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Updated gout guidelines: Don’t let kidney function dictate allopurinol dosing
ATLANTA – Soon-to-be-published gout guidelines from the American College of Rheumatology will recommend dosing allopurinol above 300 mg/day to get serum urate below 6 mg/dL, even in people with renal impairment.
It’s the same strong treat-to-target recommendation the group made in its last outing in 2012, but “we now have more evidence to support it,” said co–lead author, rheumatologist, and epidemiologist Tuhina Neogi, MD, PhD, a professor of medicine at Boston University.
She gave a sneak preview of the new guidelines, which will be published in 2020, at the ACR annual meeting. They are under review, but she said the “major recommendations will remain the same.”
“There will still be controversy that we have not yet proven that a threshold of 6 mg/dL is better than a threshold of 7 mg/dL, but we know that” at physiologic pH and temperature, monosodium urate starts to crystallize out at 6.8 mg/dL. “Serum urate is not a perfect measure or total body urate, so we need to get urate to below at least 6 mg/dL,” she said, and perhaps lower in some.
A popular alternative in primary care – where most gout is managed – is to treat to avoid symptoms. It “has no evidence,” and people “end up getting tophaceous gout with joint destruction. Suppressive colchicine therapy does not manage underlying hyperuricemia,” Dr. Neogi said.
With the symptom approach, “patients are often [profoundly] dismayed” when they find out they have large tophi and joint damage because they weren’t managed properly. “Primary care physicians [don’t often] see that because those patients don’t go back to them,” she said.
Dr. Neogi suspects that, for rheumatologists, the biggest surprise in the new guidelines will be a deemphasis on lifestyle and dietary factors. They can be triggers, but “gout is increasingly recognized as largely genetically determined,” and the impact of other factors on serum urate is low. Plus, “patients are embarrassed” by gout, and even less comfortable being honest with physicians “if they think we are blaming them,” she said.
The new document will recommend allopurinol as the definitive first-line option for hyperuricemia. Febuxostat (Uloric) was put on pretty much equal footing in 2012, but now “we acknowledge” that allopurinol dosing in head-to-head trials – 300 mg/day or 200 mg/day with renal impairment – was too low for most people, “so to say febuxostat is equivalent or superior isn’t really fair.” The substantially higher cost of febuxostat was also taken into consideration, she said.
The ACR will broaden the indications for urate lowering beyond frequent flares, tophi, and radiologic joint damage to include conditional, shared decision-making recommendations for people who have less than two flares per year, those with kidney stones, and people with a first flare if they are particularly susceptible to a second – namely those with serum urate at or above 9 mg/dL and people with stage 3 or worse chronic kidney disease, who are less able to tolerate NSAIDs and colchicine for symptom treatment.
The group will also relax its advice against treating asymptomatic hyperuricemia. Febuxostat trials have shown a reduction in incident gout, but the number needed to treat was large, so the ACR will recommend shared decision making.
Inadequate allopurinol dosing, meanwhile, has been the bête noire of rheumatology for years, but there is still reluctance among many to go above 300 mg/day. Dr. Neogi said it’s because of a decades-old concern, “unsupported by any evidence, that higher doses may be detrimental in people with renal insufficiency.” It’s frustrating, she said, because “there is good data supporting the safety of increasing the dose above 300 mg/day even in those with renal impairment,” and not doing so opens the door to entirely preventable complications.
As for allopurinol hypersensitivity – another reason people shy away from higher dosing, especially in the renally impaired – the trick is to start low and slowly titrate allopurinol up to the target urate range. Asian and black people, especially, should be screened beforehand for the HLA-B*58:01 genetic variant that increases the risk of severe reactions. Both will be strong recommendations in the new guidelines.
Dr. Neogi didn’t have any relevant industry disclosures.
ATLANTA – Soon-to-be-published gout guidelines from the American College of Rheumatology will recommend dosing allopurinol above 300 mg/day to get serum urate below 6 mg/dL, even in people with renal impairment.
It’s the same strong treat-to-target recommendation the group made in its last outing in 2012, but “we now have more evidence to support it,” said co–lead author, rheumatologist, and epidemiologist Tuhina Neogi, MD, PhD, a professor of medicine at Boston University.
She gave a sneak preview of the new guidelines, which will be published in 2020, at the ACR annual meeting. They are under review, but she said the “major recommendations will remain the same.”
“There will still be controversy that we have not yet proven that a threshold of 6 mg/dL is better than a threshold of 7 mg/dL, but we know that” at physiologic pH and temperature, monosodium urate starts to crystallize out at 6.8 mg/dL. “Serum urate is not a perfect measure or total body urate, so we need to get urate to below at least 6 mg/dL,” she said, and perhaps lower in some.
A popular alternative in primary care – where most gout is managed – is to treat to avoid symptoms. It “has no evidence,” and people “end up getting tophaceous gout with joint destruction. Suppressive colchicine therapy does not manage underlying hyperuricemia,” Dr. Neogi said.
With the symptom approach, “patients are often [profoundly] dismayed” when they find out they have large tophi and joint damage because they weren’t managed properly. “Primary care physicians [don’t often] see that because those patients don’t go back to them,” she said.
Dr. Neogi suspects that, for rheumatologists, the biggest surprise in the new guidelines will be a deemphasis on lifestyle and dietary factors. They can be triggers, but “gout is increasingly recognized as largely genetically determined,” and the impact of other factors on serum urate is low. Plus, “patients are embarrassed” by gout, and even less comfortable being honest with physicians “if they think we are blaming them,” she said.
The new document will recommend allopurinol as the definitive first-line option for hyperuricemia. Febuxostat (Uloric) was put on pretty much equal footing in 2012, but now “we acknowledge” that allopurinol dosing in head-to-head trials – 300 mg/day or 200 mg/day with renal impairment – was too low for most people, “so to say febuxostat is equivalent or superior isn’t really fair.” The substantially higher cost of febuxostat was also taken into consideration, she said.
The ACR will broaden the indications for urate lowering beyond frequent flares, tophi, and radiologic joint damage to include conditional, shared decision-making recommendations for people who have less than two flares per year, those with kidney stones, and people with a first flare if they are particularly susceptible to a second – namely those with serum urate at or above 9 mg/dL and people with stage 3 or worse chronic kidney disease, who are less able to tolerate NSAIDs and colchicine for symptom treatment.
The group will also relax its advice against treating asymptomatic hyperuricemia. Febuxostat trials have shown a reduction in incident gout, but the number needed to treat was large, so the ACR will recommend shared decision making.
Inadequate allopurinol dosing, meanwhile, has been the bête noire of rheumatology for years, but there is still reluctance among many to go above 300 mg/day. Dr. Neogi said it’s because of a decades-old concern, “unsupported by any evidence, that higher doses may be detrimental in people with renal insufficiency.” It’s frustrating, she said, because “there is good data supporting the safety of increasing the dose above 300 mg/day even in those with renal impairment,” and not doing so opens the door to entirely preventable complications.
As for allopurinol hypersensitivity – another reason people shy away from higher dosing, especially in the renally impaired – the trick is to start low and slowly titrate allopurinol up to the target urate range. Asian and black people, especially, should be screened beforehand for the HLA-B*58:01 genetic variant that increases the risk of severe reactions. Both will be strong recommendations in the new guidelines.
Dr. Neogi didn’t have any relevant industry disclosures.
ATLANTA – Soon-to-be-published gout guidelines from the American College of Rheumatology will recommend dosing allopurinol above 300 mg/day to get serum urate below 6 mg/dL, even in people with renal impairment.
It’s the same strong treat-to-target recommendation the group made in its last outing in 2012, but “we now have more evidence to support it,” said co–lead author, rheumatologist, and epidemiologist Tuhina Neogi, MD, PhD, a professor of medicine at Boston University.
She gave a sneak preview of the new guidelines, which will be published in 2020, at the ACR annual meeting. They are under review, but she said the “major recommendations will remain the same.”
“There will still be controversy that we have not yet proven that a threshold of 6 mg/dL is better than a threshold of 7 mg/dL, but we know that” at physiologic pH and temperature, monosodium urate starts to crystallize out at 6.8 mg/dL. “Serum urate is not a perfect measure or total body urate, so we need to get urate to below at least 6 mg/dL,” she said, and perhaps lower in some.
A popular alternative in primary care – where most gout is managed – is to treat to avoid symptoms. It “has no evidence,” and people “end up getting tophaceous gout with joint destruction. Suppressive colchicine therapy does not manage underlying hyperuricemia,” Dr. Neogi said.
With the symptom approach, “patients are often [profoundly] dismayed” when they find out they have large tophi and joint damage because they weren’t managed properly. “Primary care physicians [don’t often] see that because those patients don’t go back to them,” she said.
Dr. Neogi suspects that, for rheumatologists, the biggest surprise in the new guidelines will be a deemphasis on lifestyle and dietary factors. They can be triggers, but “gout is increasingly recognized as largely genetically determined,” and the impact of other factors on serum urate is low. Plus, “patients are embarrassed” by gout, and even less comfortable being honest with physicians “if they think we are blaming them,” she said.
The new document will recommend allopurinol as the definitive first-line option for hyperuricemia. Febuxostat (Uloric) was put on pretty much equal footing in 2012, but now “we acknowledge” that allopurinol dosing in head-to-head trials – 300 mg/day or 200 mg/day with renal impairment – was too low for most people, “so to say febuxostat is equivalent or superior isn’t really fair.” The substantially higher cost of febuxostat was also taken into consideration, she said.
The ACR will broaden the indications for urate lowering beyond frequent flares, tophi, and radiologic joint damage to include conditional, shared decision-making recommendations for people who have less than two flares per year, those with kidney stones, and people with a first flare if they are particularly susceptible to a second – namely those with serum urate at or above 9 mg/dL and people with stage 3 or worse chronic kidney disease, who are less able to tolerate NSAIDs and colchicine for symptom treatment.
The group will also relax its advice against treating asymptomatic hyperuricemia. Febuxostat trials have shown a reduction in incident gout, but the number needed to treat was large, so the ACR will recommend shared decision making.
Inadequate allopurinol dosing, meanwhile, has been the bête noire of rheumatology for years, but there is still reluctance among many to go above 300 mg/day. Dr. Neogi said it’s because of a decades-old concern, “unsupported by any evidence, that higher doses may be detrimental in people with renal insufficiency.” It’s frustrating, she said, because “there is good data supporting the safety of increasing the dose above 300 mg/day even in those with renal impairment,” and not doing so opens the door to entirely preventable complications.
As for allopurinol hypersensitivity – another reason people shy away from higher dosing, especially in the renally impaired – the trick is to start low and slowly titrate allopurinol up to the target urate range. Asian and black people, especially, should be screened beforehand for the HLA-B*58:01 genetic variant that increases the risk of severe reactions. Both will be strong recommendations in the new guidelines.
Dr. Neogi didn’t have any relevant industry disclosures.
REPORTING FROM ACR 2019
Scalp EEG predicts temporal lobe resection success
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
REPORTING FROM AES 2019
Single-fraction spine stereotactic radiosurgery is cost-efficient
A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.
“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.
The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).
The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.
Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.
After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.
Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.
One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.
“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.
No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.
SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.
A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.
“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.
The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).
The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.
Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.
After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.
Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.
One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.
“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.
No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.
SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.
A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.
“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.
The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).
The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.
Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.
After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.
Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.
One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.
“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.
No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.
SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.
FROM THE JOURNAL OF ONCOLOGY PRACTICE
Does using e-cigarettes increase cigarette smoking in adolescents?
EVIDENCE SUMMARY
A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.1 It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.
Further studies also support a link between e-cigarette and cigarette use
Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).2 A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.3 A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).4 A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.5
RECOMMENDATIONS
A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.6 It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).
Editor’s takeaway
While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.
1. Soneji S, Barrington-Trimis JL, Willis TA, et al. Association between initial use of e-cigarettes and subsequent cigarette smoking among adolescents and young adults, a systematic review and meta-analysis. JAMA Pediatr. 2017;171:788-797.
2. Hammond D, Reid JL, Cole AG, et al. Electronic cigarette use and smoking initiation among youth: a longitudinal cohort study. CMAJ. 2017;189:E1328-E1336.
3. Conner M, Grogan S, Simms-Ellis R, et al. Do electronic cigarettes increase cigarette smoking in UK adolescents? Evidence from a 12-month prospective study. Tob Control. 2018;27:365-372.
4. Lozano P, Barrientos-Gutierrez I, Arillo-Santillan E, et al. A longitudinal study of electronic cigarette use and onset of conventional cigarette smoking and marijuana use among Mexican adolescents. Drug Alcohol Depend. 2017;180:427-430.
5. Goldenson NI, Leventhal AM, Stone MD, et al. Associations of electronic cigarette nicotine concentration with subsequent cigarette smoking and vaping levels in adolescents. JAMA Pediatr. 2017;171:1192-1199.
6. Walley SC, Jenssen BP; Section on Tobacco Control. Electronic nicotine delivery systems. Pediatrics. 2015;136:1018-1026.
EVIDENCE SUMMARY
A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.1 It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.
Further studies also support a link between e-cigarette and cigarette use
Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).2 A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.3 A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).4 A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.5
RECOMMENDATIONS
A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.6 It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).
Editor’s takeaway
While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.
EVIDENCE SUMMARY
A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.1 It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.
Further studies also support a link between e-cigarette and cigarette use
Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).2 A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.3 A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).4 A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.5
RECOMMENDATIONS
A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.6 It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).
Editor’s takeaway
While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.
1. Soneji S, Barrington-Trimis JL, Willis TA, et al. Association between initial use of e-cigarettes and subsequent cigarette smoking among adolescents and young adults, a systematic review and meta-analysis. JAMA Pediatr. 2017;171:788-797.
2. Hammond D, Reid JL, Cole AG, et al. Electronic cigarette use and smoking initiation among youth: a longitudinal cohort study. CMAJ. 2017;189:E1328-E1336.
3. Conner M, Grogan S, Simms-Ellis R, et al. Do electronic cigarettes increase cigarette smoking in UK adolescents? Evidence from a 12-month prospective study. Tob Control. 2018;27:365-372.
4. Lozano P, Barrientos-Gutierrez I, Arillo-Santillan E, et al. A longitudinal study of electronic cigarette use and onset of conventional cigarette smoking and marijuana use among Mexican adolescents. Drug Alcohol Depend. 2017;180:427-430.
5. Goldenson NI, Leventhal AM, Stone MD, et al. Associations of electronic cigarette nicotine concentration with subsequent cigarette smoking and vaping levels in adolescents. JAMA Pediatr. 2017;171:1192-1199.
6. Walley SC, Jenssen BP; Section on Tobacco Control. Electronic nicotine delivery systems. Pediatrics. 2015;136:1018-1026.
1. Soneji S, Barrington-Trimis JL, Willis TA, et al. Association between initial use of e-cigarettes and subsequent cigarette smoking among adolescents and young adults, a systematic review and meta-analysis. JAMA Pediatr. 2017;171:788-797.
2. Hammond D, Reid JL, Cole AG, et al. Electronic cigarette use and smoking initiation among youth: a longitudinal cohort study. CMAJ. 2017;189:E1328-E1336.
3. Conner M, Grogan S, Simms-Ellis R, et al. Do electronic cigarettes increase cigarette smoking in UK adolescents? Evidence from a 12-month prospective study. Tob Control. 2018;27:365-372.
4. Lozano P, Barrientos-Gutierrez I, Arillo-Santillan E, et al. A longitudinal study of electronic cigarette use and onset of conventional cigarette smoking and marijuana use among Mexican adolescents. Drug Alcohol Depend. 2017;180:427-430.
5. Goldenson NI, Leventhal AM, Stone MD, et al. Associations of electronic cigarette nicotine concentration with subsequent cigarette smoking and vaping levels in adolescents. JAMA Pediatr. 2017;171:1192-1199.
6. Walley SC, Jenssen BP; Section on Tobacco Control. Electronic nicotine delivery systems. Pediatrics. 2015;136:1018-1026.
EVIDENCE-BASED ANSWER:
Probably. Electronic cigarette (e-cigarette) use by adolescents is associated with a 2- to 4-fold increase in cigarette smoking over the next year (strength of recommendation: A, meta-analysis and subsequent prospective cohort studies).
An erythematous facial rash
A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.
Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.
Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).
A biopsy of her right cheek was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Mycosis fungoides
Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)
MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.1 There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially presents on the palms and soles.
Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.1 Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.
MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.2
Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.3
Continue to: Differential includes rosacea and seborrheic dermatitis
Differential includes rosacea and seborrheic dermatitis
The diagnosis of MF can be difficult as it often imitates other benign inflammatory conditions.
Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.4 A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.
Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.
Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.
Misdiagnosis can lead to advanced-stage disease
This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al3 indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.3 These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.3
Continue to: Treatment with topical desonide and mechlorethamine
Treatment with topical desonide and mechlorethamine
There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.5 Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.
As MF progresses to more advanced stages, treatment often combines skin-directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.6 TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.7
While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.
CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; luciasem@usf.edu
1. Jawed S, Myskowski P, Horwitz S, et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). Part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol. 2014;70:205.e1-e16.
2. Wohl Y, Tur E. Environmental risk factors for mycosis fungoides. Curr Probl Dermatol. 2007;35:52-64.
3. Kelati A, Gallouj S, Tahiri L, et al. Defining the mimics and clinico-histological diagnosis criteria for mycosis fungoides to minimize misdiagnosis. Int J Womens Dermatol. 2017;3:100-106.
4. Two AM, Wu W, Gallo RL, et al. Rosacea. part I. Introduction, categorization, histology, pathogenesis, and risk factors. J AM Acad Dermatol. 2015;72:749-758.
5. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013;149:25-32.
6. Jawed S, Myskowski P, Horwitz S, et al. Continuing medical education: Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70:223.e1-e17.
7. De Moraes FY, Carvalho Hde A, Hanna SA, et al. Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults. Rep Pract Oncol Radiother. 2014;19:92-98.
A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.
Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.
Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).
A biopsy of her right cheek was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Mycosis fungoides
Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)
MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.1 There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially presents on the palms and soles.
Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.1 Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.
MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.2
Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.3
Continue to: Differential includes rosacea and seborrheic dermatitis
Differential includes rosacea and seborrheic dermatitis
The diagnosis of MF can be difficult as it often imitates other benign inflammatory conditions.
Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.4 A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.
Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.
Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.
Misdiagnosis can lead to advanced-stage disease
This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al3 indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.3 These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.3
Continue to: Treatment with topical desonide and mechlorethamine
Treatment with topical desonide and mechlorethamine
There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.5 Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.
As MF progresses to more advanced stages, treatment often combines skin-directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.6 TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.7
While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.
CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; luciasem@usf.edu
A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.
Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.
Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).
A biopsy of her right cheek was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Mycosis fungoides
Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)
MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.1 There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially presents on the palms and soles.
Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.1 Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.
MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.2
Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.3
Continue to: Differential includes rosacea and seborrheic dermatitis
Differential includes rosacea and seborrheic dermatitis
The diagnosis of MF can be difficult as it often imitates other benign inflammatory conditions.
Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.4 A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.
Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.
Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.
Misdiagnosis can lead to advanced-stage disease
This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al3 indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.3 These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.3
Continue to: Treatment with topical desonide and mechlorethamine
Treatment with topical desonide and mechlorethamine
There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.5 Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.
As MF progresses to more advanced stages, treatment often combines skin-directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.6 TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.7
While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.
CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; luciasem@usf.edu
1. Jawed S, Myskowski P, Horwitz S, et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). Part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol. 2014;70:205.e1-e16.
2. Wohl Y, Tur E. Environmental risk factors for mycosis fungoides. Curr Probl Dermatol. 2007;35:52-64.
3. Kelati A, Gallouj S, Tahiri L, et al. Defining the mimics and clinico-histological diagnosis criteria for mycosis fungoides to minimize misdiagnosis. Int J Womens Dermatol. 2017;3:100-106.
4. Two AM, Wu W, Gallo RL, et al. Rosacea. part I. Introduction, categorization, histology, pathogenesis, and risk factors. J AM Acad Dermatol. 2015;72:749-758.
5. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013;149:25-32.
6. Jawed S, Myskowski P, Horwitz S, et al. Continuing medical education: Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70:223.e1-e17.
7. De Moraes FY, Carvalho Hde A, Hanna SA, et al. Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults. Rep Pract Oncol Radiother. 2014;19:92-98.
1. Jawed S, Myskowski P, Horwitz S, et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). Part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol. 2014;70:205.e1-e16.
2. Wohl Y, Tur E. Environmental risk factors for mycosis fungoides. Curr Probl Dermatol. 2007;35:52-64.
3. Kelati A, Gallouj S, Tahiri L, et al. Defining the mimics and clinico-histological diagnosis criteria for mycosis fungoides to minimize misdiagnosis. Int J Womens Dermatol. 2017;3:100-106.
4. Two AM, Wu W, Gallo RL, et al. Rosacea. part I. Introduction, categorization, histology, pathogenesis, and risk factors. J AM Acad Dermatol. 2015;72:749-758.
5. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013;149:25-32.
6. Jawed S, Myskowski P, Horwitz S, et al. Continuing medical education: Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70:223.e1-e17.
7. De Moraes FY, Carvalho Hde A, Hanna SA, et al. Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults. Rep Pract Oncol Radiother. 2014;19:92-98.
What to do when the evidence is not conclusive
Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.1 And some patients swear by it!
In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).
The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.
The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.
Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.
What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?
1. Reginster JY, Deroisy R, Rovati LC, et. al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251–256.
Editor-in-Chief
Editor-in-Chief
Editor-in-Chief
Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.1 And some patients swear by it!
In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).
The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.
The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.
Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.
What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?
Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.1 And some patients swear by it!
In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).
The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.
The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.
Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.
What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?
1. Reginster JY, Deroisy R, Rovati LC, et. al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251–256.
1. Reginster JY, Deroisy R, Rovati LC, et. al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251–256.
Infant with bilious emesis
A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.
He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.
In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.
An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Nonaccidental trauma
The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.
This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.1
Ask these questions, look beyond that single bruise
When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.1 During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.
Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.3 Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.
Additional work-up should include a skeletal survey for all children younger than 24 months2 in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.4 If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.4
Continue to: Research has underscored...
Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.5 A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.5
Management depends on injury type
The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.2
Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.
We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.
CORRESPONDENCE
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; ahuyler@mmc.org
1. Berkowitz CD. Physical abuse of children. N Engl J Med. 2017;376:1659-1666.
2. Lindberg DM, Berger RP, Reynolds MS, et al. Yield of skeletal survey by age in children referred to abuse specialists. J Pediatr. 2014;164:1268-1273.e1.
3. Harper NS, Feldman KW, Sugar NF, et al. Additional injuries in young infants with concern for abuse and apparently isolated bruises. J Pediatr. 2014;165:383-388.e1.
4. Lindberg DM, Shapiro RA, Blood EA, et al. Utility of hepatic transaminases in children with concern for abuse. Pediatrics. 2013;131:268-275.
5. Lindberg DM, Shapiro RA, Laskey AL, et al. Prevalence of abusive injuries in siblings and household contacts of physically abused children. Pediatrics. 2012;130:193-201.
A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.
He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.
In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.
An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Nonaccidental trauma
The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.
This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.1
Ask these questions, look beyond that single bruise
When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.1 During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.
Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.3 Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.
Additional work-up should include a skeletal survey for all children younger than 24 months2 in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.4 If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.4
Continue to: Research has underscored...
Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.5 A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.5
Management depends on injury type
The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.2
Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.
We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.
CORRESPONDENCE
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; ahuyler@mmc.org
A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.
He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.
In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.
An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Nonaccidental trauma
The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.
This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.1
Ask these questions, look beyond that single bruise
When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.1 During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.
Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.3 Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.
Additional work-up should include a skeletal survey for all children younger than 24 months2 in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.4 If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.4
Continue to: Research has underscored...
Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.5 A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.5
Management depends on injury type
The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.2
Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.
We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.
CORRESPONDENCE
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; ahuyler@mmc.org
1. Berkowitz CD. Physical abuse of children. N Engl J Med. 2017;376:1659-1666.
2. Lindberg DM, Berger RP, Reynolds MS, et al. Yield of skeletal survey by age in children referred to abuse specialists. J Pediatr. 2014;164:1268-1273.e1.
3. Harper NS, Feldman KW, Sugar NF, et al. Additional injuries in young infants with concern for abuse and apparently isolated bruises. J Pediatr. 2014;165:383-388.e1.
4. Lindberg DM, Shapiro RA, Blood EA, et al. Utility of hepatic transaminases in children with concern for abuse. Pediatrics. 2013;131:268-275.
5. Lindberg DM, Shapiro RA, Laskey AL, et al. Prevalence of abusive injuries in siblings and household contacts of physically abused children. Pediatrics. 2012;130:193-201.
1. Berkowitz CD. Physical abuse of children. N Engl J Med. 2017;376:1659-1666.
2. Lindberg DM, Berger RP, Reynolds MS, et al. Yield of skeletal survey by age in children referred to abuse specialists. J Pediatr. 2014;164:1268-1273.e1.
3. Harper NS, Feldman KW, Sugar NF, et al. Additional injuries in young infants with concern for abuse and apparently isolated bruises. J Pediatr. 2014;165:383-388.e1.
4. Lindberg DM, Shapiro RA, Blood EA, et al. Utility of hepatic transaminases in children with concern for abuse. Pediatrics. 2013;131:268-275.
5. Lindberg DM, Shapiro RA, Laskey AL, et al. Prevalence of abusive injuries in siblings and household contacts of physically abused children. Pediatrics. 2012;130:193-201.
Was this patient's transdermal Tx making her dog sick?
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
Early pregnancy loss: Pretreat with mifepristone?
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
PRACTICE CHANGER
Pretreat patients with oral mifepristone prior to using vaginal misoprostol to increase the efficacy of medical management of early pregnancy loss over that with misoprostol alone.
STRENGTH OF RECOMMENDATION
B: Based on a single, well-executed, randomized controlled trial.1
Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
Pneumococcal conjugate vaccine update
Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).
In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.
How we got to where we are now
Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.1 In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.2 However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 13), presumably due to the decreased transmission of pneumococcal infections from children to older adults.
Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 23).
ACIP had 3 options in formulating its recommendations.
- Recommend the vaccine for routine use universally or among designated high-risk groups.
- Do not recommend the vaccine.
- Recommend the vaccine only for specific patients after individualized clinical decision making.
The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.
Practical issues
ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE1). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.
Continue to: Prior to the recent change...
Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.
3 sentences summarize change in vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences4:
- When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
- For patients ≥ 65 years, separate the vaccines by 12 months or more—regardless of which vaccine is administered first.
- For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.
Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences1:
- When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
- Administer no more than 2 doses before age 65.
- For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.
1. CDC. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816-819.
2. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822-825.
3. Matanock A. Considerations for PCV13 use among adults ≥65 years old and a summary of the evidence to recommendations framework. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/Pneumococcal-2-Matanock-508.pdf. Accessed December 5, 2019.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015; 64:944-947.
Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).
In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.
How we got to where we are now
Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.1 In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.2 However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 13), presumably due to the decreased transmission of pneumococcal infections from children to older adults.
Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 23).
ACIP had 3 options in formulating its recommendations.
- Recommend the vaccine for routine use universally or among designated high-risk groups.
- Do not recommend the vaccine.
- Recommend the vaccine only for specific patients after individualized clinical decision making.
The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.
Practical issues
ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE1). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.
Continue to: Prior to the recent change...
Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.
3 sentences summarize change in vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences4:
- When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
- For patients ≥ 65 years, separate the vaccines by 12 months or more—regardless of which vaccine is administered first.
- For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.
Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences1:
- When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
- Administer no more than 2 doses before age 65.
- For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.
Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).
In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.
How we got to where we are now
Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.1 In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.2 However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 13), presumably due to the decreased transmission of pneumococcal infections from children to older adults.
Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 23).
ACIP had 3 options in formulating its recommendations.
- Recommend the vaccine for routine use universally or among designated high-risk groups.
- Do not recommend the vaccine.
- Recommend the vaccine only for specific patients after individualized clinical decision making.
The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.
Practical issues
ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE1). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.
Continue to: Prior to the recent change...
Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.
3 sentences summarize change in vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences4:
- When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
- For patients ≥ 65 years, separate the vaccines by 12 months or more—regardless of which vaccine is administered first.
- For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.
Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences1:
- When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
- Administer no more than 2 doses before age 65.
- For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.
1. CDC. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816-819.
2. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822-825.
3. Matanock A. Considerations for PCV13 use among adults ≥65 years old and a summary of the evidence to recommendations framework. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/Pneumococcal-2-Matanock-508.pdf. Accessed December 5, 2019.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015; 64:944-947.
1. CDC. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816-819.
2. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822-825.
3. Matanock A. Considerations for PCV13 use among adults ≥65 years old and a summary of the evidence to recommendations framework. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/Pneumococcal-2-Matanock-508.pdf. Accessed December 5, 2019.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015; 64:944-947.
