted between 2016 and 2018. They included children aged 4-17 years who had a prescription for daily inhaled corticosteroids for at least 1 year before enrollment. In addition, participants had at least 1 exacerbation requiring oral corticosteroids in the previous year. They excluded children with other respiratory conditions. They also excluded participants who did not speak English because the app was available only in English.

“Sensors monitored inhaled medication use, capturing the date, time, and number of uses, and transmitted this information via Bluetooth to a paired smartphone and the provider portal in real-time,” the authors said.

Clinicians were alerted to call participants if a patient missed inhaled corticosteroid doses for 4 continuous days or used more than 4 short-acting beta-agonist doses per day. Clinicians could help guide asthma management, schedule an appointment, refill medications, and address technical difficulties with the sensors.

The intervention and control groups had similar baseline characteristics. About one-third of the patients were female, and the mean age was 9.3 years. In the control group, 28% identified as Hispanic, and 33% identified as non-Hispanic Black. In the intervention group, 40% identified as Hispanic, and 23% identified as non-Hispanic Black. About 59% reported Medicaid insurance. The intervention and control arms completed electronic surveys at 1, 3, 6, 9, and 12 months.

Average Asthma Control Test score increased from 19 to 22 in the intervention group, compared with an increase from 19 to 20 in the control group. Adjusted rates of emergency department visits and hospitalizations were greater in the intervention group (incidence rate ratios, 2.2 and 3.4, respectively). A measure of caregiver quality of life was greater in the intervention group, although the difference was not significant.

During the trial, more caregivers in the intervention group reported asthma attacks for which steroids were prescribed by a medical office (73% vs. 35%).

Some participants had to manually enter the number of daily puffs into the app because their inhalers were incompatible with the sensors. In addition, some data were missing because of incomplete or missing survey responses and sensor failure over time. “The number of intervention participants with actively transmitting sensors decreased from 102 at baseline to 56 at 12 months,” Dr. Gupta and associates noted.
 

Important area of research

“One interesting finding of this study is the increase in health care use in the intervention group to nearly twice as many emergency department (ED) visits and three times as many hospitalizations as the control group over 12 months,” Rachelle R. Ramsey, PhD, and Theresa W. Guilbert, MD, MS, of the University of Cincinnati, wrote in a related commentary. “Although it is plausible that, as the authors suggest, greater asthma knowledge and monitoring may have led to increased vigilance of asthma symptoms, it seems that this would have only led to an increase in ED visits but not hospitalizations.”

The mixture of objective electronic monitoring and subjective self-reported adherence may complicate interpretation of the results, they added.

“Overall, this article underscores the feasibility and importance of sensor-based electronic monitoring of adherence in pediatric asthma and encourages future research in this area,” Dr. Ramsey and Dr. Guilbert said.

The trial was supported by the UnitedHealth Group. Dr. Gupta has received grants from the National Institutes of Health, Rho, and other organizations, and has served as a medical consultant and adviser for a variety of companies. Dr. Ramsey is supported by the NIH. Dr. Guilbert reported fees from the American Board of Pediatrics, the Pediatric Pulmonary Subboard, and some pharmaceutical companies, plus grants from the NIH, grants and personal fees from Sanofi, Regeneron, and AstraZeneca, and royalties from UpToDate.

jremaly@mdedge.com

SOURCE: Gupta RS et al. Pediatrics. 2020 Dec 22. doi: 10.1542/peds.2020-1330.

Among children with moderate or severe persistent asthma, monitoring daily inhaler use with sensors and a mobile application may improve asthma symptom control and caregiver quality of life, a randomized trial suggests.

But the intervention also may lead to more ED visits and increased hospitalization rates.

“We improved asthma symptom control but did not reduce health care use,” Ruchi S. Gupta, MD, MPH, and colleagues, wrote in a study published in Pediatrics.

The monitoring system alerted clinicians when a patient used a short-acting beta-agonist more than four times in a day. It could be that the “alerts enabled providers to detect asthma exacerbation virtually and refer for clinically appropriate care that included directing children to the ED,” the authors suggested. It also is possible that the intervention led caregivers to be more vigilant about symptoms and more empowered to seek care.
 

Adherence to preventive regimens

Many patients with asthma need to use preventive medications such as daily inhaled corticosteroids to control symptoms. Researchers have developed sensor-based inhaler monitoring interventions to improve treatment adherence, but the effectiveness of these interventions in improving asthma outcomes in urban and minority populations is unclear.

To assess the effectiveness of a clinically integrated, sensor-based inhaler monitoring intervention on improving asthma symptom control and related outcomes in children, Dr. Gupta, of Northwestern University and Ann & Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted a randomized, unblinded study, known as the Improving Technology-Assisted Recording of Asthma Control in Children (iTRACC) trial. They included 252 children: 127 in the control group and 125 in the intervention group.

Patients in the intervention group received Propeller Health’s Food and Drug Administration–cleared inhaler sensors for inhaled corticosteroids and short-acting beta-agonists. Caregivers could use a mobile application and clinicians could use a Web portal to track patients’ medication use. The app featured personalized insights, educational content, encouragement, surveys, and care team services.

Researchers recruited caregivers and children from five Chicago clinics for the study, which was conducted between 2016 and 2018. They included children aged 4-17 years who had a prescription for daily inhaled corticosteroids for at least 1 year before enrollment. In addition, participants had at least 1 exacerbation requiring oral corticosteroids in the previous year. They excluded children with other respiratory conditions. They also excluded participants who did not speak English because the app was available only in English.

“Sensors monitored inhaled medication use, capturing the date, time, and number of uses, and transmitted this information via Bluetooth to a paired smartphone and the provider portal in real-time,” the authors said.

Clinicians were alerted to call participants if a patient missed inhaled corticosteroid doses for 4 continuous days or used more than 4 short-acting beta-agonist doses per day. Clinicians could help guide asthma management, schedule an appointment, refill medications, and address technical difficulties with the sensors.

The intervention and control groups had similar baseline characteristics. About one-third of the patients were female, and the mean age was 9.3 years. In the control group, 28% identified as Hispanic, and 33% identified as non-Hispanic Black. In the intervention group, 40% identified as Hispanic, and 23% identified as non-Hispanic Black. About 59% reported Medicaid insurance. The intervention and control arms completed electronic surveys at 1, 3, 6, 9, and 12 months.

Average Asthma Control Test score increased from 19 to 22 in the intervention group, compared with an increase from 19 to 20 in the control group. Adjusted rates of emergency department visits and hospitalizations were greater in the intervention group (incidence rate ratios, 2.2 and 3.4, respectively). A measure of caregiver quality of life was greater in the intervention group, although the difference was not significant.

During the trial, more caregivers in the intervention group reported asthma attacks for which steroids were prescribed by a medical office (73% vs. 35%).

Some participants had to manually enter the number of daily puffs into the app because their inhalers were incompatible with the sensors. In addition, some data were missing because of incomplete or missing survey responses and sensor failure over time. “The number of intervention participants with actively transmitting sensors decreased from 102 at baseline to 56 at 12 months,” Dr. Gupta and associates noted.
 

Important area of research

“One interesting finding of this study is the increase in health care use in the intervention group to nearly twice as many emergency department (ED) visits and three times as many hospitalizations as the control group over 12 months,” Rachelle R. Ramsey, PhD, and Theresa W. Guilbert, MD, MS, of the University of Cincinnati, wrote in a related commentary. “Although it is plausible that, as the authors suggest, greater asthma knowledge and monitoring may have led to increased vigilance of asthma symptoms, it seems that this would have only led to an increase in ED visits but not hospitalizations.”

The mixture of objective electronic monitoring and subjective self-reported adherence may complicate interpretation of the results, they added.

“Overall, this article underscores the feasibility and importance of sensor-based electronic monitoring of adherence in pediatric asthma and encourages future research in this area,” Dr. Ramsey and Dr. Guilbert said.

The trial was supported by the UnitedHealth Group. Dr. Gupta has received grants from the National Institutes of Health, Rho, and other organizations, and has served as a medical consultant and adviser for a variety of companies. Dr. Ramsey is supported by the NIH. Dr. Guilbert reported fees from the American Board of Pediatrics, the Pediatric Pulmonary Subboard, and some pharmaceutical companies, plus grants from the NIH, grants and personal fees from Sanofi, Regeneron, and AstraZeneca, and royalties from UpToDate.

jremaly@mdedge.com

SOURCE: Gupta RS et al. Pediatrics. 2020 Dec 22. doi: 10.1542/peds.2020-1330.

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

Dr. Craig Lyerla/CDC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Craig Lyerla/CDC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Craig Lyerla/CDC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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

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

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

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

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

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

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

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

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

The strategic objectives of this partnership include the following:

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

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

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

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

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

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

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

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

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

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

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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

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

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

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

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

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

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

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

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

The strategic objectives of this partnership include the following:

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

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

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

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

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

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

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

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

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

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

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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

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

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

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

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

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

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

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

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

The strategic objectives of this partnership include the following:

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

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

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

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

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

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

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

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

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

Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.

CDC/Molly Kurnit, M.P.H.

As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.

The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
 

MMR vaccination rates begin to drop with onset of COVID-19 pandemic.

From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid. Hispanic and Asian Americans were more likely than were White and Black patients (85% and 90% vs. 69% and 67%, respectively) to have been vaccinated.

Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.

“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.

Innovative approaches are needed to encourage families to seek preventive care.

In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.

In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”

Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.

Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.

SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.

Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.

CDC/Molly Kurnit, M.P.H.

As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.

The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
 

MMR vaccination rates begin to drop with onset of COVID-19 pandemic.

From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid. Hispanic and Asian Americans were more likely than were White and Black patients (85% and 90% vs. 69% and 67%, respectively) to have been vaccinated.

Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.

“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.

Innovative approaches are needed to encourage families to seek preventive care.

In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.

In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”

Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.

Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.

SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.

Widespread use of the MMR vaccine is not only crucial for protecting the community against infectious outbreaks, but also serves as the overall pacesetter for preventive services, said Sara M. Bode, MD and colleagues at Nationwide Children’s Hospital in Columbus.

CDC/Molly Kurnit, M.P.H.

As part of a bivariate logistic regression analysis, Dr. Bode and colleagues sought to evaluate changes in measles vaccination rates across 12 clinic sites of the Nationwide Children’s Hospital pediatric primary care network in Columbus among 23,534 children aged 16 months. The study period targeted the time between April and May 2020, when clinic access and appointment attendance declined following the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, until the June-to-August 2020 time period, when clinical care was allowed to return.

The need for the study was prompted by Centers for Disease Control and Prevention reporting on a state-specific precipitous decline in MMR vaccination rates shortly after the onset of COVID-19 in May 2020. Citing the results of one study, such reductions in vaccination have raised concerns over the possibility of a measles resurgence, noted Dr. Bode and associates.
 

MMR vaccination rates begin to drop with onset of COVID-19 pandemic.

From March 2017 to March 2020, the average rate of MMR vaccination in 16-month-olds was 72%. It subsequently decreased to 67% from April to May 2020, and then dropped further to 62% during the period June to August, 2020 (P = .001). Those without insurance were less likely to be vaccinated than were those carrying private insurance or Medicaid. Hispanic and Asian Americans were more likely than were White and Black patients (85% and 90% vs. 69% and 67%, respectively) to have been vaccinated.

Among patients who had not attended a preventive care visit after 12 months of age, the proportion who received vaccines declined during the same time periods, from 10% before the pandemic to 6% at the start of the pandemic and 3% during the summer months of 2020.

“Given the baseline low vaccination rates even before the pandemic and the subsequent decline, we face a critical need to improve timely vaccination and provide catch-up opportunities” in areas with the highest incidence of COVID-19, observed Dr. Bode and colleagues.

Innovative approaches are needed to encourage families to seek preventive care.

In response, the researchers announced the implementation of new community-based vaccination approaches in Ohio, including pop-up vaccine clinics, mobile clinics, and school-based clinics to provide families, who are reluctant to visit health care facilities over COVID-19 related concerns, with safe alternatives. “We believe that it is critical to develop innovative approaches to have families return for preventive care,” they added.

In a separate interview, Herschel Lessin, MD, a private practice pediatrician in Poughkeepsie, N.Y., noted: “This study confirms the anecdotal experience of pediatricians around the country, and our greatest fear that the pandemic will interfere with herd immunity of children for vaccine-preventable illness. Although the study was of urban offices with a primarily Medicaid population, I believe the results to be very worrisome should they prove to be generalizable to the country, as a whole. The significant reduction of well-child visits due to COVID-19 (and fear of COVID-19) seriously impaired the vaccination status of a standard required vaccine in a large population. What is even more worrisome is that the rates continued to fall even after the initial closure of many offices and well into their reopening, despite concerted efforts to try to catch up these missed visits and immunizations.”

Measles is an intensely contagious illness that has not been eradicated, as evidenced by the enormous measles outbreak stemming from Disneyland in 2014-2015, and again with the possible exposure of hundreds to an infected Disneyland visitor last fall, where coverage rates were even higher than in this study, added Dr. Lessin. “This phenomenon, unless forcefully remedied, could easily result in large outbreaks of other vaccine-preventable illness besides COVID-19,” he cautioned.

Dr. Bode and colleagues as well as Dr. Lessin had no conflicts of interest and no relevant financial disclosures.

SOURCE: Bode SM et al. Pediatrics. 2021. doi: 10.1542/peds.2020-035576.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.