When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

For pediatric patients with respiratory tract infections (RTIs), immediately prescribing antibiotics may do more harm than good, based on prospective data from 436 children treated by primary care pediatricians in Spain.

In the largest trial of its kind to date, children who were immediately prescribed antibiotics showed no significant difference in symptom severity or duration from those who received a delayed prescription for antibiotics, or no prescription at all; yet those in the immediate-prescription group had a higher rate of gastrointestinal adverse events, reported lead author Gemma Mas-Dalmau, MD, of the Sant Pau Institute for Biomedical Research, Barcelona, and colleagues.

“Most RTIs are self-limiting, and antibiotics hardly alter the course of the condition, yet antibiotics are frequently prescribed for these conditions,” the investigators wrote in Pediatrics. “Antibiotic prescription for RTIs in children is especially considered to be inappropriately high.”

This clinical behavior is driven by several factors, according to Dr. Mas-Dalmau and colleagues, including limited diagnostics in primary care, pressure to meet parental expectations, and concern for possible complications if antibiotics are withheld or delayed.

In an accompanying editorial, Jeffrey S. Gerber, MD, PhD and Bonnie F. Offit, MD, of Children’s Hospital of Philadelphia, noted that “children in the United States receive more than one antibiotic prescription per year, driven largely by acute RTIs.”

Dr. Gerber and Dr. Offit noted that some RTIs are indeed caused by bacteria, and therefore benefit from antibiotics, but it’s “not always easy” to identify these cases.

“Primary care, urgent care, and emergency medicine clinicians have a hard job,” they wrote.

According to the Centers for Disease Control and Prevention, delayed prescription of antibiotics, in which a prescription is filled upon persistence or worsening of symptoms, can balance clinical caution and antibiotic stewardship.

“An example of this approach is acute otitis media, in which delayed prescribing has been shown to safely reduce antibiotic exposure,” wrote Dr. Gerber and Dr. Offit.

In a 2017 Cochrane systematic review of both adults and children with RTIs, antibiotic prescriptions, whether immediate, delayed, or not given at all, had no significant effect on most symptoms or complications. Although several randomized trials have evaluated delayed antibiotic prescriptions in children, Dr. Mas-Dalmau and colleagues described the current body of evidence as “scant.”

The present study built upon this knowledge base by prospectively following 436 children treated at 39 primary care centers in Spain from 2012 to 2016. Patients were between 2 and 14 years of age and presented for rhinosinusitis, pharyngitis, acute otitis media, or acute bronchitis. Inclusion in the study required the pediatrician to have “reasonable doubts about the need to prescribe an antibiotic.” Clinics with access to rapid streptococcal testing did not enroll patients with pharyngitis.

Patients were randomized in approximately equal groups to receive either immediate prescription of antibiotics, delayed prescription, or no prescription. In the delayed group, caregivers were advised to fill prescriptions if any of following three events occurred:

• No symptom improvement after a certain amount of days, depending on presenting complaint (acute otitis media, 4 days; pharyngitis, 7 days; acute rhinosinusitis, 15 days; acute bronchitis, 20 days).
• Temperature of at least 39° C after 24 hours, or at least 38° C but less than 39° C after 48 hours.
• Patient feeling “much worse.”

Primary outcomes were severity and duration of symptoms over 30 days, while secondary outcomes included antibiotic use over 30 days, additional unscheduled visits to primary care over 30 days, and parental satisfaction and beliefs regarding antibiotic efficacy.

In the final dataset, 148 patients received immediate antibiotic prescriptions, while 146 received delayed prescriptions, and 142 received no prescription. Rate of antibiotic use was highest in the immediate prescription group, at 96%, versus 25.3% in the delayed group and 12% among those who received no prescription upon first presentation (P < .001).

Although the mean duration of severe symptoms was longest in the delayed-prescription group, at 12.4 days, versus 10.9 days in the no-prescription group and 10.1 days in the immediate-prescription group, these differences were not statistically significant (P = .539). Median score for greatest severity of any symptom was also similar across groups. Secondary outcomes echoed this pattern, in which reconsultation rates and caregiver satisfaction were statistically similar regardless of treatment type.

In contrast, patients who received immediate antibiotic prescriptions had a significantly higher rate of gastrointestinal adverse events (8.8%) than those who received a delayed prescription (3.4%) or no prescription (2.8%; P = .037).

“Delayed antibiotic prescription is an efficacious and safe strategy for reducing inappropriate antibiotic treatment of uncomplicated RTIs in children when the doctor has reasonable doubts regarding the indication,” the investigators concluded. “[It] is therefore a useful tool for addressing the public health issue of bacterial resistance. However, no antibiotic prescription remains the recommended strategy when it is clear that antibiotics are not indicated, like in most cases of acute bronchitis.”

“These data are reassuring,” wrote Dr. Gerber and Dr. Offit; however, they went on to suggest that the data “might not substantially move the needle.”

“With rare exceptions, children with acute pharyngitis should first receive a group A streptococcal test,” they wrote. “If results are positive, all patients should get antibiotics; if results are negative, no one gets them. Acute bronchitis (whatever that is in children) is viral. Acute sinusitis with persistent symptoms (the most commonly diagnosed variety) already has a delayed option, and the current study ... was not powered for this outcome. We are left with acute otitis media, which dominated enrollment but already has an evidence-based guideline.”

Still, Dr. Gerber and Dr. Offit suggested that the findings should further encourage pediatricians to prescribe antibiotics judiciously, and when elected, to choose the shortest duration and narrowest spectrum possible.

In a joint comment, Rana El Feghaly, MD, MSCI, director of outpatient antibiotic stewardship at Children’s Mercy, Kansas City, and her colleague, Mary Anne Jackson, MD, noted that the findings are “in accordance” with the 2017 Cochrane review.

Dr. Feghaly and Dr. Jackson said that these new data provide greater support for conservative use of antibiotics, which is badly needed, considering approximately 50% of outpatient prescriptions are unnecessary or inappropriate .

Delayed antibiotic prescription is part of a multifaceted approach to the issue, they said, joining “communication skills training, antibiotic justification documentation, audit and feedback reporting with peer comparison, diagnostic stewardship, [and] the use of clinician education on practice-based guidelines.”

“Leveraging delayed antibiotic prescription may be an excellent way to combat antibiotic overuse in the outpatient setting, while avoiding provider and parental fear of the ‘no antibiotic’ approach,” Dr. Feghaly and Dr. Jackson said.

Karlyn Kinsella, MD, of Pediatric Associates of Cheshire, Conn., suggested that clinicians discuss these findings with parents who request antibiotics for “otitis, pharyngitis, bronchitis, or sinusitis.”

“We can cite this study that antibiotics have no effect on symptom duration or severity for these illnesses,” Dr. Kinsella said. “Of course, our clinical opinion in each case takes precedent.”

According to Dr. Kinsella, conversations with parents also need to cover reasonable expectations, as the study did, with clear time frames for each condition in which children should start to get better.

“I think this is really key in our anticipatory guidance so that patients know what to expect,” she said.

The study was funded by Instituto de Salud Carlos III, the European Union, and the Spanish Ministry of Health, Social Services, and Equality. The investigators and interviewees reported no conflicts of interest.

For pediatric patients with respiratory tract infections (RTIs), immediately prescribing antibiotics may do more harm than good, based on prospective data from 436 children treated by primary care pediatricians in Spain.

In the largest trial of its kind to date, children who were immediately prescribed antibiotics showed no significant difference in symptom severity or duration from those who received a delayed prescription for antibiotics, or no prescription at all; yet those in the immediate-prescription group had a higher rate of gastrointestinal adverse events, reported lead author Gemma Mas-Dalmau, MD, of the Sant Pau Institute for Biomedical Research, Barcelona, and colleagues.

“Most RTIs are self-limiting, and antibiotics hardly alter the course of the condition, yet antibiotics are frequently prescribed for these conditions,” the investigators wrote in Pediatrics. “Antibiotic prescription for RTIs in children is especially considered to be inappropriately high.”

This clinical behavior is driven by several factors, according to Dr. Mas-Dalmau and colleagues, including limited diagnostics in primary care, pressure to meet parental expectations, and concern for possible complications if antibiotics are withheld or delayed.

In an accompanying editorial, Jeffrey S. Gerber, MD, PhD and Bonnie F. Offit, MD, of Children’s Hospital of Philadelphia, noted that “children in the United States receive more than one antibiotic prescription per year, driven largely by acute RTIs.”

Dr. Gerber and Dr. Offit noted that some RTIs are indeed caused by bacteria, and therefore benefit from antibiotics, but it’s “not always easy” to identify these cases.

“Primary care, urgent care, and emergency medicine clinicians have a hard job,” they wrote.

According to the Centers for Disease Control and Prevention, delayed prescription of antibiotics, in which a prescription is filled upon persistence or worsening of symptoms, can balance clinical caution and antibiotic stewardship.

“An example of this approach is acute otitis media, in which delayed prescribing has been shown to safely reduce antibiotic exposure,” wrote Dr. Gerber and Dr. Offit.

In a 2017 Cochrane systematic review of both adults and children with RTIs, antibiotic prescriptions, whether immediate, delayed, or not given at all, had no significant effect on most symptoms or complications. Although several randomized trials have evaluated delayed antibiotic prescriptions in children, Dr. Mas-Dalmau and colleagues described the current body of evidence as “scant.”

The present study built upon this knowledge base by prospectively following 436 children treated at 39 primary care centers in Spain from 2012 to 2016. Patients were between 2 and 14 years of age and presented for rhinosinusitis, pharyngitis, acute otitis media, or acute bronchitis. Inclusion in the study required the pediatrician to have “reasonable doubts about the need to prescribe an antibiotic.” Clinics with access to rapid streptococcal testing did not enroll patients with pharyngitis.

Patients were randomized in approximately equal groups to receive either immediate prescription of antibiotics, delayed prescription, or no prescription. In the delayed group, caregivers were advised to fill prescriptions if any of following three events occurred:

• No symptom improvement after a certain amount of days, depending on presenting complaint (acute otitis media, 4 days; pharyngitis, 7 days; acute rhinosinusitis, 15 days; acute bronchitis, 20 days).
• Temperature of at least 39° C after 24 hours, or at least 38° C but less than 39° C after 48 hours.
• Patient feeling “much worse.”

Primary outcomes were severity and duration of symptoms over 30 days, while secondary outcomes included antibiotic use over 30 days, additional unscheduled visits to primary care over 30 days, and parental satisfaction and beliefs regarding antibiotic efficacy.

In the final dataset, 148 patients received immediate antibiotic prescriptions, while 146 received delayed prescriptions, and 142 received no prescription. Rate of antibiotic use was highest in the immediate prescription group, at 96%, versus 25.3% in the delayed group and 12% among those who received no prescription upon first presentation (P < .001).

Although the mean duration of severe symptoms was longest in the delayed-prescription group, at 12.4 days, versus 10.9 days in the no-prescription group and 10.1 days in the immediate-prescription group, these differences were not statistically significant (P = .539). Median score for greatest severity of any symptom was also similar across groups. Secondary outcomes echoed this pattern, in which reconsultation rates and caregiver satisfaction were statistically similar regardless of treatment type.

In contrast, patients who received immediate antibiotic prescriptions had a significantly higher rate of gastrointestinal adverse events (8.8%) than those who received a delayed prescription (3.4%) or no prescription (2.8%; P = .037).

“Delayed antibiotic prescription is an efficacious and safe strategy for reducing inappropriate antibiotic treatment of uncomplicated RTIs in children when the doctor has reasonable doubts regarding the indication,” the investigators concluded. “[It] is therefore a useful tool for addressing the public health issue of bacterial resistance. However, no antibiotic prescription remains the recommended strategy when it is clear that antibiotics are not indicated, like in most cases of acute bronchitis.”

“These data are reassuring,” wrote Dr. Gerber and Dr. Offit; however, they went on to suggest that the data “might not substantially move the needle.”

“With rare exceptions, children with acute pharyngitis should first receive a group A streptococcal test,” they wrote. “If results are positive, all patients should get antibiotics; if results are negative, no one gets them. Acute bronchitis (whatever that is in children) is viral. Acute sinusitis with persistent symptoms (the most commonly diagnosed variety) already has a delayed option, and the current study ... was not powered for this outcome. We are left with acute otitis media, which dominated enrollment but already has an evidence-based guideline.”

Still, Dr. Gerber and Dr. Offit suggested that the findings should further encourage pediatricians to prescribe antibiotics judiciously, and when elected, to choose the shortest duration and narrowest spectrum possible.

In a joint comment, Rana El Feghaly, MD, MSCI, director of outpatient antibiotic stewardship at Children’s Mercy, Kansas City, and her colleague, Mary Anne Jackson, MD, noted that the findings are “in accordance” with the 2017 Cochrane review.

Dr. Feghaly and Dr. Jackson said that these new data provide greater support for conservative use of antibiotics, which is badly needed, considering approximately 50% of outpatient prescriptions are unnecessary or inappropriate .

Delayed antibiotic prescription is part of a multifaceted approach to the issue, they said, joining “communication skills training, antibiotic justification documentation, audit and feedback reporting with peer comparison, diagnostic stewardship, [and] the use of clinician education on practice-based guidelines.”

“Leveraging delayed antibiotic prescription may be an excellent way to combat antibiotic overuse in the outpatient setting, while avoiding provider and parental fear of the ‘no antibiotic’ approach,” Dr. Feghaly and Dr. Jackson said.

Karlyn Kinsella, MD, of Pediatric Associates of Cheshire, Conn., suggested that clinicians discuss these findings with parents who request antibiotics for “otitis, pharyngitis, bronchitis, or sinusitis.”

“We can cite this study that antibiotics have no effect on symptom duration or severity for these illnesses,” Dr. Kinsella said. “Of course, our clinical opinion in each case takes precedent.”

According to Dr. Kinsella, conversations with parents also need to cover reasonable expectations, as the study did, with clear time frames for each condition in which children should start to get better.

“I think this is really key in our anticipatory guidance so that patients know what to expect,” she said.

The study was funded by Instituto de Salud Carlos III, the European Union, and the Spanish Ministry of Health, Social Services, and Equality. The investigators and interviewees reported no conflicts of interest.

For pediatric patients with respiratory tract infections (RTIs), immediately prescribing antibiotics may do more harm than good, based on prospective data from 436 children treated by primary care pediatricians in Spain.

In the largest trial of its kind to date, children who were immediately prescribed antibiotics showed no significant difference in symptom severity or duration from those who received a delayed prescription for antibiotics, or no prescription at all; yet those in the immediate-prescription group had a higher rate of gastrointestinal adverse events, reported lead author Gemma Mas-Dalmau, MD, of the Sant Pau Institute for Biomedical Research, Barcelona, and colleagues.

“Most RTIs are self-limiting, and antibiotics hardly alter the course of the condition, yet antibiotics are frequently prescribed for these conditions,” the investigators wrote in Pediatrics. “Antibiotic prescription for RTIs in children is especially considered to be inappropriately high.”

This clinical behavior is driven by several factors, according to Dr. Mas-Dalmau and colleagues, including limited diagnostics in primary care, pressure to meet parental expectations, and concern for possible complications if antibiotics are withheld or delayed.

In an accompanying editorial, Jeffrey S. Gerber, MD, PhD and Bonnie F. Offit, MD, of Children’s Hospital of Philadelphia, noted that “children in the United States receive more than one antibiotic prescription per year, driven largely by acute RTIs.”

Dr. Gerber and Dr. Offit noted that some RTIs are indeed caused by bacteria, and therefore benefit from antibiotics, but it’s “not always easy” to identify these cases.

“Primary care, urgent care, and emergency medicine clinicians have a hard job,” they wrote.

According to the Centers for Disease Control and Prevention, delayed prescription of antibiotics, in which a prescription is filled upon persistence or worsening of symptoms, can balance clinical caution and antibiotic stewardship.

“An example of this approach is acute otitis media, in which delayed prescribing has been shown to safely reduce antibiotic exposure,” wrote Dr. Gerber and Dr. Offit.

In a 2017 Cochrane systematic review of both adults and children with RTIs, antibiotic prescriptions, whether immediate, delayed, or not given at all, had no significant effect on most symptoms or complications. Although several randomized trials have evaluated delayed antibiotic prescriptions in children, Dr. Mas-Dalmau and colleagues described the current body of evidence as “scant.”

The present study built upon this knowledge base by prospectively following 436 children treated at 39 primary care centers in Spain from 2012 to 2016. Patients were between 2 and 14 years of age and presented for rhinosinusitis, pharyngitis, acute otitis media, or acute bronchitis. Inclusion in the study required the pediatrician to have “reasonable doubts about the need to prescribe an antibiotic.” Clinics with access to rapid streptococcal testing did not enroll patients with pharyngitis.

Patients were randomized in approximately equal groups to receive either immediate prescription of antibiotics, delayed prescription, or no prescription. In the delayed group, caregivers were advised to fill prescriptions if any of following three events occurred:

• No symptom improvement after a certain amount of days, depending on presenting complaint (acute otitis media, 4 days; pharyngitis, 7 days; acute rhinosinusitis, 15 days; acute bronchitis, 20 days).
• Temperature of at least 39° C after 24 hours, or at least 38° C but less than 39° C after 48 hours.
• Patient feeling “much worse.”

Primary outcomes were severity and duration of symptoms over 30 days, while secondary outcomes included antibiotic use over 30 days, additional unscheduled visits to primary care over 30 days, and parental satisfaction and beliefs regarding antibiotic efficacy.

In the final dataset, 148 patients received immediate antibiotic prescriptions, while 146 received delayed prescriptions, and 142 received no prescription. Rate of antibiotic use was highest in the immediate prescription group, at 96%, versus 25.3% in the delayed group and 12% among those who received no prescription upon first presentation (P < .001).

Although the mean duration of severe symptoms was longest in the delayed-prescription group, at 12.4 days, versus 10.9 days in the no-prescription group and 10.1 days in the immediate-prescription group, these differences were not statistically significant (P = .539). Median score for greatest severity of any symptom was also similar across groups. Secondary outcomes echoed this pattern, in which reconsultation rates and caregiver satisfaction were statistically similar regardless of treatment type.

In contrast, patients who received immediate antibiotic prescriptions had a significantly higher rate of gastrointestinal adverse events (8.8%) than those who received a delayed prescription (3.4%) or no prescription (2.8%; P = .037).

“Delayed antibiotic prescription is an efficacious and safe strategy for reducing inappropriate antibiotic treatment of uncomplicated RTIs in children when the doctor has reasonable doubts regarding the indication,” the investigators concluded. “[It] is therefore a useful tool for addressing the public health issue of bacterial resistance. However, no antibiotic prescription remains the recommended strategy when it is clear that antibiotics are not indicated, like in most cases of acute bronchitis.”

“These data are reassuring,” wrote Dr. Gerber and Dr. Offit; however, they went on to suggest that the data “might not substantially move the needle.”

“With rare exceptions, children with acute pharyngitis should first receive a group A streptococcal test,” they wrote. “If results are positive, all patients should get antibiotics; if results are negative, no one gets them. Acute bronchitis (whatever that is in children) is viral. Acute sinusitis with persistent symptoms (the most commonly diagnosed variety) already has a delayed option, and the current study ... was not powered for this outcome. We are left with acute otitis media, which dominated enrollment but already has an evidence-based guideline.”

Still, Dr. Gerber and Dr. Offit suggested that the findings should further encourage pediatricians to prescribe antibiotics judiciously, and when elected, to choose the shortest duration and narrowest spectrum possible.

In a joint comment, Rana El Feghaly, MD, MSCI, director of outpatient antibiotic stewardship at Children’s Mercy, Kansas City, and her colleague, Mary Anne Jackson, MD, noted that the findings are “in accordance” with the 2017 Cochrane review.

Dr. Feghaly and Dr. Jackson said that these new data provide greater support for conservative use of antibiotics, which is badly needed, considering approximately 50% of outpatient prescriptions are unnecessary or inappropriate .

Delayed antibiotic prescription is part of a multifaceted approach to the issue, they said, joining “communication skills training, antibiotic justification documentation, audit and feedback reporting with peer comparison, diagnostic stewardship, [and] the use of clinician education on practice-based guidelines.”

“Leveraging delayed antibiotic prescription may be an excellent way to combat antibiotic overuse in the outpatient setting, while avoiding provider and parental fear of the ‘no antibiotic’ approach,” Dr. Feghaly and Dr. Jackson said.

Karlyn Kinsella, MD, of Pediatric Associates of Cheshire, Conn., suggested that clinicians discuss these findings with parents who request antibiotics for “otitis, pharyngitis, bronchitis, or sinusitis.”

“We can cite this study that antibiotics have no effect on symptom duration or severity for these illnesses,” Dr. Kinsella said. “Of course, our clinical opinion in each case takes precedent.”

According to Dr. Kinsella, conversations with parents also need to cover reasonable expectations, as the study did, with clear time frames for each condition in which children should start to get better.

“I think this is really key in our anticipatory guidance so that patients know what to expect,” she said.

The study was funded by Instituto de Salud Carlos III, the European Union, and the Spanish Ministry of Health, Social Services, and Equality. The investigators and interviewees reported no conflicts of interest.

A Zika virus vaccine candidate prompted antibody responses in 80% of individuals who received two doses in a phase 1 study.

©Aunt_Spray/Thinkstock

Although Zika cases have declined in recent years, “geographic expansion of the Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” wrote Nadine C. Salisch, PhD, of Janssen Vaccines and Prevention, Leiden, the Netherlands, and colleagues in a paper published in Annals of Internal Medicine.

No vaccine against Zika is yet available, although more than 10 candidates have been studied in preclinical trials to date, they said.

The researchers randomized 100 healthy adult volunteers to an experimental Zika vaccine candidate known as Ad26.ZIKV.001 in either one-dose or two-dose regimens of 5x10¹⁰ viral particles (low dose) or 1x10¹¹ viral particles (high dose) or placebo. Approximately half (55%) of the participants were women, and 72% were White.

Approximately 80% of patients in both two-dose groups showed antibody responses for a year after vaccination. Geometric mean titers (GMTs) reached peak of 823.4 in the low-dose/low-dose group and 961.5 in the high-dose/high-dose group. At day 365, the GMTs for these groups were 68.7 and 87.0, respectively.

A single high-dose vaccine achieved a similar level of neutralizing antibody titers, but lower peak neutralizing responses than the two-dose strategies, the researchers noted.

Most of the reported adverse events were mild to moderate, and short lived; the most common were injection site pain or tenderness, headache, and fatigue, the researchers said. After the first vaccination, 75% of participants in the low-dose groups, 88% of participants in high-dose groups, and 45% of participants receiving placebo reported local adverse events. In addition, 73%, 83%, and 40% of the participants in the low-dose, high-dose, and placebo groups, respectively, reported systemic adverse events. Reports were similar after the second vaccination. Two serious adverse events not related to vaccination were reported; one case of right lower lobe pneumonia and one case of incomplete spontaneous abortion.

The researchers also explored protective efficacy through a nonlethal mouse challenge model. “Transfer of 6 mg of IgG from Ad26.ZIKV.001 vaccines conferred complete protection from viremia in most recipient animals, with statistically significantly decreased breakthrough rates and cumulative viral loads per group compared with placebo,” they said.

The study findings were limited by the inability to assess safety and immunogenicity in an endemic area, the researchers noted. However, “Ad26.ZIKV.001 induces potent ZIKV-specific neutralizing responses with durability of at least 1 year, which supports further clinical development if an unmet medical need reemerges,” they said. “In addition, these data underscore the performance of the Ad26 vaccine platform, which Janssen is using for different infectious diseases, including COVID-19,” they noted.
 

Ad26 vector platform shows consistency

“Development of the investigational Janssen Zika vaccine candidate was initiated in 2015, and while the incidence of Zika virus has declined since the 2015-2016 outbreak, spread of the ‘carrier’ Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” lead author Dr. Salisch said in an interview. For this reason, researchers say the vaccine warrants further development should the need reemerge, she said.

“Our research has found that while a single higher-dose regimen had lower peak neutralizing responses than a two-dose regimen, it achieved a similar level of neutralizing antibody responses at 1 year, an encouraging finding that shows our vaccine may be a useful tool to curb Zika epidemics,” Dr. Salisch noted. “Previous experience with the Ad26 vector platform across our investigational vaccine programs have yielded similarly promising results, most recently with our investigational Janssen COVID-19 vaccine program, for which phase 3 data show a single-dose vaccine met all primary and key secondary endpoints,” she said.

“The biggest barrier [to further development of the candidate vaccine] is one that we actually consider ourselves fortunate to have: The very low incidence of reported Zika cases currently reported worldwide,” Dr. Salisch said. “However, the current Zika case rate can change at any time, and in the event the situation demands it, we are open to alternative regulatory pathways to help us glean the necessary insights on vaccine safety and efficacy to further advance the development of this candidate,” she emphasized.

As for additional research, “there are still questions surrounding Zika transmission and the pathomechanism of congenital Zika syndrome,” said Dr. Salisch. “Our hope is that a correlate of protection against Zika disease, and in particular against congenital Zika syndrome, can be identified,” she said.  

Consider pregnant women in next phase of research

“A major hurdle in ZIKV vaccine development is the inability to conduct large efficacy studies in the absence of a current outbreak,” Ann Chahroudi, MD, of Emory University, Atlanta, and Sallie Permar, MD, of Weill Cornell Medicine, New York, wrote in an accompanying editorial.

The current study provided some efficacy data using a mouse model, but “these data are obviously not conclusive for human protection,” they said.

“A further challenge for ZIKV vaccine efficacy trials will be to demonstrate fetal protection from [congenital Zika syndrome] after adult immunization. There should be a clear plan to readily deploy phase 3 trials for the most promising vaccines to emerge from phase 1 and 2 in the event of an outbreak, as was implemented for Ebola, including infant follow-up,” they emphasized.

The editorialists noted that the study did not include pregnant women, who represent a major target for immunization, but they said that vaccination of pregnant women against other neonatal pathogens such as influenza and tetanus has been effective. “Candidate ZIKV vaccines proven safe in phase 1 trials should immediately be assessed for safety and efficacy in pregnant women,” they said. Although Zika infections are not at epidemic levels currently, resurgence remains a possibility and the coronavirus pandemic “has taught us that preparedness for emerging infections is crucial,” they said.
 

Zika vaccine research is a challenge worth pursuing

“It is important to continue Zika vaccine research because of the unpredictable nature of that infection,” Kevin Ault, MD, of the University of Kansas, Kansas City, said in an interview. “Several times Zika has gained a foothold in unexposed and vulnerable populations,” Dr. Ault said.  “Additionally, there are some data about using this vector during pregnancy, and eventually this vaccine may prevent the birth defects associated with Zika infections during pregnancy, he noted.

Dr. Ault said he was not surprised by the study findings. “This is a promising early phase vaccine candidate, and this adenovirus vector has been used in other similar trials,” he said. Potential barriers to vaccine development include the challenge of conducting late phase clinical trials in pregnant women, he noted. “The relevant endpoint is going to be clinical disease, and one of the most critical populations is pregnant women,” he said. In addition, “later phase 3 trials would be conducted in a population where there is an ongoing Zika outbreak,” Dr. Ault emphasized.   

The study was supported by Janssen Vaccines and Infectious Diseases.

Dr. Chahroudi had no financial conflicts to disclose. Dr. Permar disclosed grants from Merck and Moderna unrelated to the current study. Dr. Ault had no relevant financial conflicts to disclose; he has served as an adviser to the Centers for Disease Control and Prevention, the World Medical Association, the National Vaccine Program Office, and the National Institute for Allergy and Infectious Diseases. He is a fellow of the Infectious Disease Society of American and a fellow of ACOG. 

A Zika virus vaccine candidate prompted antibody responses in 80% of individuals who received two doses in a phase 1 study.

©Aunt_Spray/Thinkstock

Although Zika cases have declined in recent years, “geographic expansion of the Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” wrote Nadine C. Salisch, PhD, of Janssen Vaccines and Prevention, Leiden, the Netherlands, and colleagues in a paper published in Annals of Internal Medicine.

No vaccine against Zika is yet available, although more than 10 candidates have been studied in preclinical trials to date, they said.

The researchers randomized 100 healthy adult volunteers to an experimental Zika vaccine candidate known as Ad26.ZIKV.001 in either one-dose or two-dose regimens of 5x10¹⁰ viral particles (low dose) or 1x10¹¹ viral particles (high dose) or placebo. Approximately half (55%) of the participants were women, and 72% were White.

Approximately 80% of patients in both two-dose groups showed antibody responses for a year after vaccination. Geometric mean titers (GMTs) reached peak of 823.4 in the low-dose/low-dose group and 961.5 in the high-dose/high-dose group. At day 365, the GMTs for these groups were 68.7 and 87.0, respectively.

A single high-dose vaccine achieved a similar level of neutralizing antibody titers, but lower peak neutralizing responses than the two-dose strategies, the researchers noted.

Most of the reported adverse events were mild to moderate, and short lived; the most common were injection site pain or tenderness, headache, and fatigue, the researchers said. After the first vaccination, 75% of participants in the low-dose groups, 88% of participants in high-dose groups, and 45% of participants receiving placebo reported local adverse events. In addition, 73%, 83%, and 40% of the participants in the low-dose, high-dose, and placebo groups, respectively, reported systemic adverse events. Reports were similar after the second vaccination. Two serious adverse events not related to vaccination were reported; one case of right lower lobe pneumonia and one case of incomplete spontaneous abortion.

The researchers also explored protective efficacy through a nonlethal mouse challenge model. “Transfer of 6 mg of IgG from Ad26.ZIKV.001 vaccines conferred complete protection from viremia in most recipient animals, with statistically significantly decreased breakthrough rates and cumulative viral loads per group compared with placebo,” they said.

The study findings were limited by the inability to assess safety and immunogenicity in an endemic area, the researchers noted. However, “Ad26.ZIKV.001 induces potent ZIKV-specific neutralizing responses with durability of at least 1 year, which supports further clinical development if an unmet medical need reemerges,” they said. “In addition, these data underscore the performance of the Ad26 vaccine platform, which Janssen is using for different infectious diseases, including COVID-19,” they noted.
 

Ad26 vector platform shows consistency

“Development of the investigational Janssen Zika vaccine candidate was initiated in 2015, and while the incidence of Zika virus has declined since the 2015-2016 outbreak, spread of the ‘carrier’ Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” lead author Dr. Salisch said in an interview. For this reason, researchers say the vaccine warrants further development should the need reemerge, she said.

“Our research has found that while a single higher-dose regimen had lower peak neutralizing responses than a two-dose regimen, it achieved a similar level of neutralizing antibody responses at 1 year, an encouraging finding that shows our vaccine may be a useful tool to curb Zika epidemics,” Dr. Salisch noted. “Previous experience with the Ad26 vector platform across our investigational vaccine programs have yielded similarly promising results, most recently with our investigational Janssen COVID-19 vaccine program, for which phase 3 data show a single-dose vaccine met all primary and key secondary endpoints,” she said.

“The biggest barrier [to further development of the candidate vaccine] is one that we actually consider ourselves fortunate to have: The very low incidence of reported Zika cases currently reported worldwide,” Dr. Salisch said. “However, the current Zika case rate can change at any time, and in the event the situation demands it, we are open to alternative regulatory pathways to help us glean the necessary insights on vaccine safety and efficacy to further advance the development of this candidate,” she emphasized.

As for additional research, “there are still questions surrounding Zika transmission and the pathomechanism of congenital Zika syndrome,” said Dr. Salisch. “Our hope is that a correlate of protection against Zika disease, and in particular against congenital Zika syndrome, can be identified,” she said.  

Consider pregnant women in next phase of research

“A major hurdle in ZIKV vaccine development is the inability to conduct large efficacy studies in the absence of a current outbreak,” Ann Chahroudi, MD, of Emory University, Atlanta, and Sallie Permar, MD, of Weill Cornell Medicine, New York, wrote in an accompanying editorial.

The current study provided some efficacy data using a mouse model, but “these data are obviously not conclusive for human protection,” they said.

“A further challenge for ZIKV vaccine efficacy trials will be to demonstrate fetal protection from [congenital Zika syndrome] after adult immunization. There should be a clear plan to readily deploy phase 3 trials for the most promising vaccines to emerge from phase 1 and 2 in the event of an outbreak, as was implemented for Ebola, including infant follow-up,” they emphasized.

The editorialists noted that the study did not include pregnant women, who represent a major target for immunization, but they said that vaccination of pregnant women against other neonatal pathogens such as influenza and tetanus has been effective. “Candidate ZIKV vaccines proven safe in phase 1 trials should immediately be assessed for safety and efficacy in pregnant women,” they said. Although Zika infections are not at epidemic levels currently, resurgence remains a possibility and the coronavirus pandemic “has taught us that preparedness for emerging infections is crucial,” they said.
 

Zika vaccine research is a challenge worth pursuing

“It is important to continue Zika vaccine research because of the unpredictable nature of that infection,” Kevin Ault, MD, of the University of Kansas, Kansas City, said in an interview. “Several times Zika has gained a foothold in unexposed and vulnerable populations,” Dr. Ault said.  “Additionally, there are some data about using this vector during pregnancy, and eventually this vaccine may prevent the birth defects associated with Zika infections during pregnancy, he noted.

Dr. Ault said he was not surprised by the study findings. “This is a promising early phase vaccine candidate, and this adenovirus vector has been used in other similar trials,” he said. Potential barriers to vaccine development include the challenge of conducting late phase clinical trials in pregnant women, he noted. “The relevant endpoint is going to be clinical disease, and one of the most critical populations is pregnant women,” he said. In addition, “later phase 3 trials would be conducted in a population where there is an ongoing Zika outbreak,” Dr. Ault emphasized.   

The study was supported by Janssen Vaccines and Infectious Diseases.

Dr. Chahroudi had no financial conflicts to disclose. Dr. Permar disclosed grants from Merck and Moderna unrelated to the current study. Dr. Ault had no relevant financial conflicts to disclose; he has served as an adviser to the Centers for Disease Control and Prevention, the World Medical Association, the National Vaccine Program Office, and the National Institute for Allergy and Infectious Diseases. He is a fellow of the Infectious Disease Society of American and a fellow of ACOG. 

A Zika virus vaccine candidate prompted antibody responses in 80% of individuals who received two doses in a phase 1 study.

©Aunt_Spray/Thinkstock

Although Zika cases have declined in recent years, “geographic expansion of the Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” wrote Nadine C. Salisch, PhD, of Janssen Vaccines and Prevention, Leiden, the Netherlands, and colleagues in a paper published in Annals of Internal Medicine.

No vaccine against Zika is yet available, although more than 10 candidates have been studied in preclinical trials to date, they said.

The researchers randomized 100 healthy adult volunteers to an experimental Zika vaccine candidate known as Ad26.ZIKV.001 in either one-dose or two-dose regimens of 5x10¹⁰ viral particles (low dose) or 1x10¹¹ viral particles (high dose) or placebo. Approximately half (55%) of the participants were women, and 72% were White.

Approximately 80% of patients in both two-dose groups showed antibody responses for a year after vaccination. Geometric mean titers (GMTs) reached peak of 823.4 in the low-dose/low-dose group and 961.5 in the high-dose/high-dose group. At day 365, the GMTs for these groups were 68.7 and 87.0, respectively.

A single high-dose vaccine achieved a similar level of neutralizing antibody titers, but lower peak neutralizing responses than the two-dose strategies, the researchers noted.

Most of the reported adverse events were mild to moderate, and short lived; the most common were injection site pain or tenderness, headache, and fatigue, the researchers said. After the first vaccination, 75% of participants in the low-dose groups, 88% of participants in high-dose groups, and 45% of participants receiving placebo reported local adverse events. In addition, 73%, 83%, and 40% of the participants in the low-dose, high-dose, and placebo groups, respectively, reported systemic adverse events. Reports were similar after the second vaccination. Two serious adverse events not related to vaccination were reported; one case of right lower lobe pneumonia and one case of incomplete spontaneous abortion.

The researchers also explored protective efficacy through a nonlethal mouse challenge model. “Transfer of 6 mg of IgG from Ad26.ZIKV.001 vaccines conferred complete protection from viremia in most recipient animals, with statistically significantly decreased breakthrough rates and cumulative viral loads per group compared with placebo,” they said.

The study findings were limited by the inability to assess safety and immunogenicity in an endemic area, the researchers noted. However, “Ad26.ZIKV.001 induces potent ZIKV-specific neutralizing responses with durability of at least 1 year, which supports further clinical development if an unmet medical need reemerges,” they said. “In addition, these data underscore the performance of the Ad26 vaccine platform, which Janssen is using for different infectious diseases, including COVID-19,” they noted.
 

Ad26 vector platform shows consistency

“Development of the investigational Janssen Zika vaccine candidate was initiated in 2015, and while the incidence of Zika virus has declined since the 2015-2016 outbreak, spread of the ‘carrier’ Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics,” lead author Dr. Salisch said in an interview. For this reason, researchers say the vaccine warrants further development should the need reemerge, she said.

“Our research has found that while a single higher-dose regimen had lower peak neutralizing responses than a two-dose regimen, it achieved a similar level of neutralizing antibody responses at 1 year, an encouraging finding that shows our vaccine may be a useful tool to curb Zika epidemics,” Dr. Salisch noted. “Previous experience with the Ad26 vector platform across our investigational vaccine programs have yielded similarly promising results, most recently with our investigational Janssen COVID-19 vaccine program, for which phase 3 data show a single-dose vaccine met all primary and key secondary endpoints,” she said.

“The biggest barrier [to further development of the candidate vaccine] is one that we actually consider ourselves fortunate to have: The very low incidence of reported Zika cases currently reported worldwide,” Dr. Salisch said. “However, the current Zika case rate can change at any time, and in the event the situation demands it, we are open to alternative regulatory pathways to help us glean the necessary insights on vaccine safety and efficacy to further advance the development of this candidate,” she emphasized.

As for additional research, “there are still questions surrounding Zika transmission and the pathomechanism of congenital Zika syndrome,” said Dr. Salisch. “Our hope is that a correlate of protection against Zika disease, and in particular against congenital Zika syndrome, can be identified,” she said.  

Consider pregnant women in next phase of research

“A major hurdle in ZIKV vaccine development is the inability to conduct large efficacy studies in the absence of a current outbreak,” Ann Chahroudi, MD, of Emory University, Atlanta, and Sallie Permar, MD, of Weill Cornell Medicine, New York, wrote in an accompanying editorial.

The current study provided some efficacy data using a mouse model, but “these data are obviously not conclusive for human protection,” they said.

“A further challenge for ZIKV vaccine efficacy trials will be to demonstrate fetal protection from [congenital Zika syndrome] after adult immunization. There should be a clear plan to readily deploy phase 3 trials for the most promising vaccines to emerge from phase 1 and 2 in the event of an outbreak, as was implemented for Ebola, including infant follow-up,” they emphasized.

The editorialists noted that the study did not include pregnant women, who represent a major target for immunization, but they said that vaccination of pregnant women against other neonatal pathogens such as influenza and tetanus has been effective. “Candidate ZIKV vaccines proven safe in phase 1 trials should immediately be assessed for safety and efficacy in pregnant women,” they said. Although Zika infections are not at epidemic levels currently, resurgence remains a possibility and the coronavirus pandemic “has taught us that preparedness for emerging infections is crucial,” they said.
 

Zika vaccine research is a challenge worth pursuing

“It is important to continue Zika vaccine research because of the unpredictable nature of that infection,” Kevin Ault, MD, of the University of Kansas, Kansas City, said in an interview. “Several times Zika has gained a foothold in unexposed and vulnerable populations,” Dr. Ault said.  “Additionally, there are some data about using this vector during pregnancy, and eventually this vaccine may prevent the birth defects associated with Zika infections during pregnancy, he noted.

Dr. Ault said he was not surprised by the study findings. “This is a promising early phase vaccine candidate, and this adenovirus vector has been used in other similar trials,” he said. Potential barriers to vaccine development include the challenge of conducting late phase clinical trials in pregnant women, he noted. “The relevant endpoint is going to be clinical disease, and one of the most critical populations is pregnant women,” he said. In addition, “later phase 3 trials would be conducted in a population where there is an ongoing Zika outbreak,” Dr. Ault emphasized.   

The study was supported by Janssen Vaccines and Infectious Diseases.

Dr. Chahroudi had no financial conflicts to disclose. Dr. Permar disclosed grants from Merck and Moderna unrelated to the current study. Dr. Ault had no relevant financial conflicts to disclose; he has served as an adviser to the Centers for Disease Control and Prevention, the World Medical Association, the National Vaccine Program Office, and the National Institute for Allergy and Infectious Diseases. He is a fellow of the Infectious Disease Society of American and a fellow of ACOG. 

It is well established that LGBTQ individuals experience more health disparities compared with their cisgender, heterosexual counterparts. In general, LGBTQ adolescents and young adults have higher levels of depression, suicide attempts, and substance use than those of their heterosexual peers. However, a key protective factor is family acceptance and support. By encouraging families to modify and change behaviors that are experienced by their LGBTQ children as rejecting and to engage in supportive and affirming behaviors, providers can help families to decrease risk and promote healthy outcomes for LGBTQ youth and young adults.

The Family Acceptance Project

The Family Acceptance Project

The Family Acceptance Project

To reduce risk, pediatricians should ask LGBTQ patients about family rejecting behaviors and help parents and caregivers to identify and understand the effect of such behaviors to reduce health risks and conflict that can lead to running away, expulsion, and removal from the home. Even decreasing rejecting behaviors to moderate levels can significantly improve negative outcomes.⁵

Caitlin Ryan, PhD, and her team also identified and measured more than 50 family accepting behaviors that help protect against risk and promote well-being. They found that young adults who experience high levels of family acceptance during adolescence report significantly higher levels of self-esteem, social support, and general health with much lower levels of depression, suicidality, and substance abuse.⁷ Family accepting and supportive behaviors include talking with the child about their LGBTQ identity; advocating for their LGBTQ child when others mistreat them; requiring other family members to treat their LGBTQ child with respect; and supporting their child’s gender identity.⁵ FAP has developed an evidence-informed family support model and multilingual educational resources for families, providers, youth and religious leaders to decrease rejection and increase family support. These are available in print copies and for download at familyproject.sfsu.edu.

In addition, Dr. Ryan and colleagues^1,4,8 recommend the following guidance for providers:

• Ask LGBTQ adolescents about family reactions to their sexual orientation, gender identity, and expression, and refer to LGBTQ community support programs and for supportive counseling, as needed.
• Identify LGBTQ community support programs and online resources to educate parents about how to help their children. Parents need culturally relevant peer support to help decrease rejection and increase family support.
• Advise parents that negative reactions to their adolescent’s LGBTQ identity may negatively impact their child’s health and mental health while supportive and affirming reactions promote well-being.
• Advise parents and caregivers to modify and change family rejecting behaviors that increase their child’s risk for suicide, depression, substance abuse ,and risky sexual behaviors.
• Expand anticipatory guidance to include information on the need for support and the link between family rejection and negative health problems.
• Provide guidance on sexual orientation and gender identity as part of normative child development during well-baby and early childhood care.
• Use FAP’s multilingual family education booklets and Healthy Futures poster series in family and patient education and provide these materials in clinical and community settings. FAP’s Healthy Futures posters include a poster guidance, a version on family acceptance, a version on family rejection and a family acceptance version for conservative families and settings. They are available in camera-ready art in four sizes in English and Spanish and are forthcoming in five Asian languages: familyproject.sfsu.edu/poster.

Dr. Lawlis is assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures.
 

Resources

• Family Acceptance Project – consultation and training; evidence-based educational materials for families, providers, religious leaders and youth.

• PFLAG – peer support for parents and friends with LGBTQ children in all states and several other countries.
 

References

1. Ryan C. Generating a revolution in prevention, wellness & care for LGBT children & youth. Temple Political & Civil Rights Law Review. 2014;23(2):331-44.

2. Ryan C. Healthy Futures Poster Series – Family Accepting & Rejecting Behaviors That Impact LGBTQ Children’s Health & Well-Being. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2019.

3. Ryan C. Family Acceptance Project: Culturally grounded framework for supporting LGBTQ children and youth. J Am Acad Child Adolesc Psychiatr. 2019;58(10):S58-9.

4. Ryan C et al. Family rejection as a predictor of negative health outcomes in White and Latino lesbian, gay, and bisexual young adults. Pediatrics. 2009;123(1):346-52.

5. Ryan C. Supportive families, healthy children: Helping families with lesbian, gay, bisexual & transgender children. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2009.

6. Ryan C et al. Parent-initiated sexual orientation change efforts with LGBT adolescents: Implications for young adult mental health and adjustment. J Homosexuality. 2020;67(2):159-73.

7. Ryan C et al. Family acceptance in adolescence and the health of LGBT young adults. J Child Adolesc Psychiatr Nursing. 2010;23(4):205-13. 8. Substance Abuse and Mental Health Services Administration. A Practitioner’s Guide: Helping Families to Support Their LGBT Children. In: Administration SAaMhS, ed. Vol PEP14-LGBTKIDS. Rockville, MD: HHS Publication; 2014.

It is well established that LGBTQ individuals experience more health disparities compared with their cisgender, heterosexual counterparts. In general, LGBTQ adolescents and young adults have higher levels of depression, suicide attempts, and substance use than those of their heterosexual peers. However, a key protective factor is family acceptance and support. By encouraging families to modify and change behaviors that are experienced by their LGBTQ children as rejecting and to engage in supportive and affirming behaviors, providers can help families to decrease risk and promote healthy outcomes for LGBTQ youth and young adults.

The Family Acceptance Project

The Family Acceptance Project

The Family Acceptance Project

To reduce risk, pediatricians should ask LGBTQ patients about family rejecting behaviors and help parents and caregivers to identify and understand the effect of such behaviors to reduce health risks and conflict that can lead to running away, expulsion, and removal from the home. Even decreasing rejecting behaviors to moderate levels can significantly improve negative outcomes.⁵

Caitlin Ryan, PhD, and her team also identified and measured more than 50 family accepting behaviors that help protect against risk and promote well-being. They found that young adults who experience high levels of family acceptance during adolescence report significantly higher levels of self-esteem, social support, and general health with much lower levels of depression, suicidality, and substance abuse.⁷ Family accepting and supportive behaviors include talking with the child about their LGBTQ identity; advocating for their LGBTQ child when others mistreat them; requiring other family members to treat their LGBTQ child with respect; and supporting their child’s gender identity.⁵ FAP has developed an evidence-informed family support model and multilingual educational resources for families, providers, youth and religious leaders to decrease rejection and increase family support. These are available in print copies and for download at familyproject.sfsu.edu.

In addition, Dr. Ryan and colleagues^1,4,8 recommend the following guidance for providers:

• Ask LGBTQ adolescents about family reactions to their sexual orientation, gender identity, and expression, and refer to LGBTQ community support programs and for supportive counseling, as needed.
• Identify LGBTQ community support programs and online resources to educate parents about how to help their children. Parents need culturally relevant peer support to help decrease rejection and increase family support.
• Advise parents that negative reactions to their adolescent’s LGBTQ identity may negatively impact their child’s health and mental health while supportive and affirming reactions promote well-being.
• Advise parents and caregivers to modify and change family rejecting behaviors that increase their child’s risk for suicide, depression, substance abuse ,and risky sexual behaviors.
• Expand anticipatory guidance to include information on the need for support and the link between family rejection and negative health problems.
• Provide guidance on sexual orientation and gender identity as part of normative child development during well-baby and early childhood care.
• Use FAP’s multilingual family education booklets and Healthy Futures poster series in family and patient education and provide these materials in clinical and community settings. FAP’s Healthy Futures posters include a poster guidance, a version on family acceptance, a version on family rejection and a family acceptance version for conservative families and settings. They are available in camera-ready art in four sizes in English and Spanish and are forthcoming in five Asian languages: familyproject.sfsu.edu/poster.

Dr. Lawlis is assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures.
 

Resources

• Family Acceptance Project – consultation and training; evidence-based educational materials for families, providers, religious leaders and youth.

• PFLAG – peer support for parents and friends with LGBTQ children in all states and several other countries.
 

References

1. Ryan C. Generating a revolution in prevention, wellness & care for LGBT children & youth. Temple Political & Civil Rights Law Review. 2014;23(2):331-44.

2. Ryan C. Healthy Futures Poster Series – Family Accepting & Rejecting Behaviors That Impact LGBTQ Children’s Health & Well-Being. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2019.

3. Ryan C. Family Acceptance Project: Culturally grounded framework for supporting LGBTQ children and youth. J Am Acad Child Adolesc Psychiatr. 2019;58(10):S58-9.

4. Ryan C et al. Family rejection as a predictor of negative health outcomes in White and Latino lesbian, gay, and bisexual young adults. Pediatrics. 2009;123(1):346-52.

5. Ryan C. Supportive families, healthy children: Helping families with lesbian, gay, bisexual & transgender children. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2009.

6. Ryan C et al. Parent-initiated sexual orientation change efforts with LGBT adolescents: Implications for young adult mental health and adjustment. J Homosexuality. 2020;67(2):159-73.

7. Ryan C et al. Family acceptance in adolescence and the health of LGBT young adults. J Child Adolesc Psychiatr Nursing. 2010;23(4):205-13. 8. Substance Abuse and Mental Health Services Administration. A Practitioner’s Guide: Helping Families to Support Their LGBT Children. In: Administration SAaMhS, ed. Vol PEP14-LGBTKIDS. Rockville, MD: HHS Publication; 2014.

It is well established that LGBTQ individuals experience more health disparities compared with their cisgender, heterosexual counterparts. In general, LGBTQ adolescents and young adults have higher levels of depression, suicide attempts, and substance use than those of their heterosexual peers. However, a key protective factor is family acceptance and support. By encouraging families to modify and change behaviors that are experienced by their LGBTQ children as rejecting and to engage in supportive and affirming behaviors, providers can help families to decrease risk and promote healthy outcomes for LGBTQ youth and young adults.

The Family Acceptance Project

The Family Acceptance Project

The Family Acceptance Project

To reduce risk, pediatricians should ask LGBTQ patients about family rejecting behaviors and help parents and caregivers to identify and understand the effect of such behaviors to reduce health risks and conflict that can lead to running away, expulsion, and removal from the home. Even decreasing rejecting behaviors to moderate levels can significantly improve negative outcomes.⁵

Caitlin Ryan, PhD, and her team also identified and measured more than 50 family accepting behaviors that help protect against risk and promote well-being. They found that young adults who experience high levels of family acceptance during adolescence report significantly higher levels of self-esteem, social support, and general health with much lower levels of depression, suicidality, and substance abuse.⁷ Family accepting and supportive behaviors include talking with the child about their LGBTQ identity; advocating for their LGBTQ child when others mistreat them; requiring other family members to treat their LGBTQ child with respect; and supporting their child’s gender identity.⁵ FAP has developed an evidence-informed family support model and multilingual educational resources for families, providers, youth and religious leaders to decrease rejection and increase family support. These are available in print copies and for download at familyproject.sfsu.edu.

In addition, Dr. Ryan and colleagues^1,4,8 recommend the following guidance for providers:

• Ask LGBTQ adolescents about family reactions to their sexual orientation, gender identity, and expression, and refer to LGBTQ community support programs and for supportive counseling, as needed.
• Identify LGBTQ community support programs and online resources to educate parents about how to help their children. Parents need culturally relevant peer support to help decrease rejection and increase family support.
• Advise parents that negative reactions to their adolescent’s LGBTQ identity may negatively impact their child’s health and mental health while supportive and affirming reactions promote well-being.
• Advise parents and caregivers to modify and change family rejecting behaviors that increase their child’s risk for suicide, depression, substance abuse ,and risky sexual behaviors.
• Expand anticipatory guidance to include information on the need for support and the link between family rejection and negative health problems.
• Provide guidance on sexual orientation and gender identity as part of normative child development during well-baby and early childhood care.
• Use FAP’s multilingual family education booklets and Healthy Futures poster series in family and patient education and provide these materials in clinical and community settings. FAP’s Healthy Futures posters include a poster guidance, a version on family acceptance, a version on family rejection and a family acceptance version for conservative families and settings. They are available in camera-ready art in four sizes in English and Spanish and are forthcoming in five Asian languages: familyproject.sfsu.edu/poster.

Dr. Lawlis is assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures.
 

Resources

• Family Acceptance Project – consultation and training; evidence-based educational materials for families, providers, religious leaders and youth.

• PFLAG – peer support for parents and friends with LGBTQ children in all states and several other countries.
 

References

1. Ryan C. Generating a revolution in prevention, wellness & care for LGBT children & youth. Temple Political & Civil Rights Law Review. 2014;23(2):331-44.

2. Ryan C. Healthy Futures Poster Series – Family Accepting & Rejecting Behaviors That Impact LGBTQ Children’s Health & Well-Being. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2019.

3. Ryan C. Family Acceptance Project: Culturally grounded framework for supporting LGBTQ children and youth. J Am Acad Child Adolesc Psychiatr. 2019;58(10):S58-9.

4. Ryan C et al. Family rejection as a predictor of negative health outcomes in White and Latino lesbian, gay, and bisexual young adults. Pediatrics. 2009;123(1):346-52.

5. Ryan C. Supportive families, healthy children: Helping families with lesbian, gay, bisexual & transgender children. In: Family Acceptance Project Marian Wright Edelman Institute SFSU, ed. San Francisco, CA2009.

6. Ryan C et al. Parent-initiated sexual orientation change efforts with LGBT adolescents: Implications for young adult mental health and adjustment. J Homosexuality. 2020;67(2):159-73.

7. Ryan C et al. Family acceptance in adolescence and the health of LGBT young adults. J Child Adolesc Psychiatr Nursing. 2010;23(4):205-13. 8. Substance Abuse and Mental Health Services Administration. A Practitioner’s Guide: Helping Families to Support Their LGBT Children. In: Administration SAaMhS, ed. Vol PEP14-LGBTKIDS. Rockville, MD: HHS Publication; 2014.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

“What kind of parent are you? Why don’t you straighten him out!” rants the woman being jostled in the grocery store by your patient. “Easy for you to say,” thinks your patient’s frazzled and now insulted parent.

Blaming the parent for an out-of-control child has historically been a common refrain of neighbors, relatives, and even strangers. But considering child behavior as resulting from both parent and child factors is central to the current transactional model of child development. In this model, mismatch of the parent’s and child’s response patterns is seen as setting them up for chronically rough interactions around parent requests/demands. A parent escalating quickly from a briefly stated request to a tirade may create more tension paired with an anxious child who takes time to act, for example. Once a parent (and ultimately the child) recognize patterns in what leads to conflict, they can become more proactive in predicting and negotiating these situations. Ross Greene, PhD, explains this in his book “The Explosive Child,” calling the method Collaborative Problem Solving (now Collaborative & Proactive Solutions or CPS).

While there are general principles parents can use to modify what they consider “mis”behaviors, these methods often do not account for the “missing” skills of the individual child (and parent) predisposing to those “mis”takes. Thinking of misbehaviors as being because of a kind of “learning disability” in the child rather than willful defiance can help cool off interactions by instead focusing on solving the underlying problem.

What kinds of “gaps in skills” set a child up for defiant or explosive reactions? If you think about what features of children, and parent-child relationships are associated with harmonious interactions this becomes evident. Children over 3 who are patient, easygoing, flexible or adaptable, and good at transitions and problem-solving can delay gratification and tolerate frustration, regulate their emotions, explain their desires, and multitask. They are better at reading the parent’s needs and intent and tend to interpret requests as positive or at least neutral and are more likely to comply with parent requests without a fuss.

What? No kid you know is great at all of these? These skills, at best variable, develop with maturation. Some are part of temperament, considered normal variation in personality. For example, so-called difficult temperament includes low adaptability, high-intensity reactions, low regularity, tendency to withdraw, and negative mood. But in the extreme, weaknesses in these skills are core to or comorbid with diagnosable mental health disorders. Defiance and irritable responses are criteria for oppositional defiant disorder (ODD), and less severe categories called aggressive/oppositional problem or variation. ODD is often found in children diagnosed with ADHD (65%), Tourette’s (15%-65%), depression (70% if severe), bipolar disorder (85%), OCD, anxiety (45%), autism, and language-processing disorders (55%), or trauma. These conditions variably include lower emotion regulation, poorer executive functioning including poor task shifting and impulsivity, obsessiveness, lower expressive and receptive communication skills, and less social awareness that facilitates harmonious problem solving.

The basic components of the CPS approach to addressing parent-child conflict sound intuitive but defining them clearly is important when families are stuck. There are three levels of plans. If the problem is an emergency or nonnegotiable, e.g., child hurting the cat, it may call for Plan A – parent-imposed solutions, sometimes with consequences or rewards. As children mature, Plan A should be used less frequently. If solving the problem is not a top life priority, Plan C – postponing action, may be appropriate. Plan C highlights that behavior change is a long-term project and “picking your fights” is important.

The biggest value of CPS for resolving behavior problems comes from intermediate Plan B. In Plan B the first step of problem solving for parents facing child defiance or upset is to empathically and nonjudgmentally figure out the child’s concern. Questions such as “I’ve noticed that when I remind you that it is trash night you start shouting. What’s up with that?” then patiently asking about the who, what, where, and when of their concern and checking to ensure understanding. Specificity is important as well as noting times when the reaction occurs or not.

Once the child’s concern is clear, e.g., feeling that the demand to take out the trash now interrupts his games during the only time his friends are online, the parents should echo the child’s concern then express their own concern about how the behavior is affecting them and others, potentially including the child; e.g., mother is so upset by the shouting that she can’t sleep, and worry that the child is not learning responsibility, and then checking for child understanding.

Finally, the parent invites brainstorming for a solution that addresses both of their concerns, first asking the child for suggestions, aiming for a strategy that is realistic and specific. Children reluctant to make suggestions may need more time and the parent may be wondering “if there is a way for both of our concerns to be addressed.” Solutions chosen are then tried for several weeks, success tracked, and needed changes negotiated.

For parents, using a collaborative approach to dealing with their child’s behavior takes skills they may not have at the moment, or ever. Especially under the stresses of COVID-19 lockdown, taking a step back from an encounter to consider lack of a skill to turn off the video game promptly when a Zoom meeting starts is challenging. Parents may also genetically share the child’s predisposing ADHD, anxiety, depression, OCD, or weakness in communication or social sensitivity.

Sometimes part of the solution for a conflict is for the parent to reduce expectations. This requires understanding and accepting the child’s cognitive or emotional limitations. Reducing expectations is ideally done before a request rather than by giving in after it, which reinforces protests. For authoritarian adults rigid in their belief that parents are boss, changing expectations can be tough and can feel like losing control or failing as a leader. One benefit of working with a CPS coach (see livesinthebalance.org or ThinkKids.org) is to help parents identify their own limitations.

Predicting the types of demands that tend to create conflict, such as to act immediately or be flexible about options, allows parents to prioritize those requests for calmer moments or when there is more time for discussion. Reviewing a checklist of common gaps in skills and creating a list of expectations and triggers that are difficult for the child helps the family be more proactive in developing solutions. Authors of CPS have validated a checklist of skill deficits, “Thinking Skills Inventory,” to facilitate detection of gaps that is educational plus useful for planning specific solutions.

CPS has been shown in randomized trials with both parent groups and in home counseling to be as effective as Parent Training in reducing oppositional behavior and reducing maternal stress, with effects lasting even longer.

CPS Plan B notably has no reward or punishment components as it assumes the child wants to behave acceptably but can’t; has the “will but not the skill.” When skill deficits are worked around the child is satisfied with complying and pleasing the parents. The idea of a “function” of the misbehavior for the child of gaining attention or reward or avoiding consequences is reinterpreted as serving to communicate the problem the child is having trouble in meeting the parent’s demand. When the parent understands and helps the child solve the problem his/her misbehavior is no longer needed. A benefit of the communication and mutual problem solving used in CPS is on not only improving behavior but empowering parents and children, building parental empathy, and improving child skills.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].

Reference

Greene RW et al. A transactional model of oppositional behavior: Underpinnings of the Collaborative Problem Solving approach. J Psychosom Res. 2003;55(1):67-75.

“What kind of parent are you? Why don’t you straighten him out!” rants the woman being jostled in the grocery store by your patient. “Easy for you to say,” thinks your patient’s frazzled and now insulted parent.

Blaming the parent for an out-of-control child has historically been a common refrain of neighbors, relatives, and even strangers. But considering child behavior as resulting from both parent and child factors is central to the current transactional model of child development. In this model, mismatch of the parent’s and child’s response patterns is seen as setting them up for chronically rough interactions around parent requests/demands. A parent escalating quickly from a briefly stated request to a tirade may create more tension paired with an anxious child who takes time to act, for example. Once a parent (and ultimately the child) recognize patterns in what leads to conflict, they can become more proactive in predicting and negotiating these situations. Ross Greene, PhD, explains this in his book “The Explosive Child,” calling the method Collaborative Problem Solving (now Collaborative & Proactive Solutions or CPS).

While there are general principles parents can use to modify what they consider “mis”behaviors, these methods often do not account for the “missing” skills of the individual child (and parent) predisposing to those “mis”takes. Thinking of misbehaviors as being because of a kind of “learning disability” in the child rather than willful defiance can help cool off interactions by instead focusing on solving the underlying problem.

What kinds of “gaps in skills” set a child up for defiant or explosive reactions? If you think about what features of children, and parent-child relationships are associated with harmonious interactions this becomes evident. Children over 3 who are patient, easygoing, flexible or adaptable, and good at transitions and problem-solving can delay gratification and tolerate frustration, regulate their emotions, explain their desires, and multitask. They are better at reading the parent’s needs and intent and tend to interpret requests as positive or at least neutral and are more likely to comply with parent requests without a fuss.

What? No kid you know is great at all of these? These skills, at best variable, develop with maturation. Some are part of temperament, considered normal variation in personality. For example, so-called difficult temperament includes low adaptability, high-intensity reactions, low regularity, tendency to withdraw, and negative mood. But in the extreme, weaknesses in these skills are core to or comorbid with diagnosable mental health disorders. Defiance and irritable responses are criteria for oppositional defiant disorder (ODD), and less severe categories called aggressive/oppositional problem or variation. ODD is often found in children diagnosed with ADHD (65%), Tourette’s (15%-65%), depression (70% if severe), bipolar disorder (85%), OCD, anxiety (45%), autism, and language-processing disorders (55%), or trauma. These conditions variably include lower emotion regulation, poorer executive functioning including poor task shifting and impulsivity, obsessiveness, lower expressive and receptive communication skills, and less social awareness that facilitates harmonious problem solving.

The basic components of the CPS approach to addressing parent-child conflict sound intuitive but defining them clearly is important when families are stuck. There are three levels of plans. If the problem is an emergency or nonnegotiable, e.g., child hurting the cat, it may call for Plan A – parent-imposed solutions, sometimes with consequences or rewards. As children mature, Plan A should be used less frequently. If solving the problem is not a top life priority, Plan C – postponing action, may be appropriate. Plan C highlights that behavior change is a long-term project and “picking your fights” is important.

The biggest value of CPS for resolving behavior problems comes from intermediate Plan B. In Plan B the first step of problem solving for parents facing child defiance or upset is to empathically and nonjudgmentally figure out the child’s concern. Questions such as “I’ve noticed that when I remind you that it is trash night you start shouting. What’s up with that?” then patiently asking about the who, what, where, and when of their concern and checking to ensure understanding. Specificity is important as well as noting times when the reaction occurs or not.

Once the child’s concern is clear, e.g., feeling that the demand to take out the trash now interrupts his games during the only time his friends are online, the parents should echo the child’s concern then express their own concern about how the behavior is affecting them and others, potentially including the child; e.g., mother is so upset by the shouting that she can’t sleep, and worry that the child is not learning responsibility, and then checking for child understanding.

Finally, the parent invites brainstorming for a solution that addresses both of their concerns, first asking the child for suggestions, aiming for a strategy that is realistic and specific. Children reluctant to make suggestions may need more time and the parent may be wondering “if there is a way for both of our concerns to be addressed.” Solutions chosen are then tried for several weeks, success tracked, and needed changes negotiated.

For parents, using a collaborative approach to dealing with their child’s behavior takes skills they may not have at the moment, or ever. Especially under the stresses of COVID-19 lockdown, taking a step back from an encounter to consider lack of a skill to turn off the video game promptly when a Zoom meeting starts is challenging. Parents may also genetically share the child’s predisposing ADHD, anxiety, depression, OCD, or weakness in communication or social sensitivity.

Sometimes part of the solution for a conflict is for the parent to reduce expectations. This requires understanding and accepting the child’s cognitive or emotional limitations. Reducing expectations is ideally done before a request rather than by giving in after it, which reinforces protests. For authoritarian adults rigid in their belief that parents are boss, changing expectations can be tough and can feel like losing control or failing as a leader. One benefit of working with a CPS coach (see livesinthebalance.org or ThinkKids.org) is to help parents identify their own limitations.

Predicting the types of demands that tend to create conflict, such as to act immediately or be flexible about options, allows parents to prioritize those requests for calmer moments or when there is more time for discussion. Reviewing a checklist of common gaps in skills and creating a list of expectations and triggers that are difficult for the child helps the family be more proactive in developing solutions. Authors of CPS have validated a checklist of skill deficits, “Thinking Skills Inventory,” to facilitate detection of gaps that is educational plus useful for planning specific solutions.

CPS has been shown in randomized trials with both parent groups and in home counseling to be as effective as Parent Training in reducing oppositional behavior and reducing maternal stress, with effects lasting even longer.

CPS Plan B notably has no reward or punishment components as it assumes the child wants to behave acceptably but can’t; has the “will but not the skill.” When skill deficits are worked around the child is satisfied with complying and pleasing the parents. The idea of a “function” of the misbehavior for the child of gaining attention or reward or avoiding consequences is reinterpreted as serving to communicate the problem the child is having trouble in meeting the parent’s demand. When the parent understands and helps the child solve the problem his/her misbehavior is no longer needed. A benefit of the communication and mutual problem solving used in CPS is on not only improving behavior but empowering parents and children, building parental empathy, and improving child skills.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].

Reference

Greene RW et al. A transactional model of oppositional behavior: Underpinnings of the Collaborative Problem Solving approach. J Psychosom Res. 2003;55(1):67-75.

“What kind of parent are you? Why don’t you straighten him out!” rants the woman being jostled in the grocery store by your patient. “Easy for you to say,” thinks your patient’s frazzled and now insulted parent.

Blaming the parent for an out-of-control child has historically been a common refrain of neighbors, relatives, and even strangers. But considering child behavior as resulting from both parent and child factors is central to the current transactional model of child development. In this model, mismatch of the parent’s and child’s response patterns is seen as setting them up for chronically rough interactions around parent requests/demands. A parent escalating quickly from a briefly stated request to a tirade may create more tension paired with an anxious child who takes time to act, for example. Once a parent (and ultimately the child) recognize patterns in what leads to conflict, they can become more proactive in predicting and negotiating these situations. Ross Greene, PhD, explains this in his book “The Explosive Child,” calling the method Collaborative Problem Solving (now Collaborative & Proactive Solutions or CPS).

While there are general principles parents can use to modify what they consider “mis”behaviors, these methods often do not account for the “missing” skills of the individual child (and parent) predisposing to those “mis”takes. Thinking of misbehaviors as being because of a kind of “learning disability” in the child rather than willful defiance can help cool off interactions by instead focusing on solving the underlying problem.

What kinds of “gaps in skills” set a child up for defiant or explosive reactions? If you think about what features of children, and parent-child relationships are associated with harmonious interactions this becomes evident. Children over 3 who are patient, easygoing, flexible or adaptable, and good at transitions and problem-solving can delay gratification and tolerate frustration, regulate their emotions, explain their desires, and multitask. They are better at reading the parent’s needs and intent and tend to interpret requests as positive or at least neutral and are more likely to comply with parent requests without a fuss.

What? No kid you know is great at all of these? These skills, at best variable, develop with maturation. Some are part of temperament, considered normal variation in personality. For example, so-called difficult temperament includes low adaptability, high-intensity reactions, low regularity, tendency to withdraw, and negative mood. But in the extreme, weaknesses in these skills are core to or comorbid with diagnosable mental health disorders. Defiance and irritable responses are criteria for oppositional defiant disorder (ODD), and less severe categories called aggressive/oppositional problem or variation. ODD is often found in children diagnosed with ADHD (65%), Tourette’s (15%-65%), depression (70% if severe), bipolar disorder (85%), OCD, anxiety (45%), autism, and language-processing disorders (55%), or trauma. These conditions variably include lower emotion regulation, poorer executive functioning including poor task shifting and impulsivity, obsessiveness, lower expressive and receptive communication skills, and less social awareness that facilitates harmonious problem solving.

The basic components of the CPS approach to addressing parent-child conflict sound intuitive but defining them clearly is important when families are stuck. There are three levels of plans. If the problem is an emergency or nonnegotiable, e.g., child hurting the cat, it may call for Plan A – parent-imposed solutions, sometimes with consequences or rewards. As children mature, Plan A should be used less frequently. If solving the problem is not a top life priority, Plan C – postponing action, may be appropriate. Plan C highlights that behavior change is a long-term project and “picking your fights” is important.

The biggest value of CPS for resolving behavior problems comes from intermediate Plan B. In Plan B the first step of problem solving for parents facing child defiance or upset is to empathically and nonjudgmentally figure out the child’s concern. Questions such as “I’ve noticed that when I remind you that it is trash night you start shouting. What’s up with that?” then patiently asking about the who, what, where, and when of their concern and checking to ensure understanding. Specificity is important as well as noting times when the reaction occurs or not.

Once the child’s concern is clear, e.g., feeling that the demand to take out the trash now interrupts his games during the only time his friends are online, the parents should echo the child’s concern then express their own concern about how the behavior is affecting them and others, potentially including the child; e.g., mother is so upset by the shouting that she can’t sleep, and worry that the child is not learning responsibility, and then checking for child understanding.

Finally, the parent invites brainstorming for a solution that addresses both of their concerns, first asking the child for suggestions, aiming for a strategy that is realistic and specific. Children reluctant to make suggestions may need more time and the parent may be wondering “if there is a way for both of our concerns to be addressed.” Solutions chosen are then tried for several weeks, success tracked, and needed changes negotiated.

For parents, using a collaborative approach to dealing with their child’s behavior takes skills they may not have at the moment, or ever. Especially under the stresses of COVID-19 lockdown, taking a step back from an encounter to consider lack of a skill to turn off the video game promptly when a Zoom meeting starts is challenging. Parents may also genetically share the child’s predisposing ADHD, anxiety, depression, OCD, or weakness in communication or social sensitivity.

Sometimes part of the solution for a conflict is for the parent to reduce expectations. This requires understanding and accepting the child’s cognitive or emotional limitations. Reducing expectations is ideally done before a request rather than by giving in after it, which reinforces protests. For authoritarian adults rigid in their belief that parents are boss, changing expectations can be tough and can feel like losing control or failing as a leader. One benefit of working with a CPS coach (see livesinthebalance.org or ThinkKids.org) is to help parents identify their own limitations.

Predicting the types of demands that tend to create conflict, such as to act immediately or be flexible about options, allows parents to prioritize those requests for calmer moments or when there is more time for discussion. Reviewing a checklist of common gaps in skills and creating a list of expectations and triggers that are difficult for the child helps the family be more proactive in developing solutions. Authors of CPS have validated a checklist of skill deficits, “Thinking Skills Inventory,” to facilitate detection of gaps that is educational plus useful for planning specific solutions.

CPS has been shown in randomized trials with both parent groups and in home counseling to be as effective as Parent Training in reducing oppositional behavior and reducing maternal stress, with effects lasting even longer.

CPS Plan B notably has no reward or punishment components as it assumes the child wants to behave acceptably but can’t; has the “will but not the skill.” When skill deficits are worked around the child is satisfied with complying and pleasing the parents. The idea of a “function” of the misbehavior for the child of gaining attention or reward or avoiding consequences is reinterpreted as serving to communicate the problem the child is having trouble in meeting the parent’s demand. When the parent understands and helps the child solve the problem his/her misbehavior is no longer needed. A benefit of the communication and mutual problem solving used in CPS is on not only improving behavior but empowering parents and children, building parental empathy, and improving child skills.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She has no other relevant disclosures. Dr. Howard’s contribution to this publication is as a paid expert to MDedge News. Email her at [email protected].

Reference

Greene RW et al. A transactional model of oppositional behavior: Underpinnings of the Collaborative Problem Solving approach. J Psychosom Res. 2003;55(1):67-75.

Heart failure (HF) hospitalizations and readmissions are on the rise in the United States, reversing a multiyear downward trend, a new national cohort study shows.

Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.

Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.

Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).

“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.

Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.

“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.

Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”

As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.

In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.

The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.

“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.

The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.

A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.

The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.

“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.

One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.

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

Heart failure (HF) hospitalizations and readmissions are on the rise in the United States, reversing a multiyear downward trend, a new national cohort study shows.

Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.

Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.

Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).

“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.

Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.

“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.

Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”

As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.

In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.

The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.

“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.

The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.

A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.

The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.

“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.

One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.

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

Heart failure (HF) hospitalizations and readmissions are on the rise in the United States, reversing a multiyear downward trend, a new national cohort study shows.

Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.

Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.

Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).

“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.

Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.

“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.

Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”

As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.

In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.

The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.

“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.

The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.

A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.

The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.

“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.

One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.

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

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

In this column in September 2020, you read how common respiratory viruses’ seasons are usually so predictable, each virus arising, peaking, and then dying out in a predictable virus parade (Figure 1).¹ Well, the predictable virus seasonal pattern was lost in 2020. Since March of 2020, it is striking how little activity was detected for the usual seasonal viruses in Kansas City after mid-March 2020 (Figure 2).² So, my concern in September 2020 for possible rampant coinfections of common viruses with or in tandem with SARS-CoV-2 did not pan out. That said, the seasons for non–SARS-CoV-2 viruses did change; I just didn’t expect they would nearly disappear.

Dr. Christoper Harrison

The 2020 winter-spring. In the first quarter (the last part of the overall 2019-2020 respiratory viral season), viral detections were chugging along as usual up to mid-March (Figure 2); influenza, respiratory syncytial virus (RSV), and rhinovirus were the big players.

Influenza. In most years, influenza type B leads off and is quickly replaced by type A only to see B reemerge to end influenza season in March-April. In early 2020, both influenza type A and influenza type B cocirculated nearly equally, but both dropped like a rock in mid-March (Figure 2).² Neither type has been seen since with the exception of sporadic detections – perhaps being false positives.

RSV. In the usual year in temperate mid-latitudes of the northern hemisphere, RSV season usually starts in early December, peaks in January-March, and declines gradually until the end of RSV season in April (Figure 1). In southern latitudes, RSV is less seasonal, being present most of the year, but peaking in “winter” months.³ But in 2020, RSV also disappeared in mid-March and has yet to reappear.

Other viruses. Small bumps in detection of parainfluenza of varying types usually frame influenza season, one B bump in early autumn and another in April-May. In most years, human metapneumovirus is detected on and off, with worse years at 2- to 3-year intervals. Adenovirus occurs year-round with bumps as children get back to school in autumn. Yet in 2020, almost no parainfluenza, adenovirus, common coronaviruses, or human metapneumovirus were detected in either spring or autumn. This was supposed to be a banner summer-autumn for EV-D68 – but almost none was detected. Interestingly, the cockroach of viruses, rhinovirus, has its usual year (Figure 2).

Dr. Christopher Harrison

What happened? Intense social mitigation interventions, including social distancing and closing daycares and schools, were likely major factors.⁴ For influenza, vaccine may have helped but uptake was not remarkably better than most prior years. There may have been “viral competition,”where a new or highly transmissible virus outcompetes less-transmissible viruses with lower affinity for respiratory receptors.^5,6 Note that SARS-CoV-2 has very high affinity for the ACE2 receptor and has been highly prevalent. So, SARS-CoV-2 could fit the theoretical mold for a virus that outcompetes others.

Does it matter for the future? Blunted 2019-2020 and nearly absent 2020-2021 respiratory virus season may have set the stage for intense 2021-2022 rebounds for the non–SARS-CoV-2 viruses. We now have two whole and one partial birth cohort with no experience with seasonal respiratory viruses, including EV-D68 (and nonrespiratory viruses too – like norovirus, parechovirus, and other enteroviruses). Most viruses have particularly bad seasons every 2-3 years, thought to be caused by increasing accumulation of susceptible individuals in consecutive birth cohorts until a critical mass of susceptible individuals is achieved. The excess in susceptible individuals means that each contagious case is likely to expose one or more susceptible individuals, enhancing transmission and infection numbers in an ever-extending ripple effect. We have never had this many children aged under 3 years with no immunity to influenza, RSV, etc. So unless mother nature is kind (when has that happened lately?), expect rebound years for seasonal viruses as children return to daycare/schools and as social mitigation becomes less necessary in the waning pandemic.

Options? If you ramped up telehealth visits for the pandemic, that may be a saving grace, i.e., more efficiency so more “visits” can be completed per day, and less potential contact in reception rooms between well and ill children. And if there was ever a time to really intensify efforts to immunize all our pediatric patients, the next two seasons are just that. Adding a bit of a warning to families with young children also seems warranted. If they understand that, while 2021-2022 will be better for SARS-CoV-2, it is likely going to be worse for the other viruses.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

References

1. Harrison CJ. 2020-2021 respiratory viral season: Onset, presentations, and testing likely to differ in pandemic, Pediatric News: September 17, 2020.

2. Olsen SJ et al. MMWR Morb Mortal Wkly Rep. 2020;69:1305-9.

3. Respiratory Syncytial Virus Surveillance. http://www.floridahealth.gov/diseases-and-conditions/respiratory-syncytial-virus/_documents/2021-w4-rsv-summary.pdf

4. Baker RE et al. PNAS. Dec 2020 117;(48):30547-53.

5. Sema Nickbakhsh et al. PNAS. Dec 2019 116;(52):27142-50.

6. Kirsten M et al. PNAS. Mar 2020 117;(13):6987.

In this column in September 2020, you read how common respiratory viruses’ seasons are usually so predictable, each virus arising, peaking, and then dying out in a predictable virus parade (Figure 1).¹ Well, the predictable virus seasonal pattern was lost in 2020. Since March of 2020, it is striking how little activity was detected for the usual seasonal viruses in Kansas City after mid-March 2020 (Figure 2).² So, my concern in September 2020 for possible rampant coinfections of common viruses with or in tandem with SARS-CoV-2 did not pan out. That said, the seasons for non–SARS-CoV-2 viruses did change; I just didn’t expect they would nearly disappear.

Dr. Christoper Harrison

The 2020 winter-spring. In the first quarter (the last part of the overall 2019-2020 respiratory viral season), viral detections were chugging along as usual up to mid-March (Figure 2); influenza, respiratory syncytial virus (RSV), and rhinovirus were the big players.

Influenza. In most years, influenza type B leads off and is quickly replaced by type A only to see B reemerge to end influenza season in March-April. In early 2020, both influenza type A and influenza type B cocirculated nearly equally, but both dropped like a rock in mid-March (Figure 2).² Neither type has been seen since with the exception of sporadic detections – perhaps being false positives.

RSV. In the usual year in temperate mid-latitudes of the northern hemisphere, RSV season usually starts in early December, peaks in January-March, and declines gradually until the end of RSV season in April (Figure 1). In southern latitudes, RSV is less seasonal, being present most of the year, but peaking in “winter” months.³ But in 2020, RSV also disappeared in mid-March and has yet to reappear.

Other viruses. Small bumps in detection of parainfluenza of varying types usually frame influenza season, one B bump in early autumn and another in April-May. In most years, human metapneumovirus is detected on and off, with worse years at 2- to 3-year intervals. Adenovirus occurs year-round with bumps as children get back to school in autumn. Yet in 2020, almost no parainfluenza, adenovirus, common coronaviruses, or human metapneumovirus were detected in either spring or autumn. This was supposed to be a banner summer-autumn for EV-D68 – but almost none was detected. Interestingly, the cockroach of viruses, rhinovirus, has its usual year (Figure 2).

Dr. Christopher Harrison

What happened? Intense social mitigation interventions, including social distancing and closing daycares and schools, were likely major factors.⁴ For influenza, vaccine may have helped but uptake was not remarkably better than most prior years. There may have been “viral competition,”where a new or highly transmissible virus outcompetes less-transmissible viruses with lower affinity for respiratory receptors.^5,6 Note that SARS-CoV-2 has very high affinity for the ACE2 receptor and has been highly prevalent. So, SARS-CoV-2 could fit the theoretical mold for a virus that outcompetes others.

Does it matter for the future? Blunted 2019-2020 and nearly absent 2020-2021 respiratory virus season may have set the stage for intense 2021-2022 rebounds for the non–SARS-CoV-2 viruses. We now have two whole and one partial birth cohort with no experience with seasonal respiratory viruses, including EV-D68 (and nonrespiratory viruses too – like norovirus, parechovirus, and other enteroviruses). Most viruses have particularly bad seasons every 2-3 years, thought to be caused by increasing accumulation of susceptible individuals in consecutive birth cohorts until a critical mass of susceptible individuals is achieved. The excess in susceptible individuals means that each contagious case is likely to expose one or more susceptible individuals, enhancing transmission and infection numbers in an ever-extending ripple effect. We have never had this many children aged under 3 years with no immunity to influenza, RSV, etc. So unless mother nature is kind (when has that happened lately?), expect rebound years for seasonal viruses as children return to daycare/schools and as social mitigation becomes less necessary in the waning pandemic.

Options? If you ramped up telehealth visits for the pandemic, that may be a saving grace, i.e., more efficiency so more “visits” can be completed per day, and less potential contact in reception rooms between well and ill children. And if there was ever a time to really intensify efforts to immunize all our pediatric patients, the next two seasons are just that. Adding a bit of a warning to families with young children also seems warranted. If they understand that, while 2021-2022 will be better for SARS-CoV-2, it is likely going to be worse for the other viruses.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

References

1. Harrison CJ. 2020-2021 respiratory viral season: Onset, presentations, and testing likely to differ in pandemic, Pediatric News: September 17, 2020.

2. Olsen SJ et al. MMWR Morb Mortal Wkly Rep. 2020;69:1305-9.

3. Respiratory Syncytial Virus Surveillance. http://www.floridahealth.gov/diseases-and-conditions/respiratory-syncytial-virus/_documents/2021-w4-rsv-summary.pdf

4. Baker RE et al. PNAS. Dec 2020 117;(48):30547-53.

5. Sema Nickbakhsh et al. PNAS. Dec 2019 116;(52):27142-50.

6. Kirsten M et al. PNAS. Mar 2020 117;(13):6987.

In this column in September 2020, you read how common respiratory viruses’ seasons are usually so predictable, each virus arising, peaking, and then dying out in a predictable virus parade (Figure 1).¹ Well, the predictable virus seasonal pattern was lost in 2020. Since March of 2020, it is striking how little activity was detected for the usual seasonal viruses in Kansas City after mid-March 2020 (Figure 2).² So, my concern in September 2020 for possible rampant coinfections of common viruses with or in tandem with SARS-CoV-2 did not pan out. That said, the seasons for non–SARS-CoV-2 viruses did change; I just didn’t expect they would nearly disappear.

Dr. Christoper Harrison

The 2020 winter-spring. In the first quarter (the last part of the overall 2019-2020 respiratory viral season), viral detections were chugging along as usual up to mid-March (Figure 2); influenza, respiratory syncytial virus (RSV), and rhinovirus were the big players.

Influenza. In most years, influenza type B leads off and is quickly replaced by type A only to see B reemerge to end influenza season in March-April. In early 2020, both influenza type A and influenza type B cocirculated nearly equally, but both dropped like a rock in mid-March (Figure 2).² Neither type has been seen since with the exception of sporadic detections – perhaps being false positives.

RSV. In the usual year in temperate mid-latitudes of the northern hemisphere, RSV season usually starts in early December, peaks in January-March, and declines gradually until the end of RSV season in April (Figure 1). In southern latitudes, RSV is less seasonal, being present most of the year, but peaking in “winter” months.³ But in 2020, RSV also disappeared in mid-March and has yet to reappear.

Other viruses. Small bumps in detection of parainfluenza of varying types usually frame influenza season, one B bump in early autumn and another in April-May. In most years, human metapneumovirus is detected on and off, with worse years at 2- to 3-year intervals. Adenovirus occurs year-round with bumps as children get back to school in autumn. Yet in 2020, almost no parainfluenza, adenovirus, common coronaviruses, or human metapneumovirus were detected in either spring or autumn. This was supposed to be a banner summer-autumn for EV-D68 – but almost none was detected. Interestingly, the cockroach of viruses, rhinovirus, has its usual year (Figure 2).

Dr. Christopher Harrison

What happened? Intense social mitigation interventions, including social distancing and closing daycares and schools, were likely major factors.⁴ For influenza, vaccine may have helped but uptake was not remarkably better than most prior years. There may have been “viral competition,”where a new or highly transmissible virus outcompetes less-transmissible viruses with lower affinity for respiratory receptors.^5,6 Note that SARS-CoV-2 has very high affinity for the ACE2 receptor and has been highly prevalent. So, SARS-CoV-2 could fit the theoretical mold for a virus that outcompetes others.

Does it matter for the future? Blunted 2019-2020 and nearly absent 2020-2021 respiratory virus season may have set the stage for intense 2021-2022 rebounds for the non–SARS-CoV-2 viruses. We now have two whole and one partial birth cohort with no experience with seasonal respiratory viruses, including EV-D68 (and nonrespiratory viruses too – like norovirus, parechovirus, and other enteroviruses). Most viruses have particularly bad seasons every 2-3 years, thought to be caused by increasing accumulation of susceptible individuals in consecutive birth cohorts until a critical mass of susceptible individuals is achieved. The excess in susceptible individuals means that each contagious case is likely to expose one or more susceptible individuals, enhancing transmission and infection numbers in an ever-extending ripple effect. We have never had this many children aged under 3 years with no immunity to influenza, RSV, etc. So unless mother nature is kind (when has that happened lately?), expect rebound years for seasonal viruses as children return to daycare/schools and as social mitigation becomes less necessary in the waning pandemic.

Options? If you ramped up telehealth visits for the pandemic, that may be a saving grace, i.e., more efficiency so more “visits” can be completed per day, and less potential contact in reception rooms between well and ill children. And if there was ever a time to really intensify efforts to immunize all our pediatric patients, the next two seasons are just that. Adding a bit of a warning to families with young children also seems warranted. If they understand that, while 2021-2022 will be better for SARS-CoV-2, it is likely going to be worse for the other viruses.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

References

1. Harrison CJ. 2020-2021 respiratory viral season: Onset, presentations, and testing likely to differ in pandemic, Pediatric News: September 17, 2020.

2. Olsen SJ et al. MMWR Morb Mortal Wkly Rep. 2020;69:1305-9.

3. Respiratory Syncytial Virus Surveillance. http://www.floridahealth.gov/diseases-and-conditions/respiratory-syncytial-virus/_documents/2021-w4-rsv-summary.pdf

4. Baker RE et al. PNAS. Dec 2020 117;(48):30547-53.

5. Sema Nickbakhsh et al. PNAS. Dec 2019 116;(52):27142-50.

6. Kirsten M et al. PNAS. Mar 2020 117;(13):6987.