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‘Plethora’ of new MCL treatment options
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
When cisplatin won’t do, try carboplatin in head and neck cancer
Among patients with locally advanced head and neck squamous cell carcinoma who are ineligible to receive cisplatin, carboplatin-based chemoradiotherapy (CRT) may be a better option than cetuximab-based chemoradiotherapy, according to a new cohort study of U.S. veterans.
Although cisplatin is the favored treatment choice for these patients, kidney dysfunction, hearing loss, neuropathy, advanced age, and performance status can be contraindications. As radiosensitizing agents, both cetuximab and carboplatin-fluorouracil combined with radiotherapy have increased survival compared to radiotherapy alone in randomized, controlled trials.
, but no prospective trials have compared cetuximab and carboplatin-based radiosensitization, according to the authors of the new report, published online in JAMA Otolaryngology – Head & Neck Surgery.
Some small retrospective studies, generally performed at one or two institutions, found that carboplatin outperformed cetuximab with respect to progression-free and overall survival, but these were subject to natural biases as well as imbalances between the two treatment groups.
To address this literature gap, the authors conducted a nationwide retrospective analysis of 8,290 U.S. veterans, who have a high rate of frailty and comorbidities such as heart disease and tobacco use that could make them ineligible for treatment with cisplatin. Among the veterans, 5,566 were treated with cisplatin, 1,231 with carboplatin, and 1,493 with cetuximab. The overall median age was 63 years, 98.9% were male, 82.6% were White, 15.8% were Black or African American, 68.5% were current smokers, 13.0% were former smokers, and 18.5% had never smoked.
Patients treated with carboplatin and cetuximab were older and had more comorbidities than those treated with cisplatin. Sixty-five percent of patients treated with carboplatin also received paclitaxel. Fifty-eight percent had a primary oropharynx cancer.
Median overall survival was 59.3 months among all patients (interquartile range [IQR, 18.5-140.9 months]. Median OS was 74.4 months in the cisplatin group (IQR, 22.3-162.2), 43.4 months in the carboplatin group (IQR, 15.3-123.8), and 31.1 months in the cetuximab group (IQR, 12.4-87.8). There was a lower inverse probability weighted cause-specific hazard ratio (csHR) of death associated with carboplatin (csHR, 0.85; 95% confidence interval [CI], 0.78-0.93). The researchers compared survival associations in oropharynx and nonoropharynx subgroups and found a significant association in the oropharynx group (csHR, 0.82; 95% CI, 0.72-0.94) but only a trend in the nonoropharynx group (csHR, 0.88; 95% CI, 0.78-1.00).
Given that most oropharynx cancers are likely related to HPV, the authors speculate that the finding of an association in the oropharynx group but not the nonoropharynx group may be attributable to differences in treatment efficacy due to HPV status, since there is evidence beginning to mount that cetuximab may have lower efficacy in these cancers. “For patients who are ineligible for treatment with cisplatin, carboplatin-based radiosensitization may provide better oncologic outcomes than cetuximab, particularly for oropharynx cancer,” the authors wrote.
The study is limited by its retrospective nature and a lack of patient-level data on HPV status. The researchers did not have information on neuropathy, hearing loss, treatment toxicity, or disease progression.
Among patients with locally advanced head and neck squamous cell carcinoma who are ineligible to receive cisplatin, carboplatin-based chemoradiotherapy (CRT) may be a better option than cetuximab-based chemoradiotherapy, according to a new cohort study of U.S. veterans.
Although cisplatin is the favored treatment choice for these patients, kidney dysfunction, hearing loss, neuropathy, advanced age, and performance status can be contraindications. As radiosensitizing agents, both cetuximab and carboplatin-fluorouracil combined with radiotherapy have increased survival compared to radiotherapy alone in randomized, controlled trials.
, but no prospective trials have compared cetuximab and carboplatin-based radiosensitization, according to the authors of the new report, published online in JAMA Otolaryngology – Head & Neck Surgery.
Some small retrospective studies, generally performed at one or two institutions, found that carboplatin outperformed cetuximab with respect to progression-free and overall survival, but these were subject to natural biases as well as imbalances between the two treatment groups.
To address this literature gap, the authors conducted a nationwide retrospective analysis of 8,290 U.S. veterans, who have a high rate of frailty and comorbidities such as heart disease and tobacco use that could make them ineligible for treatment with cisplatin. Among the veterans, 5,566 were treated with cisplatin, 1,231 with carboplatin, and 1,493 with cetuximab. The overall median age was 63 years, 98.9% were male, 82.6% were White, 15.8% were Black or African American, 68.5% were current smokers, 13.0% were former smokers, and 18.5% had never smoked.
Patients treated with carboplatin and cetuximab were older and had more comorbidities than those treated with cisplatin. Sixty-five percent of patients treated with carboplatin also received paclitaxel. Fifty-eight percent had a primary oropharynx cancer.
Median overall survival was 59.3 months among all patients (interquartile range [IQR, 18.5-140.9 months]. Median OS was 74.4 months in the cisplatin group (IQR, 22.3-162.2), 43.4 months in the carboplatin group (IQR, 15.3-123.8), and 31.1 months in the cetuximab group (IQR, 12.4-87.8). There was a lower inverse probability weighted cause-specific hazard ratio (csHR) of death associated with carboplatin (csHR, 0.85; 95% confidence interval [CI], 0.78-0.93). The researchers compared survival associations in oropharynx and nonoropharynx subgroups and found a significant association in the oropharynx group (csHR, 0.82; 95% CI, 0.72-0.94) but only a trend in the nonoropharynx group (csHR, 0.88; 95% CI, 0.78-1.00).
Given that most oropharynx cancers are likely related to HPV, the authors speculate that the finding of an association in the oropharynx group but not the nonoropharynx group may be attributable to differences in treatment efficacy due to HPV status, since there is evidence beginning to mount that cetuximab may have lower efficacy in these cancers. “For patients who are ineligible for treatment with cisplatin, carboplatin-based radiosensitization may provide better oncologic outcomes than cetuximab, particularly for oropharynx cancer,” the authors wrote.
The study is limited by its retrospective nature and a lack of patient-level data on HPV status. The researchers did not have information on neuropathy, hearing loss, treatment toxicity, or disease progression.
Among patients with locally advanced head and neck squamous cell carcinoma who are ineligible to receive cisplatin, carboplatin-based chemoradiotherapy (CRT) may be a better option than cetuximab-based chemoradiotherapy, according to a new cohort study of U.S. veterans.
Although cisplatin is the favored treatment choice for these patients, kidney dysfunction, hearing loss, neuropathy, advanced age, and performance status can be contraindications. As radiosensitizing agents, both cetuximab and carboplatin-fluorouracil combined with radiotherapy have increased survival compared to radiotherapy alone in randomized, controlled trials.
, but no prospective trials have compared cetuximab and carboplatin-based radiosensitization, according to the authors of the new report, published online in JAMA Otolaryngology – Head & Neck Surgery.
Some small retrospective studies, generally performed at one or two institutions, found that carboplatin outperformed cetuximab with respect to progression-free and overall survival, but these were subject to natural biases as well as imbalances between the two treatment groups.
To address this literature gap, the authors conducted a nationwide retrospective analysis of 8,290 U.S. veterans, who have a high rate of frailty and comorbidities such as heart disease and tobacco use that could make them ineligible for treatment with cisplatin. Among the veterans, 5,566 were treated with cisplatin, 1,231 with carboplatin, and 1,493 with cetuximab. The overall median age was 63 years, 98.9% were male, 82.6% were White, 15.8% were Black or African American, 68.5% were current smokers, 13.0% were former smokers, and 18.5% had never smoked.
Patients treated with carboplatin and cetuximab were older and had more comorbidities than those treated with cisplatin. Sixty-five percent of patients treated with carboplatin also received paclitaxel. Fifty-eight percent had a primary oropharynx cancer.
Median overall survival was 59.3 months among all patients (interquartile range [IQR, 18.5-140.9 months]. Median OS was 74.4 months in the cisplatin group (IQR, 22.3-162.2), 43.4 months in the carboplatin group (IQR, 15.3-123.8), and 31.1 months in the cetuximab group (IQR, 12.4-87.8). There was a lower inverse probability weighted cause-specific hazard ratio (csHR) of death associated with carboplatin (csHR, 0.85; 95% confidence interval [CI], 0.78-0.93). The researchers compared survival associations in oropharynx and nonoropharynx subgroups and found a significant association in the oropharynx group (csHR, 0.82; 95% CI, 0.72-0.94) but only a trend in the nonoropharynx group (csHR, 0.88; 95% CI, 0.78-1.00).
Given that most oropharynx cancers are likely related to HPV, the authors speculate that the finding of an association in the oropharynx group but not the nonoropharynx group may be attributable to differences in treatment efficacy due to HPV status, since there is evidence beginning to mount that cetuximab may have lower efficacy in these cancers. “For patients who are ineligible for treatment with cisplatin, carboplatin-based radiosensitization may provide better oncologic outcomes than cetuximab, particularly for oropharynx cancer,” the authors wrote.
The study is limited by its retrospective nature and a lack of patient-level data on HPV status. The researchers did not have information on neuropathy, hearing loss, treatment toxicity, or disease progression.
FROM JAMA OTOLARYNGOLOGY – HEAD & NECK SURGERY
Mutation burden predicts ICI response in lung cancer
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
Salt pills for patients with acute decompensated heart failure?
Restriction of dietary salt to alleviate or prevent volume overload in patients with acute decompensated heart failure (ADHF) is common hospital practice, but without a solid evidence base. A trial testing whether taking salt pills might have benefits for patients with ADHF undergoing intensive diuresis, therefore, may seem a bit counterintuitive.
In just such a randomized, placebo-controlled trial, the approach made no difference to weight loss on diuresis, a proxy for volume reduction, or to serum creatinine levels in ADHF patients receiving high-dose intravenous diuretic therapy.
The patients consumed the extra salt during their intravenous therapy in the form of tablets providing 6 g sodium chloride daily on top of their hospital-provided, low-sodium meals.
During that time, serum sodium levels remained stable for the 34 patients assigned to the salt tablets but dropped significantly in the 31 given placebo pills.
They lost about the same weight, averages of 4 kg and 4.6 kg (8.8-10 lb), respectively, and their urine output was also similar. Patients who took the salt tablets showed less of an increase in blood urea nitrogen (BUN) at both 96 hours and at discharge.
The findings “challenge the routine practice of sodium chloride restriction in acute heart failure, something done thousands of times a day, millions of times a year,” Robert A. Montgomery, MD, Cleveland Clinic, said when presenting the study at the annual scientific meeting of the Heart Failure Society of America.
The trial, called OSPREY-AHF (Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure), also may encourage a shift in ADHF management from a preoccupation with salt restriction to focus more on fighting fluid retention.
OSPREY-HF took on “an established practice that doesn’t have much high-quality evidentiary support,” one guided primarily by consensus and observational data, Montgomery said in an interview.
There are also potential downsides to dietary sodium restriction, including some that may complicate or block ADHF therapies.
“Low-sodium diets can be associated with decreased caloric intake and nutritional quality,” Dr. Montgomery observed. And observational studies suggest that “patients who are on a low sodium diet can develop increased neurohormonal activation. The kidney is not sensing salt, and so starts ramping up the hormones,” which promotes diuretic resistance.
But emerging evidence also suggests “that giving sodium chloride in the form of hypertonic saline can help patients who are diuretic resistant.” The intervention, which appears to attenuate the neurohormonal activation associated with high-dose intravenous diuretics, Dr. Montgomery noted, helped inspire the design of OSPREY-AHF.
Edema consists of “a gallon of water and a pinch of salt, so we really should stop being so salt-centric and think much more about water as the problem in decompensated heart failure,” said John G.F. Cleland, MD, PhD, during the question-and-answer period after Montgomery’s presentation. Dr. Cleland, of the University of Glasgow Institute of Health and Wellbeing, is not connected to OSPREY-AHF.
“I think that maybe we overinterpret how important salt is” as a focus of volume management in ADHF, offered David Lanfear, MD, Henry Ford Health System, Detroit, who is also not part of the study.
OSPREY-AHF was well conducted but applies to a “very specific” clinical setting, Dr. Lanfear said in an interview. “These people are getting aggressive diuresis, a big dose and continuous infusion. It’s not everybody that has heart failure.”
Although the study was small, “I think it will fuel interest in this area and, probably, further investigation,” he said. The trial on its own won’t change practice, “but it will raise some eyebrows.”
The trial included patients with ADHF who have been “admitted to a cardiovascular medicine floor, not the intensive care unit” and were receiving at least 10 mg per hour of furosemide. It excluded any who were “hypernatremic or severely hyponatremic,” said Dr. Montgomery when presenting the study. They were required to have an initial estimated glomerular filtration rate (eGFR) of at least 15 mL/min per 1.73 m2.
The patients were randomly assigned double blind at a single center to receive tablets providing 2 g sodium chloride or placebo pills – 34 and 31 patients, respectively – three times daily during intravenous diuresis.
At 96 hours, the two groups showed no difference in change in creatinine levels or change in weight, both primary endpoints. Nor did they differ in urine output or change in eGFR. But serum sodium levels fell further, and BUN levels went up more in those given placebo.
The two groups showed no differences in hospital length of stay, use of renal replacement therapy at 90 days, ICU time during the index hospitalization, 30-day readmission, or 90-day mortality – although the trial wasn’t powered for clinical outcomes, Dr. Montgomery reported.
"We have patients who complain about their sodium-restricted diet, we have patients that have cachexia, who have a lot of complaints about provider-ordered meals and recommendations,” Dr. Montgomery explained in an interview.
Clinicians provide education and invest a lot of effort into getting patients with heart failure to start and maintain a low-sodium diet, he said. “But a low-sodium diet, in prior studies – and our study adds to this – is not a lever that actually seems to positively or adversely affect patients.”
Dr. Montgomery pointed to the recently published SODIUM-HF trial comparing low-sodium and unrestricted-sodium diets in outpatients with heart failure. It saw no clinical benefit from the low-sodium intervention.
Until studies show, potentially, that sodium restriction in hospitalized patients with heart failure makes a clinical difference, Dr. Montgomery said, “I’d say we should invest our time in things that we know are the most helpful, like getting them on guideline-directed medical therapy, when instead we spend an enormous amount of time counseling on and enforcing dietary restriction.”
Support for this study was provided by Cleveland Clinic Heart Vascular and Thoracic Institute’s Wilson Grant and Kaufman Center for Heart Failure Treatment and Recovery Grant. Dr. Lanfear disclosed research support from SomaLogic and Lilly; consulting for Abbott Laboratories, AstraZeneca, Janssen, Martin Pharmaceuticals, and Amgen; and serving on advisory panels for Illumina and Cytokinetics. Dr. Montgomery and Dr. Cleland disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Restriction of dietary salt to alleviate or prevent volume overload in patients with acute decompensated heart failure (ADHF) is common hospital practice, but without a solid evidence base. A trial testing whether taking salt pills might have benefits for patients with ADHF undergoing intensive diuresis, therefore, may seem a bit counterintuitive.
In just such a randomized, placebo-controlled trial, the approach made no difference to weight loss on diuresis, a proxy for volume reduction, or to serum creatinine levels in ADHF patients receiving high-dose intravenous diuretic therapy.
The patients consumed the extra salt during their intravenous therapy in the form of tablets providing 6 g sodium chloride daily on top of their hospital-provided, low-sodium meals.
During that time, serum sodium levels remained stable for the 34 patients assigned to the salt tablets but dropped significantly in the 31 given placebo pills.
They lost about the same weight, averages of 4 kg and 4.6 kg (8.8-10 lb), respectively, and their urine output was also similar. Patients who took the salt tablets showed less of an increase in blood urea nitrogen (BUN) at both 96 hours and at discharge.
The findings “challenge the routine practice of sodium chloride restriction in acute heart failure, something done thousands of times a day, millions of times a year,” Robert A. Montgomery, MD, Cleveland Clinic, said when presenting the study at the annual scientific meeting of the Heart Failure Society of America.
The trial, called OSPREY-AHF (Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure), also may encourage a shift in ADHF management from a preoccupation with salt restriction to focus more on fighting fluid retention.
OSPREY-HF took on “an established practice that doesn’t have much high-quality evidentiary support,” one guided primarily by consensus and observational data, Montgomery said in an interview.
There are also potential downsides to dietary sodium restriction, including some that may complicate or block ADHF therapies.
“Low-sodium diets can be associated with decreased caloric intake and nutritional quality,” Dr. Montgomery observed. And observational studies suggest that “patients who are on a low sodium diet can develop increased neurohormonal activation. The kidney is not sensing salt, and so starts ramping up the hormones,” which promotes diuretic resistance.
But emerging evidence also suggests “that giving sodium chloride in the form of hypertonic saline can help patients who are diuretic resistant.” The intervention, which appears to attenuate the neurohormonal activation associated with high-dose intravenous diuretics, Dr. Montgomery noted, helped inspire the design of OSPREY-AHF.
Edema consists of “a gallon of water and a pinch of salt, so we really should stop being so salt-centric and think much more about water as the problem in decompensated heart failure,” said John G.F. Cleland, MD, PhD, during the question-and-answer period after Montgomery’s presentation. Dr. Cleland, of the University of Glasgow Institute of Health and Wellbeing, is not connected to OSPREY-AHF.
“I think that maybe we overinterpret how important salt is” as a focus of volume management in ADHF, offered David Lanfear, MD, Henry Ford Health System, Detroit, who is also not part of the study.
OSPREY-AHF was well conducted but applies to a “very specific” clinical setting, Dr. Lanfear said in an interview. “These people are getting aggressive diuresis, a big dose and continuous infusion. It’s not everybody that has heart failure.”
Although the study was small, “I think it will fuel interest in this area and, probably, further investigation,” he said. The trial on its own won’t change practice, “but it will raise some eyebrows.”
The trial included patients with ADHF who have been “admitted to a cardiovascular medicine floor, not the intensive care unit” and were receiving at least 10 mg per hour of furosemide. It excluded any who were “hypernatremic or severely hyponatremic,” said Dr. Montgomery when presenting the study. They were required to have an initial estimated glomerular filtration rate (eGFR) of at least 15 mL/min per 1.73 m2.
The patients were randomly assigned double blind at a single center to receive tablets providing 2 g sodium chloride or placebo pills – 34 and 31 patients, respectively – three times daily during intravenous diuresis.
At 96 hours, the two groups showed no difference in change in creatinine levels or change in weight, both primary endpoints. Nor did they differ in urine output or change in eGFR. But serum sodium levels fell further, and BUN levels went up more in those given placebo.
The two groups showed no differences in hospital length of stay, use of renal replacement therapy at 90 days, ICU time during the index hospitalization, 30-day readmission, or 90-day mortality – although the trial wasn’t powered for clinical outcomes, Dr. Montgomery reported.
"We have patients who complain about their sodium-restricted diet, we have patients that have cachexia, who have a lot of complaints about provider-ordered meals and recommendations,” Dr. Montgomery explained in an interview.
Clinicians provide education and invest a lot of effort into getting patients with heart failure to start and maintain a low-sodium diet, he said. “But a low-sodium diet, in prior studies – and our study adds to this – is not a lever that actually seems to positively or adversely affect patients.”
Dr. Montgomery pointed to the recently published SODIUM-HF trial comparing low-sodium and unrestricted-sodium diets in outpatients with heart failure. It saw no clinical benefit from the low-sodium intervention.
Until studies show, potentially, that sodium restriction in hospitalized patients with heart failure makes a clinical difference, Dr. Montgomery said, “I’d say we should invest our time in things that we know are the most helpful, like getting them on guideline-directed medical therapy, when instead we spend an enormous amount of time counseling on and enforcing dietary restriction.”
Support for this study was provided by Cleveland Clinic Heart Vascular and Thoracic Institute’s Wilson Grant and Kaufman Center for Heart Failure Treatment and Recovery Grant. Dr. Lanfear disclosed research support from SomaLogic and Lilly; consulting for Abbott Laboratories, AstraZeneca, Janssen, Martin Pharmaceuticals, and Amgen; and serving on advisory panels for Illumina and Cytokinetics. Dr. Montgomery and Dr. Cleland disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Restriction of dietary salt to alleviate or prevent volume overload in patients with acute decompensated heart failure (ADHF) is common hospital practice, but without a solid evidence base. A trial testing whether taking salt pills might have benefits for patients with ADHF undergoing intensive diuresis, therefore, may seem a bit counterintuitive.
In just such a randomized, placebo-controlled trial, the approach made no difference to weight loss on diuresis, a proxy for volume reduction, or to serum creatinine levels in ADHF patients receiving high-dose intravenous diuretic therapy.
The patients consumed the extra salt during their intravenous therapy in the form of tablets providing 6 g sodium chloride daily on top of their hospital-provided, low-sodium meals.
During that time, serum sodium levels remained stable for the 34 patients assigned to the salt tablets but dropped significantly in the 31 given placebo pills.
They lost about the same weight, averages of 4 kg and 4.6 kg (8.8-10 lb), respectively, and their urine output was also similar. Patients who took the salt tablets showed less of an increase in blood urea nitrogen (BUN) at both 96 hours and at discharge.
The findings “challenge the routine practice of sodium chloride restriction in acute heart failure, something done thousands of times a day, millions of times a year,” Robert A. Montgomery, MD, Cleveland Clinic, said when presenting the study at the annual scientific meeting of the Heart Failure Society of America.
The trial, called OSPREY-AHF (Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure), also may encourage a shift in ADHF management from a preoccupation with salt restriction to focus more on fighting fluid retention.
OSPREY-HF took on “an established practice that doesn’t have much high-quality evidentiary support,” one guided primarily by consensus and observational data, Montgomery said in an interview.
There are also potential downsides to dietary sodium restriction, including some that may complicate or block ADHF therapies.
“Low-sodium diets can be associated with decreased caloric intake and nutritional quality,” Dr. Montgomery observed. And observational studies suggest that “patients who are on a low sodium diet can develop increased neurohormonal activation. The kidney is not sensing salt, and so starts ramping up the hormones,” which promotes diuretic resistance.
But emerging evidence also suggests “that giving sodium chloride in the form of hypertonic saline can help patients who are diuretic resistant.” The intervention, which appears to attenuate the neurohormonal activation associated with high-dose intravenous diuretics, Dr. Montgomery noted, helped inspire the design of OSPREY-AHF.
Edema consists of “a gallon of water and a pinch of salt, so we really should stop being so salt-centric and think much more about water as the problem in decompensated heart failure,” said John G.F. Cleland, MD, PhD, during the question-and-answer period after Montgomery’s presentation. Dr. Cleland, of the University of Glasgow Institute of Health and Wellbeing, is not connected to OSPREY-AHF.
“I think that maybe we overinterpret how important salt is” as a focus of volume management in ADHF, offered David Lanfear, MD, Henry Ford Health System, Detroit, who is also not part of the study.
OSPREY-AHF was well conducted but applies to a “very specific” clinical setting, Dr. Lanfear said in an interview. “These people are getting aggressive diuresis, a big dose and continuous infusion. It’s not everybody that has heart failure.”
Although the study was small, “I think it will fuel interest in this area and, probably, further investigation,” he said. The trial on its own won’t change practice, “but it will raise some eyebrows.”
The trial included patients with ADHF who have been “admitted to a cardiovascular medicine floor, not the intensive care unit” and were receiving at least 10 mg per hour of furosemide. It excluded any who were “hypernatremic or severely hyponatremic,” said Dr. Montgomery when presenting the study. They were required to have an initial estimated glomerular filtration rate (eGFR) of at least 15 mL/min per 1.73 m2.
The patients were randomly assigned double blind at a single center to receive tablets providing 2 g sodium chloride or placebo pills – 34 and 31 patients, respectively – three times daily during intravenous diuresis.
At 96 hours, the two groups showed no difference in change in creatinine levels or change in weight, both primary endpoints. Nor did they differ in urine output or change in eGFR. But serum sodium levels fell further, and BUN levels went up more in those given placebo.
The two groups showed no differences in hospital length of stay, use of renal replacement therapy at 90 days, ICU time during the index hospitalization, 30-day readmission, or 90-day mortality – although the trial wasn’t powered for clinical outcomes, Dr. Montgomery reported.
"We have patients who complain about their sodium-restricted diet, we have patients that have cachexia, who have a lot of complaints about provider-ordered meals and recommendations,” Dr. Montgomery explained in an interview.
Clinicians provide education and invest a lot of effort into getting patients with heart failure to start and maintain a low-sodium diet, he said. “But a low-sodium diet, in prior studies – and our study adds to this – is not a lever that actually seems to positively or adversely affect patients.”
Dr. Montgomery pointed to the recently published SODIUM-HF trial comparing low-sodium and unrestricted-sodium diets in outpatients with heart failure. It saw no clinical benefit from the low-sodium intervention.
Until studies show, potentially, that sodium restriction in hospitalized patients with heart failure makes a clinical difference, Dr. Montgomery said, “I’d say we should invest our time in things that we know are the most helpful, like getting them on guideline-directed medical therapy, when instead we spend an enormous amount of time counseling on and enforcing dietary restriction.”
Support for this study was provided by Cleveland Clinic Heart Vascular and Thoracic Institute’s Wilson Grant and Kaufman Center for Heart Failure Treatment and Recovery Grant. Dr. Lanfear disclosed research support from SomaLogic and Lilly; consulting for Abbott Laboratories, AstraZeneca, Janssen, Martin Pharmaceuticals, and Amgen; and serving on advisory panels for Illumina and Cytokinetics. Dr. Montgomery and Dr. Cleland disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HFSA 2022
Analysis of PsA guidelines reveals much room for improvement on conflicts of interest
, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).
In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”
Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:
- Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
- Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
- Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
- Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.
Financial conflicts of interest
The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”
The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.
A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,
The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.
Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.
The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).
“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
Nonfinancial conflicts of interest
Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.
The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.
The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.
Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.
This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.
, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).
In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”
Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:
- Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
- Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
- Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
- Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.
Financial conflicts of interest
The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”
The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.
A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,
The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.
Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.
The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).
“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
Nonfinancial conflicts of interest
Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.
The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.
The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.
Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.
This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.
, according to a retrospective analysis of all authors on the most recent guidelines issued by the American College of Rheumatology (ACR) and the Japanese Dermatological Association (JDA).
In addition to finding that the majority of the authors of psoriatic arthritis (PsA) clinical practice guidelines (CPGs) issued by the JDA and ACR received substantial personal payments from pharmaceutical companies before and during CPG development, researchers led by Hanano Mamada and Anju Murayama of the Medical Governance Research Institute, Tokyo, wrote in Arthritis Care & Research that “several CPG authors self-cited their articles without the disclosure of NFCOI [nonfinancial conflicts of interest], and most of the recommendations were based on low or very low quality of evidence. Although the COI policies used by JDA and ACR are clearly inadequate, no significant revisions have been made for the last 3 years.”
Based on their findings, which were made using payment data from major Japanese pharmaceutical companies and the U.S. Open Payments Database from 2016 to 2018, the researchers suggested that the medical societies should:
- Adopt global standard COI policies from organizations such as the National Academy of Medicine and Guidelines International Network, including a 3-year lookback period for COI declaration.
- Consider a comprehensive definition and rigorous management with full disclosure of NFCOI.
- Publish a list of authors making each recommendation to grasp the implications of COI in clinical practice guidelines.
- Mention the detailed date of the COI disclosure, which should be close to the publication date as much as possible.
Financial conflicts of interest
The researchers used payment data published between 2016 and 2018 for all 83 companies belonging to the Japan Pharmaceutical Manufacturers Association, focusing on personal payments (for lecturing, writing, and consultancy) and excluding research payments, “since in Japan, the name, institution, and position of the author or researcher who received the research payment is not disclosed, which makes assessing research payments difficult.” To evaluate authors’ FCOI in the ACR’s CPG, the researchers analyzed the U.S. Open Payments Database “for all categories of general payments such as speaking, consulting, meals, and travel expenses 3 years from before the guideline’s first online publication on November 30, 2018.”
The 2018 ACR/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis had 36 authors and the JDA’s Clinical Practice Guideline for the Treatment of Psoriatic Arthritis 2019 had 23. Overall, 61% of JDA authors and half of ACR authors voluntarily declared FCOI with pharmaceutical companies; 25 of the ACR authors were U.S. physicians and could be included in the Open Payments Database search.
A total of 21 (91.3%) JDA authors and 21 (84.0%) ACR authors received at least one payment, with the combined total of $3,335,413 and $4,081,629 payments, respectively, over the 3 years. The average and median personal payments were $145,018 and $123,876 for JDA authors and $162,825 and $58,826 for ACR authors. When the payments to ACR authors were limited to lecturing, writing, and consulting fees that are required under the ACR’s COI policy, the mean was $130,102 and median was $39,375. The corresponding payments for JDA authors were $123,876 and $8,170, respectively,
The researchers found undisclosed payments for more than three-quarters of physician authors of the Japanese guideline, and nearly half of the doctors authoring the American guideline had undisclosed payments. These added up to $474,000 for the JDA, which amounted to 38% of the total for personal payments that must be reported to the JDA based on its COI policy for clinical practice guidelines, and $218,000 for the ACR, amounting to 18% of the total for personal payments that must be reported to the society based on its COI policy.
Of the 11 ACR authors who were not eligible for the U.S. Open Payments Database search, 5 declared FCOI with pharmaceutical companies in the guideline, meaning that 26 (72%) of the 36 authors had FCOI with pharmaceutical companies.
The ACR only required authors to declare FCOI covering 1 year before and during guideline development, and although the JDA required authors to declare their FCOI for the past 3 years of guideline development, the study authors noted that the JDA guideline disclosed them for only 2 years (between Jan. 1, 2017, and Dec. 31, 2018).
“It is true that influential doctors such as clinical practice guideline authors tend to receive various types of payments from pharmaceutical companies and that it is difficult to conduct research without funding from pharmaceutical companies. However, our current research mainly focuses on personal payments from pharmaceutical companies such as lecture fees and consulting fees. These payments are recognized as pocket money and are not used for research. Thus, it is questionable that the observed relationships are something evitable,” the researchers wrote.
Nonfinancial conflicts of interest
Many authors of the ACR’s CPG and the JDA’s CPG also had NFCOI, defined objectively in this study as self-citation rate. NFCOI have been more broadly defined by the International Committee of Medical Journal Editors (ICMJE) as “conflicts, such as personal relationships or rivalries, academic competition, and intellectual beliefs”; the ICMJE recommends reporting NFCOI on its COI form.
The JDA guideline included self-citations by 78% of its authors, compared with 32% of the ACR guideline authors, but this weighed differently among the two guidelines in that only 12 of the 354 (3.4%) citations in the JDA guideline were self-cited, compared with 46 of 137 (34%) citations in the ACR guideline.
The researchers noted that while the self-citation rates between JDA and ACR authors “differed remarkably,” the impact of ACR authors on CPG recommendations was much more direct. Three-quarters of JDA authors’ self-cited articles were about observational studies, whereas 52% of the ACR authors’ self-cited articles were clinical trials, most of which were randomized, controlled studies, and these NFCOI were not disclosed in the guideline.
Half of the strong recommendations in the JDA guideline were based on low or very low quality of evidence, whereas the ACR guideline had no strong recommendations based on low or very low quality of evidence.
This study was supported by the nonprofit Medical Governance Research Institute, which receives donations from Ain Pharmacies Inc., other organizations, and private individuals. The study also received support from the Tansa (formerly known as the Waseda Chronicle), an independent nonprofit news organization dedicated to investigative journalism. Three authors reported receiving personal fees from several pharmaceutical companies for work outside of the scope of this study.
FROM ARTHRITIS CARE & RESEARCH
Newer drugs not cost effective for first-line diabetes therapy
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To be cost effective, compared with metformin, for initial therapy for type 2 diabetes, prices for a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist would have to fall by at least 70% and at least 90%, respectively, according to estimates.
The study, modeled on U.S. patients, by Jin G. Choi, MD, and colleagues, was published online Oct. 3 in the Annals of Internal Medicine.
The researchers simulated the lifetime incidence, prevalence, mortality, and costs associated with three different first-line treatment strategies – metformin, an SGLT2 inhibitor, or a GLP-1 agonist – in U.S. patients with untreated type 2 diabetes.
Compared with patients who received initial treatment with metformin, those who received one of the newer drugs had 4.4% to 5.2% lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke.
However, to be cost-effective at under $150,000 per quality-adjusted life-years (QALY), SGLT2 inhibitors would need to cost less than $5 a day ($1,800 a year), and GLP-1 agonists would have to cost less than $6 a day ($2,100 a year), a lot less than now.
Knowing how expensive these drugs are, “I am not surprised” that the model predicts that the price would have to drop so much to make them cost-effective, compared with first-line treatment with metformin, senior author Neda Laiteerapong, MD, said in an interview.
“But I am disappointed,” she said, because these drugs are very effective, and if the prices were lower, more people could benefit.
“In the interest of improving access to high-quality care in the United States, our study results indicate the need to reduce SGLT2 inhibitor and GLP-1 receptor agonist medication costs substantially for patients with type 2 [diabetes] to improve health outcomes and prevent exacerbating diabetes health disparities,” the researchers conclude.
One way that the newer drugs might be more widely affordable is if the government became involved, possibly by passing a law similar to the Affordable Insulin Now Act, speculated Dr. Laiteerapong, who is associate director at the Center for Chronic Disease Research and Policy, University of Chicago.
‘Current prices too high to encourage first-line adoption’
Guidelines recommend the use of SGLT2 inhibitors and GLP-1 agonists as second-line therapies for patients with type 2 diabetes, but it has not been clear if clinical benefits would outweigh costs for use as first-line therapies.
“Although clinical trials have demonstrated the clinical effectiveness of these newer drugs, they are hundreds of times more expensive than other ... diabetes drugs,” the researchers note.
On the other hand, costs may fall in the coming years when these new drugs come off-patent.
The current study was designed to help inform future clinical guidelines.
The researchers created a population simulation model based on the United Kingdom Prospective Diabetes Study, Outcomes Model version 2 (UKPDS OM2) for diabetes-related complications and mortality, with added information about hypoglycemic events, quality of life, and U.S. costs.
The researchers also identified a nationally representative sample of people who would be eligible to start first-line diabetes therapy when their A1c reached 7% for the model.
Using National Health and Nutrition Examination Survey (NHANES) data (2013-2016), the researchers identified about 7.3 million U.S. adults aged 18 and older with self-reported diabetes or an A1c greater than 6.5% with no reported use of diabetes medications.
Patients were an average age of 55, and 55% were women. They had had diabetes for an average of 4.2 years, and 36% had a history of diabetes complications.
The model projected that patients would have an improved life expectancy of 3.0 and 3.4 months from first-line SGLT2 inhibitors and GLP-1 agonists, respectively, compared with initial therapy with metformin due to reduced rates of macrovascular disease.
“However, the current drug costs would be too high to encourage their adoption as first-line for usual clinical practice,” the researchers report.
‘Disparities could remain for decades’
Generic SGLT2 inhibitors could enter the marketplace shortly, because one of two dapagliflozin patents expired in October 2020 and approval for generic alternatives has been sought from the U.S. Food and Drug Administration, Dr. Choi and colleagues note.
However, it could still take decades for medication prices to drop low enough to become affordable, the group cautions. For example, a generic GLP-1 agonist became available in 2017, but costs remain high.
“Without external incentives,” the group writes, “limited access to these drug classes will likely persist (for example, due to higher copays or requirements for prior authorizations), as will further diabetes disparities – for decades into the future – because of differential access to care due to insurance (for example, private vs. public), which often tracks race and ethnicity.”
The study was supported by the American Diabetes Association. Dr. Choi was supported by a National Institutes of Health, National Institute on Aging grant. Dr. Laiteerapong and other co-authors are members of the National Institute of Diabetes and Digestive and Kidney Diseases Chicago Center for Diabetes Translation Research at the University of Chicago. Dr. Choi and Dr. Laiteerapong have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
A Patient With Recurrent Immune Stromal Keratitis and Adherence Challenges
Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.1 The Herpetic Eye Disease Study established the standard of care in HSK management.2 Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.3 Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.4 ISK is classified by a cellular and neovascularization infiltration of the cornea.5 We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.
Case Presentation
A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.
On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with
The patient returned a week later having only used the prednisolone drops for 2 days before discontinuing. Examination showed no change in his corneal appearance from the previous week. The patient was counseled on the importance of adherence to the regimen of topical prednisolone and oral valacyclovir.
The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.
At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.
Discussion
HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.2 This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.6
ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.7 Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.7 This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.
Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.7 Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.
The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.9 Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.
As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.7
Conclusions
ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.
1. Sibley D, Larkin DFP. Update on Herpes simplex keratitis management. Eye (Lond). 2020;34(12):2219-2226. doi:10.1038/s41433-020-01153-x
2. Chodosh J, Ung L. Adoption of innovation in herpes simplex virus keratitis. Cornea. 2020;39(1)(suppl 1):S7-S18. doi:10.1097/ICO.0000000000002425
3. Pérez-Bartolomé F, Botín DM, de Dompablo P, de Arriba P, Arnalich Montiel F, Muñoz Negrete FJ. Post-herpes neurotrophic keratopathy: pathogenesis, clinical signs and current therapies. Arch Soc Esp Oftalmol. 2019;94(4):171-183. doi:10.1016/j.oftal.2019.01.002
4. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea. 1999;18(2):144-154.
5. Gauthier AS, Noureddine S, Delbosc B. Interstitial keratitis diagnosis and treatment. J Fr Ophtalmol. 2019;42(6):e229-e237. doi:10.1016/j.jfo.2019.04.001
6. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012;5(57):448-462. doi:10.1016/jsurvophthal.2012.01.005
7. Wang L, Wang R, Xu C, Zhou H. Pathogenesis of herpes stromal keratitis: immune inflammatory response mediated by inflammatory regulators. Front Immunol. 2020;11:766. Published 2020 May 13. doi:10.3389/fimmu.2020.00766
8. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002;186(suppl 1):S40-S46. doi:10.1086/342966
9. Dawson CR. The herpetic eye disease study. Arch Ophthalmol. 1990;108(2):191-192. doi:10.1001/archopht.1990.01070040043027
Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.1 The Herpetic Eye Disease Study established the standard of care in HSK management.2 Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.3 Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.4 ISK is classified by a cellular and neovascularization infiltration of the cornea.5 We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.
Case Presentation
A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.
On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with
The patient returned a week later having only used the prednisolone drops for 2 days before discontinuing. Examination showed no change in his corneal appearance from the previous week. The patient was counseled on the importance of adherence to the regimen of topical prednisolone and oral valacyclovir.
The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.
At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.
Discussion
HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.2 This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.6
ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.7 Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.7 This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.
Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.7 Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.
The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.9 Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.
As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.7
Conclusions
ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.
Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.1 The Herpetic Eye Disease Study established the standard of care in HSK management.2 Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.3 Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.4 ISK is classified by a cellular and neovascularization infiltration of the cornea.5 We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.
Case Presentation
A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.
On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with
The patient returned a week later having only used the prednisolone drops for 2 days before discontinuing. Examination showed no change in his corneal appearance from the previous week. The patient was counseled on the importance of adherence to the regimen of topical prednisolone and oral valacyclovir.
The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.
At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.
Discussion
HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.2 This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.6
ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.7 Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.7 This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.
Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.7 Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.
The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.9 Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.
As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.7
Conclusions
ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.
1. Sibley D, Larkin DFP. Update on Herpes simplex keratitis management. Eye (Lond). 2020;34(12):2219-2226. doi:10.1038/s41433-020-01153-x
2. Chodosh J, Ung L. Adoption of innovation in herpes simplex virus keratitis. Cornea. 2020;39(1)(suppl 1):S7-S18. doi:10.1097/ICO.0000000000002425
3. Pérez-Bartolomé F, Botín DM, de Dompablo P, de Arriba P, Arnalich Montiel F, Muñoz Negrete FJ. Post-herpes neurotrophic keratopathy: pathogenesis, clinical signs and current therapies. Arch Soc Esp Oftalmol. 2019;94(4):171-183. doi:10.1016/j.oftal.2019.01.002
4. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea. 1999;18(2):144-154.
5. Gauthier AS, Noureddine S, Delbosc B. Interstitial keratitis diagnosis and treatment. J Fr Ophtalmol. 2019;42(6):e229-e237. doi:10.1016/j.jfo.2019.04.001
6. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012;5(57):448-462. doi:10.1016/jsurvophthal.2012.01.005
7. Wang L, Wang R, Xu C, Zhou H. Pathogenesis of herpes stromal keratitis: immune inflammatory response mediated by inflammatory regulators. Front Immunol. 2020;11:766. Published 2020 May 13. doi:10.3389/fimmu.2020.00766
8. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002;186(suppl 1):S40-S46. doi:10.1086/342966
9. Dawson CR. The herpetic eye disease study. Arch Ophthalmol. 1990;108(2):191-192. doi:10.1001/archopht.1990.01070040043027
1. Sibley D, Larkin DFP. Update on Herpes simplex keratitis management. Eye (Lond). 2020;34(12):2219-2226. doi:10.1038/s41433-020-01153-x
2. Chodosh J, Ung L. Adoption of innovation in herpes simplex virus keratitis. Cornea. 2020;39(1)(suppl 1):S7-S18. doi:10.1097/ICO.0000000000002425
3. Pérez-Bartolomé F, Botín DM, de Dompablo P, de Arriba P, Arnalich Montiel F, Muñoz Negrete FJ. Post-herpes neurotrophic keratopathy: pathogenesis, clinical signs and current therapies. Arch Soc Esp Oftalmol. 2019;94(4):171-183. doi:10.1016/j.oftal.2019.01.002
4. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea. 1999;18(2):144-154.
5. Gauthier AS, Noureddine S, Delbosc B. Interstitial keratitis diagnosis and treatment. J Fr Ophtalmol. 2019;42(6):e229-e237. doi:10.1016/j.jfo.2019.04.001
6. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012;5(57):448-462. doi:10.1016/jsurvophthal.2012.01.005
7. Wang L, Wang R, Xu C, Zhou H. Pathogenesis of herpes stromal keratitis: immune inflammatory response mediated by inflammatory regulators. Front Immunol. 2020;11:766. Published 2020 May 13. doi:10.3389/fimmu.2020.00766
8. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002;186(suppl 1):S40-S46. doi:10.1086/342966
9. Dawson CR. The herpetic eye disease study. Arch Ophthalmol. 1990;108(2):191-192. doi:10.1001/archopht.1990.01070040043027
Sleep Medicine Network
Respiratory-Related Sleep Disorders Section
Sleep health and fatigue mitigation during medical training
Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).
Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.
A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.
Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.
Aesha Jobanputra, MD
Section Member
Sreelatha Naik, MD
Member-at-Large
Respiratory-Related Sleep Disorders Section
Sleep health and fatigue mitigation during medical training
Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).
Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.
A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.
Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.
Aesha Jobanputra, MD
Section Member
Sreelatha Naik, MD
Member-at-Large
Respiratory-Related Sleep Disorders Section
Sleep health and fatigue mitigation during medical training
Medical trainees may experience acute or chronic sleep deprivation due to extended work hours and shift-work sleep schedules. Extended work hours may lead to serious medical errors, percutaneous injuries, prolonged task completion, and car crashes or near misses while driving (Landrigan, et al. N Engl J Med. 2004;351:1838; Ayas, et al. JAMA. 2006;296[9]:1055; Taffinder, et al. Lancet. 1998;352[9135]:1191; Barger, et al. N Engl J Med. 2005 Jan 13;352[2]:125).
Chronic sleep restriction also results in neurobehavioral and cognitive dysfunction without a proportionate increase in self-perceived sleepiness [Belenky, et al. J Sleep Res. 2003;12[1]:1; Van Dongen, et al. Sleep. 2003;26[2]:117). In 1987, when sleep deprivation was cited as a major cause of 18-year-old Libby Zion’s death, the ACGME restricted residents from working more than 80 hours per week. ACGME mandates that training programs provide yearly fatigue mitigation education.
A “Sleep Alertness and Fatigue Education in Residency” module may be purchased through the American Academy of Sleep Medicine. While one-time education opportunities are available, there remains a need for access to longitudinal, individualized tools during varying rotations and circumstances, as education alone has not been shown to improve sleep quality (Mazar D, et al. J Clin Sleep Med. 2021;17[6]:1211). The American Thoracic Society Early Career Professional Working Group offers individualized lectures to training programs. Wake Up and Learn is a sleep education program for children and teens that is currently being expanded for medical trainees.
Further data are needed to see if longitudinal and individualized support can promote better sleep quality among trainees.
Aesha Jobanputra, MD
Section Member
Sreelatha Naik, MD
Member-at-Large
Death of son reinforces flu vaccination message
“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”
Two days later, his son called again.
“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care.
“Then I got the call that no parent wants to get.”
Brent’s cousin Jake called saying he couldn’t wake Brent up.
“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”
“To this day when I close my eyes at night, I still hear the beeping of those monitors.”
Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.
Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.
“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
New survey numbers ‘alarming’
The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.
“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”
In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said.
An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death.
“So, most people know what to do. We just need to do it,” she said.
The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.”
The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older.
Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.”
“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
Higher doses for 65+ Americans
The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”
During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths.
“They are the largest vulnerable segment of our society,” Dr. Walensky said.
What will this flu season be like?
Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.
“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing.
How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.
“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus.
“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said.
For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”
What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season.
Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”
The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.
“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.
“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”
To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing.
“This one is for Brent,” Dr. Teichman said.
A version of this article first appeared on WebMD.com.
“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”
Two days later, his son called again.
“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care.
“Then I got the call that no parent wants to get.”
Brent’s cousin Jake called saying he couldn’t wake Brent up.
“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”
“To this day when I close my eyes at night, I still hear the beeping of those monitors.”
Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.
Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.
“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
New survey numbers ‘alarming’
The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.
“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”
In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said.
An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death.
“So, most people know what to do. We just need to do it,” she said.
The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.”
The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older.
Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.”
“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
Higher doses for 65+ Americans
The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”
During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths.
“They are the largest vulnerable segment of our society,” Dr. Walensky said.
What will this flu season be like?
Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.
“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing.
How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.
“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus.
“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said.
For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”
What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season.
Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”
The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.
“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.
“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”
To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing.
“This one is for Brent,” Dr. Teichman said.
A version of this article first appeared on WebMD.com.
“It was what the CDC [Centers for Disease Control and Prevention] would call classic influenza-like illness,” Dr. Teichman said. “It was too late to start antivirals, so I gave him advice on symptomatic treatment. We texted the next day, and I was glad to hear that his fever was trending down and that he was feeling a little bit better.”
Two days later, his son called again.
“He said he was having trouble breathing, and over the phone I could hear him hyperventilating.” The retired pediatrician and health care executive told his son to seek medical care.
“Then I got the call that no parent wants to get.”
Brent’s cousin Jake called saying he couldn’t wake Brent up.
“I called Jake back a few minutes later and asked him to hold up the phone,” Dr. Teichman said. “I listened to EMS working on my son, calling for round after round of many medications. He was in arrest and they couldn’t revive him.”
“To this day when I close my eyes at night, I still hear the beeping of those monitors.”
Brent had no health conditions to put him at higher risk for complications of the flu. “Brent was a wonderful son, brother, uncle, and friend. He had a passion for everything he did, and that included his chosen calling of the culinary arts but also included University of Kentucky sports,” Dr. Teichman said.
Brent planned to get a flu vaccine but had not done it yet. “In his obituary, we requested that, in lieu of flowers or donations, people go get their flu shot,” Dr. Teichman said.
“I’m here today to put a face on influenza,” Dr. Teichman said at a news briefing Oct. 4 on preventing the flu and pneumococcal disease, sponsored by the National Foundation for Infectious Diseases.
New survey numbers ‘alarming’
The NFID commissioned a national survey of more than 1,000 U.S. adults to better understand their knowledge and attitudes about the flu, pneumococcal disease, vaccines, and the impact of COVID-19.
“We were alarmed to learn that only 49% of U.S. adults plan to get their flu vaccine this season,” said Patricia A. “Patsy” Stinchfield, a registered nurse, NFID president, and moderator of the news briefing. “That is not good enough.”
In addition, 22% of people at higher risk for flu-related complications do not plan to get vaccinated this season. “That’s a dangerous risk to take,” Ms. Stinchfield said.
An encouraging finding, she said, is that 69% of adults surveyed recognize that an annual flu vaccination is the best way to prevent flu-related hospitalizations and death.
“So, most people know what to do. We just need to do it,” she said.
The top reason for not getting a flu shot in 2022 mentioned by 41% of people surveyed, is they do not think vaccines work very well. Another 39% are concerned about vaccine side effects, and 28% skip the vaccine because they “never get the flu.”
The experts on the panel emphasized the recommendation that all Americans 6 months or older get the flu vaccine, preferably by the end of October. Vaccination is especially important for those at higher risk of complications from the flu, including children under 5, pregnant women, people with one or more health conditions, the immunocompromised, and Americans 65 years and older.
Ms. Stinchfield acknowledged that the effectiveness of the flu vaccine varies season to season, but even if the vaccine does not completely match the circulating viruses, it can help prevent serious outcomes like hospitalization and death. One of the serious potential complications is pneumonia or “pneumococcal disease.”
“Our survey shows that only 29% of those at risk have been advised to receive a pneumococcal vaccine,” Ms. Stinchfield said. “The good news is that, among those who were advised to get the vaccine, 74% did receive their pneumococcal vaccine,” she said. “This underscores a key point to you, my fellow clinicians: As health professionals, our recommendations matter.”
Higher doses for 65+ Americans
The CDC updated recommendations this flu season for adults 65 and older to receive one of three preferentially recommended flu vaccines, said CDC Director Rochelle Walensky, MD. The CDC is recommending higher-dose, stronger vaccines for older Americans “based on a review of the available studies, which suggested that in this age group, these vaccines are potentially more effective than standard-dose ... vaccines.”
During most seasons, people 65 and older bear the greatest burden of severe flu disease, accounting for most flu-related hospitalizations and deaths.
“They are the largest vulnerable segment of our society,” Dr. Walensky said.
What will this flu season be like?
Health officials in the flu vaccine business also tend to be in the flu season prediction business. That includes Dr. Walensky.
“While we will never exactly know what each flu season will hold, we do know that every year, the best way you can protect yourself and those around you is to get your annual flu vaccine,” she said while taking part remotely in the briefing.
How severe will the flu season be in 2022-23? William Schaffner, MD, said he gets that question a lot. “Don’t think about that. Just focus on the fact that flu will be with us each year.
“We were a little bit spoiled. We’ve had two mild influenza seasons,” said Dr. Schaffner, medical director of NFID and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “I think with all the interest in COVID, people have rather forgotten about influenza. I’ve had to remind them that this is yet another serious winter respiratory virus.
“As I like to say, flu is fickle. It’s difficult to predict how serious this next outbreak of influenza this season is going to be. We could look at what happened in the Southern Hemisphere,” he said.
For example, Australia had the worst influenza season in the past 5 years, Schaffner said. “If you want a hint of what might happen here and you want yet another reason to be vaccinated, there it is.”
What we do know, Dr. Walensky said, is that the timing and severity of the past two flu seasons in the U.S. have been different than typical flu seasons. “And this is likely due to the COVID mitigation measures and other changes in circulating respiratory viruses.” Also, although last flu season was “relatively mild,” there was more flu activity than in the prior, 2020-21 season.
Also, Dr. Walensky said, last season’s flu cases began to increase in November and remained elevated until mid-June, “making it the latest season on record.”
The official cause of Brent Teichman’s death was multilobar pneumonia, cause undetermined. “But after 30-plus years as a pediatrician ... I know influenza when I see it,” Dr. Teichman said.
“There’s a hole in our hearts that will never heal. Loss of a child is devastating,” he said. The flu “can take the life of a healthy young person, as it did to my son.
“And for all those listening to my story who are vaccine hesitant, do it for those who love you. So that they won’t walk the path that we and many other families in this country have walked.”
To prove their point, Dr. Teichman and Ms. Stinchfield raised their sleeves and received flu shots during the news briefing.
“This one is for Brent,” Dr. Teichman said.
A version of this article first appeared on WebMD.com.
Thoracic Oncology and Chest Procedures Network
Pleural Disease Section
Aspirate or wait: changing the paradigm for PSP care
Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.
Tejaswi R. Nadig, MBBS
Member-at-Large
Yaron Gesthalter, MD
Member-at-Large
Priya P. Nath, MD
Member-at-Large
Pleural Disease Section
Aspirate or wait: changing the paradigm for PSP care
Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.
Tejaswi R. Nadig, MBBS
Member-at-Large
Yaron Gesthalter, MD
Member-at-Large
Priya P. Nath, MD
Member-at-Large
Pleural Disease Section
Aspirate or wait: changing the paradigm for PSP care
Although observation for small asymptomatic PSP is supported by current guidelines, management recommendations for larger PSP remains unclear (MacDuff, et al. Thorax. 2010;65[Suppl 2]:ii18-ii31; Tschopp JM, et al. Eur Respir J. 2015;46[2]:321). Two recent RCTs explore conservative vs intervention-based management in those with larger or symptomatic PSP. In the PSP trial, Brown and colleagues prospectively randomized 316 patients with moderate to large PSP to either conservative management (≥ 4 hour observation) or small-bore chest tube without suction (Brown, et al. N Engl J Med. 2020;382[5]:405). Although noninferiority criteria were met, the primary outcome of radiographic resolution of pneumothorax within 8 weeks of randomization was not statistically robust to conservative assumptions about missing data. They concluded that conservative management was noninferior to intervention, and it resulted in a lower risk of serious adverse events or PSP recurrence than interventional management. The multicenter randomized Ambulatory Management of Primary Pneumothorax (RAMPP) trial compared ambulatory management of PSP using an 8F drainage device to a guideline-driven approach (drainage, aspiration, or both) amongst 236 patients with symptomatic PSP. Intervention shortened length of hospital stay (median 0 vs 4 days, P<.0001), but the intervention arm experienced more adverse events (including enlargement of pneumothorax, as well as device malfunction) (Hallifax RJ, et al. Lancet. 2020;396[10243]:39). These two trials challenge the current guidelines for management for patients with PSP, but both had limitations. Though more data are needed to establish a clear consensus, these studies suggest that a conservative pathway for PSP warrants further consideration.
Tejaswi R. Nadig, MBBS
Member-at-Large
Yaron Gesthalter, MD
Member-at-Large
Priya P. Nath, MD
Member-at-Large