Study Overview

Objective. To determine the efficacy and safety of delayed antibiotic prescribing strategies in acute uncomplicated respiratory infections.

Design. Randomized, multicenter, open-label clinical trial.

Setting and participants. The setting was 23 primary care centers in Spain. The study recruited patients who were 18 years of age or older with an acute uncomplicated respiratory infection (acute pharyngitis, rhinosinusitis, acute bronchitis, exacerbations of chronic bronchitis or mild to moderate chronic obstructive pulmonary disease). Patients with these infections were included by the physicians as long as they were unsure of whether to use antibiotics or not. The study protocol has been published elsewhere [1].

Intervention. Patients were randomized to 1 of 4 potential prescription strategies: (1) a delayed patient-led prescription strategy where patients were given an antibiotic prescription at first consultation but instructed to fill the prescription only if they felt substantially worse or saw no improvement in symptoms in the first few days after initial consultation; (2) a delayed prescription collection strategy requiring patients to collect their prescription from the primary care center reception desk 3 days after the first consultation; (3) an immediate prescription strategy; or (4) no antibiotic strategy. The patient-led and delayed collection strategies were considered delayed prescription strategies.

Main outcome measures. Duration of symptoms and severity of symptoms. Patients filled out a daily questionnaire for a maximum of 30 days, which listed common symptoms such as fever, discomfort or general pain, cough, difficulty sleeping, and changes in everyday life, and specific symptoms according to condition. Patients assessed severity of their symptoms using 6-point Likert scale, with scores of 1-2 considered mild, 3-4 moderate, and 5-6 severe. Secondary outcomes included antibiotic use, patient satisfaction, patients’ beliefs in the effectiveness of antibiotics, and absenteeism (absence from work or doing their daily activities).

Main results. A total of 405 patients were recruited, 398 of whom were included in the analysis. 136 patients (34.2%) were men. The mean (SD) age was 45 (17) years and 265 patients (72%) had at least a secondary education level. The most common infection was pharyngitis (n = 184; 46.2%), followed by acute bronchitis (n = 128; 32.2%). The mean severity of symptoms ranged from 1.8 to 3.5 points on the Likert scale, and mean (SD) duration of symptoms described on first visit was 6 (6) days. The mean (SD) general health status on first visit was 54 (20) based on a scale with 0 indicating worst health status and 100 indicating best health status. 314 patients (80.1%) were nonsmokers, and 372 patients (93.5%) did not have a respiratory comorbidity. The presence of symptoms on first visit was similar among the 4 groups.

The duration of the common symptoms of fever, discomfort or general pain, and cough was shorter in the immediate prescription group versus the no prescription group (P < 0.05 for all). In the immediate prescription group, the duration of patient symptoms after first visit was significantly different from that of the prescription collection and patient-led prescription groups only for discomfort or general pain. The mean (SD) duration of severe symptoms was 3.6 (3.3) days for the immediate prescription group, 4.0 (4.2) days for the prescription collection group, 5.1 (6.3) days for the patient-led prescription group, and 4.7 (3.6) days for the no prescription group. The median (interquartile range [IQR]) of severe symptoms was 3 (1–4) days for the prescription collection group and 3 (2–6) days for the patient-led prescription group. The median (IQR) of the maximum severity for any symptom was 5 (3–5) for the immediate prescription group and the prescription collection group; 5 (4–5) for the patient-led prescription group; and 5 (4–6) for the no prescription group. Patients randomized to the no prescription strategy or to either of the delayed strategies used fewer antibiotics and less frequently believed in antibiotic effectiveness. Among patients in the immediate prescription group, 91.1% used antibiotics; in the delayed patient-led, delayed collection, and no prescription groups, the  rates of antibiotic use were 32.6%, 23.0%, and 12.1%, respectively. There were very few adverse events across groups, although the no prescription group had 3 adverse events compared with 0-1 in the other groups. Satisfaction was similar across groups.

Conclusion. Delayed strategies were associated with slightly greater but clinically similar symptom burden and duration and also with substantially reduced antibiotic use when compared with an immediate strategy.

Commentary

Acute respiratory infections are a common reasons for physician visits. These infections tend to be self-limiting and overuse of antibiotics for these infections is widespread. Approximately 60% of patients with a sore throat and ~70% of patients with acute uncomplicated bronchitis receive antibiotic prescriptions despite the literature suggesting no or limited benefit [2,3].Antibiotic resistance is a growing problem and the main cause of this problem is misuse of antibiotics.

Often physicians feel pressured into prescribing anti-biotics due to patient expectation and patient satisfaction metrics. In the face of the critical need to reduce overuse, delayed antibiotic prescribing strategies offers a compromise between immediate and no prescription [4]. Delayed prescribing strategies have been evaluated previously [5–8], with findings suggesting they do reduce antibiotic use. This study strengthens the evidence base supporting the delayed strategy.

This study has a few limitations. The sample size was small, and symptom data was obtained via patient self-report. In addition, the randomization procedure was not described. However, the investigators were able to achieve good patient retention, with very few patients lost to follow-up. The investigators used an intention to treat analysis; thus, the estimate of treatment effect size can be considered conservative.

In terms of baseline characteristics of the study participants, there was a lower overall education level, fewer smokers, and less respiratory comorbidity (defined as only cardiovascular comorbidity [P = 0.12] and diabetes [P = 0.19]) in the patient-led group. Otherwise, groups were very well-matched. Most patients in the study had pharyngitis and bronchitis, limiting the inferences for patients with rhinosinusitis or exacerbation of mild-to-moderate COPD.

Applications for Clinical Practice

Delayed antibiotic prescribing for acute uncomplicated respiratory infections appears to be an acceptable strategy for reducing the overuse of antibiotics. As patients may lack knowledge of this prescribing strategy [9], clinicians may need to spend time explaining the concept. Using the term “back-up antibiotics” instead of “delayed prescription” [10] may help to increase patients’ understanding and acceptance.

—Ajay Dharod, MD

Study Overview

Objective. To determine the efficacy and safety of delayed antibiotic prescribing strategies in acute uncomplicated respiratory infections.

Design. Randomized, multicenter, open-label clinical trial.

Setting and participants. The setting was 23 primary care centers in Spain. The study recruited patients who were 18 years of age or older with an acute uncomplicated respiratory infection (acute pharyngitis, rhinosinusitis, acute bronchitis, exacerbations of chronic bronchitis or mild to moderate chronic obstructive pulmonary disease). Patients with these infections were included by the physicians as long as they were unsure of whether to use antibiotics or not. The study protocol has been published elsewhere [1].

Intervention. Patients were randomized to 1 of 4 potential prescription strategies: (1) a delayed patient-led prescription strategy where patients were given an antibiotic prescription at first consultation but instructed to fill the prescription only if they felt substantially worse or saw no improvement in symptoms in the first few days after initial consultation; (2) a delayed prescription collection strategy requiring patients to collect their prescription from the primary care center reception desk 3 days after the first consultation; (3) an immediate prescription strategy; or (4) no antibiotic strategy. The patient-led and delayed collection strategies were considered delayed prescription strategies.

Main outcome measures. Duration of symptoms and severity of symptoms. Patients filled out a daily questionnaire for a maximum of 30 days, which listed common symptoms such as fever, discomfort or general pain, cough, difficulty sleeping, and changes in everyday life, and specific symptoms according to condition. Patients assessed severity of their symptoms using 6-point Likert scale, with scores of 1-2 considered mild, 3-4 moderate, and 5-6 severe. Secondary outcomes included antibiotic use, patient satisfaction, patients’ beliefs in the effectiveness of antibiotics, and absenteeism (absence from work or doing their daily activities).

Main results. A total of 405 patients were recruited, 398 of whom were included in the analysis. 136 patients (34.2%) were men. The mean (SD) age was 45 (17) years and 265 patients (72%) had at least a secondary education level. The most common infection was pharyngitis (n = 184; 46.2%), followed by acute bronchitis (n = 128; 32.2%). The mean severity of symptoms ranged from 1.8 to 3.5 points on the Likert scale, and mean (SD) duration of symptoms described on first visit was 6 (6) days. The mean (SD) general health status on first visit was 54 (20) based on a scale with 0 indicating worst health status and 100 indicating best health status. 314 patients (80.1%) were nonsmokers, and 372 patients (93.5%) did not have a respiratory comorbidity. The presence of symptoms on first visit was similar among the 4 groups.

The duration of the common symptoms of fever, discomfort or general pain, and cough was shorter in the immediate prescription group versus the no prescription group (P < 0.05 for all). In the immediate prescription group, the duration of patient symptoms after first visit was significantly different from that of the prescription collection and patient-led prescription groups only for discomfort or general pain. The mean (SD) duration of severe symptoms was 3.6 (3.3) days for the immediate prescription group, 4.0 (4.2) days for the prescription collection group, 5.1 (6.3) days for the patient-led prescription group, and 4.7 (3.6) days for the no prescription group. The median (interquartile range [IQR]) of severe symptoms was 3 (1–4) days for the prescription collection group and 3 (2–6) days for the patient-led prescription group. The median (IQR) of the maximum severity for any symptom was 5 (3–5) for the immediate prescription group and the prescription collection group; 5 (4–5) for the patient-led prescription group; and 5 (4–6) for the no prescription group. Patients randomized to the no prescription strategy or to either of the delayed strategies used fewer antibiotics and less frequently believed in antibiotic effectiveness. Among patients in the immediate prescription group, 91.1% used antibiotics; in the delayed patient-led, delayed collection, and no prescription groups, the  rates of antibiotic use were 32.6%, 23.0%, and 12.1%, respectively. There were very few adverse events across groups, although the no prescription group had 3 adverse events compared with 0-1 in the other groups. Satisfaction was similar across groups.

Conclusion. Delayed strategies were associated with slightly greater but clinically similar symptom burden and duration and also with substantially reduced antibiotic use when compared with an immediate strategy.

Commentary

Acute respiratory infections are a common reasons for physician visits. These infections tend to be self-limiting and overuse of antibiotics for these infections is widespread. Approximately 60% of patients with a sore throat and ~70% of patients with acute uncomplicated bronchitis receive antibiotic prescriptions despite the literature suggesting no or limited benefit [2,3].Antibiotic resistance is a growing problem and the main cause of this problem is misuse of antibiotics.

Often physicians feel pressured into prescribing anti-biotics due to patient expectation and patient satisfaction metrics. In the face of the critical need to reduce overuse, delayed antibiotic prescribing strategies offers a compromise between immediate and no prescription [4]. Delayed prescribing strategies have been evaluated previously [5–8], with findings suggesting they do reduce antibiotic use. This study strengthens the evidence base supporting the delayed strategy.

This study has a few limitations. The sample size was small, and symptom data was obtained via patient self-report. In addition, the randomization procedure was not described. However, the investigators were able to achieve good patient retention, with very few patients lost to follow-up. The investigators used an intention to treat analysis; thus, the estimate of treatment effect size can be considered conservative.

In terms of baseline characteristics of the study participants, there was a lower overall education level, fewer smokers, and less respiratory comorbidity (defined as only cardiovascular comorbidity [P = 0.12] and diabetes [P = 0.19]) in the patient-led group. Otherwise, groups were very well-matched. Most patients in the study had pharyngitis and bronchitis, limiting the inferences for patients with rhinosinusitis or exacerbation of mild-to-moderate COPD.

Applications for Clinical Practice

Delayed antibiotic prescribing for acute uncomplicated respiratory infections appears to be an acceptable strategy for reducing the overuse of antibiotics. As patients may lack knowledge of this prescribing strategy [9], clinicians may need to spend time explaining the concept. Using the term “back-up antibiotics” instead of “delayed prescription” [10] may help to increase patients’ understanding and acceptance.

—Ajay Dharod, MD

Study Overview

Objective. To determine the efficacy and safety of delayed antibiotic prescribing strategies in acute uncomplicated respiratory infections.

Design. Randomized, multicenter, open-label clinical trial.

Setting and participants. The setting was 23 primary care centers in Spain. The study recruited patients who were 18 years of age or older with an acute uncomplicated respiratory infection (acute pharyngitis, rhinosinusitis, acute bronchitis, exacerbations of chronic bronchitis or mild to moderate chronic obstructive pulmonary disease). Patients with these infections were included by the physicians as long as they were unsure of whether to use antibiotics or not. The study protocol has been published elsewhere [1].

Intervention. Patients were randomized to 1 of 4 potential prescription strategies: (1) a delayed patient-led prescription strategy where patients were given an antibiotic prescription at first consultation but instructed to fill the prescription only if they felt substantially worse or saw no improvement in symptoms in the first few days after initial consultation; (2) a delayed prescription collection strategy requiring patients to collect their prescription from the primary care center reception desk 3 days after the first consultation; (3) an immediate prescription strategy; or (4) no antibiotic strategy. The patient-led and delayed collection strategies were considered delayed prescription strategies.

Main outcome measures. Duration of symptoms and severity of symptoms. Patients filled out a daily questionnaire for a maximum of 30 days, which listed common symptoms such as fever, discomfort or general pain, cough, difficulty sleeping, and changes in everyday life, and specific symptoms according to condition. Patients assessed severity of their symptoms using 6-point Likert scale, with scores of 1-2 considered mild, 3-4 moderate, and 5-6 severe. Secondary outcomes included antibiotic use, patient satisfaction, patients’ beliefs in the effectiveness of antibiotics, and absenteeism (absence from work or doing their daily activities).

Main results. A total of 405 patients were recruited, 398 of whom were included in the analysis. 136 patients (34.2%) were men. The mean (SD) age was 45 (17) years and 265 patients (72%) had at least a secondary education level. The most common infection was pharyngitis (n = 184; 46.2%), followed by acute bronchitis (n = 128; 32.2%). The mean severity of symptoms ranged from 1.8 to 3.5 points on the Likert scale, and mean (SD) duration of symptoms described on first visit was 6 (6) days. The mean (SD) general health status on first visit was 54 (20) based on a scale with 0 indicating worst health status and 100 indicating best health status. 314 patients (80.1%) were nonsmokers, and 372 patients (93.5%) did not have a respiratory comorbidity. The presence of symptoms on first visit was similar among the 4 groups.

The duration of the common symptoms of fever, discomfort or general pain, and cough was shorter in the immediate prescription group versus the no prescription group (P < 0.05 for all). In the immediate prescription group, the duration of patient symptoms after first visit was significantly different from that of the prescription collection and patient-led prescription groups only for discomfort or general pain. The mean (SD) duration of severe symptoms was 3.6 (3.3) days for the immediate prescription group, 4.0 (4.2) days for the prescription collection group, 5.1 (6.3) days for the patient-led prescription group, and 4.7 (3.6) days for the no prescription group. The median (interquartile range [IQR]) of severe symptoms was 3 (1–4) days for the prescription collection group and 3 (2–6) days for the patient-led prescription group. The median (IQR) of the maximum severity for any symptom was 5 (3–5) for the immediate prescription group and the prescription collection group; 5 (4–5) for the patient-led prescription group; and 5 (4–6) for the no prescription group. Patients randomized to the no prescription strategy or to either of the delayed strategies used fewer antibiotics and less frequently believed in antibiotic effectiveness. Among patients in the immediate prescription group, 91.1% used antibiotics; in the delayed patient-led, delayed collection, and no prescription groups, the  rates of antibiotic use were 32.6%, 23.0%, and 12.1%, respectively. There were very few adverse events across groups, although the no prescription group had 3 adverse events compared with 0-1 in the other groups. Satisfaction was similar across groups.

Conclusion. Delayed strategies were associated with slightly greater but clinically similar symptom burden and duration and also with substantially reduced antibiotic use when compared with an immediate strategy.

Commentary

Acute respiratory infections are a common reasons for physician visits. These infections tend to be self-limiting and overuse of antibiotics for these infections is widespread. Approximately 60% of patients with a sore throat and ~70% of patients with acute uncomplicated bronchitis receive antibiotic prescriptions despite the literature suggesting no or limited benefit [2,3].Antibiotic resistance is a growing problem and the main cause of this problem is misuse of antibiotics.

Often physicians feel pressured into prescribing anti-biotics due to patient expectation and patient satisfaction metrics. In the face of the critical need to reduce overuse, delayed antibiotic prescribing strategies offers a compromise between immediate and no prescription [4]. Delayed prescribing strategies have been evaluated previously [5–8], with findings suggesting they do reduce antibiotic use. This study strengthens the evidence base supporting the delayed strategy.

This study has a few limitations. The sample size was small, and symptom data was obtained via patient self-report. In addition, the randomization procedure was not described. However, the investigators were able to achieve good patient retention, with very few patients lost to follow-up. The investigators used an intention to treat analysis; thus, the estimate of treatment effect size can be considered conservative.

In terms of baseline characteristics of the study participants, there was a lower overall education level, fewer smokers, and less respiratory comorbidity (defined as only cardiovascular comorbidity [P = 0.12] and diabetes [P = 0.19]) in the patient-led group. Otherwise, groups were very well-matched. Most patients in the study had pharyngitis and bronchitis, limiting the inferences for patients with rhinosinusitis or exacerbation of mild-to-moderate COPD.

Applications for Clinical Practice

Delayed antibiotic prescribing for acute uncomplicated respiratory infections appears to be an acceptable strategy for reducing the overuse of antibiotics. As patients may lack knowledge of this prescribing strategy [9], clinicians may need to spend time explaining the concept. Using the term “back-up antibiotics” instead of “delayed prescription” [10] may help to increase patients’ understanding and acceptance.

—Ajay Dharod, MD

Yes, it’s time for another “year ahead” type column where the writer attempts to provide clarity on future events. What does “Hospital Medicine 2016” hold for us? I hope by the time Hospital Medicine 2017 rolls around, everyone will have forgotten the wrong predictions and only remember those that reveal my exceptional clairvoyance and prescient knowledge.

NP and PA Practice in Hospital Medicine Will Continue to Grow

Well, it doesn’t take a crystal ball or tarot cards to predict this. One only has to look at the data. The 2012 State of Hospital Medicine report revealed that 51.7% of hospital medicine groups (HMGs) employed nurse practitioners (NPs) and/or physician assistants (PAs) in their practice. Two short years later, the survey showed 83% of HMGs reported having NPs and/or PAs in their groups. That is an astounding amount of growth in a short period of time, which brings me to my next prediction.

HMGs Will Have to Continue to Figure Out How to Hire and Deploy NPs and PAs in Sensible Ways

I know that statement is very controversial. Not. But the true work of utilizing NP and PA providers in hospitalist practice is not in the hiring; it’s how to use these providers in thoughtful, sensible, and cost-effective ways.

A group leader really needs to know and understand the drivers behind the need for these hires as well as understand the financial landscape in the hiring. Are you hiring an NP/PA because you want to reduce your provider workforce cost? Are you hiring to target quality outcomes in a specific patient population? Are you hiring to staff your observation unit, freeing up your physicians for higher-acuity work? Are you hiring to treat and improve physician burnout? Or is this the only carbon-based life form you can attract to the outer boroughs of your northern clime in the deepest, darkest days of January?

All these may or may not be good reasons, but understanding those variables will help you get the right person for the right reason and will help you evaluate the return on investment and the impact on practice.

Diversity Prevents Disease

Much like the potato monoculture of McDonald’s french fries increasing the risk of potato diseases, monoculture in your hospitalist group may breed burnout and bad attitudes. Diversity of experience, perspective, and skill set may inoculate your group, keeping the dreaded crispy coated from complaining about schedule, workload, or acuity or, worse yet, simply leaving.

I don’t have data to support this, but I have heard anecdotally from more than one HMG leader that the addition of NP/PA providers to physician teams has improved physician satisfaction. SHM obviously agrees with this philosophy, as they value and support the value of a “big tent” philosophy. This big tent includes all types of people who contribute to the culture of this organization, making it stronger, more nimble and innovative, and definitely more fun.

Diversity in providers can only have a positive impact on your organization’s culture.

Whatever the Reason You Hire Them, Get Ready for Change

Be prepared for evolution. You may have initially hired an NP or PA simply to do admissions or to see all of your orthopedic co-management patients. But over time, your practice is going to morph and evolve, hopefully, in positive ways. Bring your NP/PA colleagues along for the ride; pull up a chair to the table. They may be able to provide new direction, support, or service lines to your practice in ways you hadn’t considered.

NP/PA providers’ abilities and ambitions will change over time as well. Make sure that change goes both ways. You may find that their influence and impact on your organization’s productivity and growth go beyond their industry. Consider utilizing NP/PA providers in novel ways; maybe they have great onboarding skills, are fabulous at scheduling, or can look at a spreadsheet without going cross-eyed or bald.

Change is growth. And growth is good. Unless you would rather die.

HM Needs to Develop Innovative Care Models; NPs/PAs Provide a Platform for Innovation

Inpatient medicine is changing in a rapid and unpredictable way. Some of the necessity of that work is driven by financial incentives and quality indicators, but necessity is the biggest driver of all. People, patients, and providers are getting old (thank God it’s not just me). There simply are not enough physicians to care for our rapidly aging population, or if there are, they are all employed in sunny Southern California. How we respond to this threat or opportunity is one of our most important charges. We own the inpatient kingdom. We need to lead with benevolence and thoughtfulness. We need to really look ahead and identify new ways to manage the complexity of a system whose complexity continues to mutate like some avian virus. I can’t see a future without a crucial role played by my NP/PA brethren. Can we begin this conversation with the long view in mind and really begin to own this in a true and responsible way?

Thanks for your attention, and remember, in 2017 you will have forgotten all the ways, if any, that I was wrong. TH

Ms. Cardin is a nurse practitioner in the Section of Hospital Medicine at the University of Chicago and is chair of SHM’s NP/PA Committee. She is a newly elected SHM board member.

Yes, it’s time for another “year ahead” type column where the writer attempts to provide clarity on future events. What does “Hospital Medicine 2016” hold for us? I hope by the time Hospital Medicine 2017 rolls around, everyone will have forgotten the wrong predictions and only remember those that reveal my exceptional clairvoyance and prescient knowledge.

NP and PA Practice in Hospital Medicine Will Continue to Grow

Well, it doesn’t take a crystal ball or tarot cards to predict this. One only has to look at the data. The 2012 State of Hospital Medicine report revealed that 51.7% of hospital medicine groups (HMGs) employed nurse practitioners (NPs) and/or physician assistants (PAs) in their practice. Two short years later, the survey showed 83% of HMGs reported having NPs and/or PAs in their groups. That is an astounding amount of growth in a short period of time, which brings me to my next prediction.

HMGs Will Have to Continue to Figure Out How to Hire and Deploy NPs and PAs in Sensible Ways

I know that statement is very controversial. Not. But the true work of utilizing NP and PA providers in hospitalist practice is not in the hiring; it’s how to use these providers in thoughtful, sensible, and cost-effective ways.

A group leader really needs to know and understand the drivers behind the need for these hires as well as understand the financial landscape in the hiring. Are you hiring an NP/PA because you want to reduce your provider workforce cost? Are you hiring to target quality outcomes in a specific patient population? Are you hiring to staff your observation unit, freeing up your physicians for higher-acuity work? Are you hiring to treat and improve physician burnout? Or is this the only carbon-based life form you can attract to the outer boroughs of your northern clime in the deepest, darkest days of January?

All these may or may not be good reasons, but understanding those variables will help you get the right person for the right reason and will help you evaluate the return on investment and the impact on practice.

Diversity Prevents Disease

Much like the potato monoculture of McDonald’s french fries increasing the risk of potato diseases, monoculture in your hospitalist group may breed burnout and bad attitudes. Diversity of experience, perspective, and skill set may inoculate your group, keeping the dreaded crispy coated from complaining about schedule, workload, or acuity or, worse yet, simply leaving.

I don’t have data to support this, but I have heard anecdotally from more than one HMG leader that the addition of NP/PA providers to physician teams has improved physician satisfaction. SHM obviously agrees with this philosophy, as they value and support the value of a “big tent” philosophy. This big tent includes all types of people who contribute to the culture of this organization, making it stronger, more nimble and innovative, and definitely more fun.

Diversity in providers can only have a positive impact on your organization’s culture.

Whatever the Reason You Hire Them, Get Ready for Change

Be prepared for evolution. You may have initially hired an NP or PA simply to do admissions or to see all of your orthopedic co-management patients. But over time, your practice is going to morph and evolve, hopefully, in positive ways. Bring your NP/PA colleagues along for the ride; pull up a chair to the table. They may be able to provide new direction, support, or service lines to your practice in ways you hadn’t considered.

NP/PA providers’ abilities and ambitions will change over time as well. Make sure that change goes both ways. You may find that their influence and impact on your organization’s productivity and growth go beyond their industry. Consider utilizing NP/PA providers in novel ways; maybe they have great onboarding skills, are fabulous at scheduling, or can look at a spreadsheet without going cross-eyed or bald.

Change is growth. And growth is good. Unless you would rather die.

HM Needs to Develop Innovative Care Models; NPs/PAs Provide a Platform for Innovation

Inpatient medicine is changing in a rapid and unpredictable way. Some of the necessity of that work is driven by financial incentives and quality indicators, but necessity is the biggest driver of all. People, patients, and providers are getting old (thank God it’s not just me). There simply are not enough physicians to care for our rapidly aging population, or if there are, they are all employed in sunny Southern California. How we respond to this threat or opportunity is one of our most important charges. We own the inpatient kingdom. We need to lead with benevolence and thoughtfulness. We need to really look ahead and identify new ways to manage the complexity of a system whose complexity continues to mutate like some avian virus. I can’t see a future without a crucial role played by my NP/PA brethren. Can we begin this conversation with the long view in mind and really begin to own this in a true and responsible way?

Thanks for your attention, and remember, in 2017 you will have forgotten all the ways, if any, that I was wrong. TH

Ms. Cardin is a nurse practitioner in the Section of Hospital Medicine at the University of Chicago and is chair of SHM’s NP/PA Committee. She is a newly elected SHM board member.

Yes, it’s time for another “year ahead” type column where the writer attempts to provide clarity on future events. What does “Hospital Medicine 2016” hold for us? I hope by the time Hospital Medicine 2017 rolls around, everyone will have forgotten the wrong predictions and only remember those that reveal my exceptional clairvoyance and prescient knowledge.

NP and PA Practice in Hospital Medicine Will Continue to Grow

Well, it doesn’t take a crystal ball or tarot cards to predict this. One only has to look at the data. The 2012 State of Hospital Medicine report revealed that 51.7% of hospital medicine groups (HMGs) employed nurse practitioners (NPs) and/or physician assistants (PAs) in their practice. Two short years later, the survey showed 83% of HMGs reported having NPs and/or PAs in their groups. That is an astounding amount of growth in a short period of time, which brings me to my next prediction.

HMGs Will Have to Continue to Figure Out How to Hire and Deploy NPs and PAs in Sensible Ways

I know that statement is very controversial. Not. But the true work of utilizing NP and PA providers in hospitalist practice is not in the hiring; it’s how to use these providers in thoughtful, sensible, and cost-effective ways.

A group leader really needs to know and understand the drivers behind the need for these hires as well as understand the financial landscape in the hiring. Are you hiring an NP/PA because you want to reduce your provider workforce cost? Are you hiring to target quality outcomes in a specific patient population? Are you hiring to staff your observation unit, freeing up your physicians for higher-acuity work? Are you hiring to treat and improve physician burnout? Or is this the only carbon-based life form you can attract to the outer boroughs of your northern clime in the deepest, darkest days of January?

All these may or may not be good reasons, but understanding those variables will help you get the right person for the right reason and will help you evaluate the return on investment and the impact on practice.

Diversity Prevents Disease

Much like the potato monoculture of McDonald’s french fries increasing the risk of potato diseases, monoculture in your hospitalist group may breed burnout and bad attitudes. Diversity of experience, perspective, and skill set may inoculate your group, keeping the dreaded crispy coated from complaining about schedule, workload, or acuity or, worse yet, simply leaving.

I don’t have data to support this, but I have heard anecdotally from more than one HMG leader that the addition of NP/PA providers to physician teams has improved physician satisfaction. SHM obviously agrees with this philosophy, as they value and support the value of a “big tent” philosophy. This big tent includes all types of people who contribute to the culture of this organization, making it stronger, more nimble and innovative, and definitely more fun.

Diversity in providers can only have a positive impact on your organization’s culture.

Whatever the Reason You Hire Them, Get Ready for Change

Be prepared for evolution. You may have initially hired an NP or PA simply to do admissions or to see all of your orthopedic co-management patients. But over time, your practice is going to morph and evolve, hopefully, in positive ways. Bring your NP/PA colleagues along for the ride; pull up a chair to the table. They may be able to provide new direction, support, or service lines to your practice in ways you hadn’t considered.

NP/PA providers’ abilities and ambitions will change over time as well. Make sure that change goes both ways. You may find that their influence and impact on your organization’s productivity and growth go beyond their industry. Consider utilizing NP/PA providers in novel ways; maybe they have great onboarding skills, are fabulous at scheduling, or can look at a spreadsheet without going cross-eyed or bald.

Change is growth. And growth is good. Unless you would rather die.

HM Needs to Develop Innovative Care Models; NPs/PAs Provide a Platform for Innovation

Inpatient medicine is changing in a rapid and unpredictable way. Some of the necessity of that work is driven by financial incentives and quality indicators, but necessity is the biggest driver of all. People, patients, and providers are getting old (thank God it’s not just me). There simply are not enough physicians to care for our rapidly aging population, or if there are, they are all employed in sunny Southern California. How we respond to this threat or opportunity is one of our most important charges. We own the inpatient kingdom. We need to lead with benevolence and thoughtfulness. We need to really look ahead and identify new ways to manage the complexity of a system whose complexity continues to mutate like some avian virus. I can’t see a future without a crucial role played by my NP/PA brethren. Can we begin this conversation with the long view in mind and really begin to own this in a true and responsible way?

Thanks for your attention, and remember, in 2017 you will have forgotten all the ways, if any, that I was wrong. TH

Ms. Cardin is a nurse practitioner in the Section of Hospital Medicine at the University of Chicago and is chair of SHM’s NP/PA Committee. She is a newly elected SHM board member.

ATLANTA (Reuters) - Did you get enough sleep last night? If not, you are not alone. More than one out of three American adults do not get enough sleep, according to a study released Thursday from the U.S. Centers for Disease Control and Prevention.

"That's a big problem," says Dr. Nancy Collop, director of the Emory Sleep Center at Emory University School of Medicine in Atlanta, who is familiar with the study. "You don't function as well, your ability to pay attention is reduced, and it can have serious, long term side effects. It can change your metabolism for the worse."

At least seven hours of sleep is considered healthy for an adults aged 18 to 60, according to the American Academy of Sleep Medicine and the Sleep Research Society. The CDC analyzed data from a 2014 survey of 444,306 adults and found roughly 65% of respondents reported getting that amount of

sleep.

"Lifestyle changes such as going to bed at the same time each night; rising at the same time each morning; and turning off or removing televisions, computers, mobile devices from the bedroom, can help people get the healthy sleep they need," said Dr. Wayne Giles, director of the CDC's Division of Population Health, in a statement.

Getting less than seven hours a night is associated with an increased risk of obesity, diabetes, high blood pressure, heart disease, stroke and frequent mental distress, the study shows. Published in the CDC's Morbidity and Mortality Weekly Report, the study is the first of its kind to look at all 50 U.S. states and the District of Columbia.

The study found that among those most likely to get great sleep were married or have a job, with 67% and 65%, respectively saying they get enough. Only 56% of divorced adults said they get enough sleep, and just over half of jobless adults sleep seven hours a night regularly. Among the best sleepers were college graduates, with 72% reporting seven hours or more.

The study found geographical differences as well as ethnic disparities. Hawaiian residents get less sleep than those living in South Dakota, the study found. Non-Hispanic whites sleep better than non-Hispanic black residents, with 67% and 54%, respectively.

ATLANTA (Reuters) - Did you get enough sleep last night? If not, you are not alone. More than one out of three American adults do not get enough sleep, according to a study released Thursday from the U.S. Centers for Disease Control and Prevention.

"That's a big problem," says Dr. Nancy Collop, director of the Emory Sleep Center at Emory University School of Medicine in Atlanta, who is familiar with the study. "You don't function as well, your ability to pay attention is reduced, and it can have serious, long term side effects. It can change your metabolism for the worse."

At least seven hours of sleep is considered healthy for an adults aged 18 to 60, according to the American Academy of Sleep Medicine and the Sleep Research Society. The CDC analyzed data from a 2014 survey of 444,306 adults and found roughly 65% of respondents reported getting that amount of

sleep.

"Lifestyle changes such as going to bed at the same time each night; rising at the same time each morning; and turning off or removing televisions, computers, mobile devices from the bedroom, can help people get the healthy sleep they need," said Dr. Wayne Giles, director of the CDC's Division of Population Health, in a statement.

Getting less than seven hours a night is associated with an increased risk of obesity, diabetes, high blood pressure, heart disease, stroke and frequent mental distress, the study shows. Published in the CDC's Morbidity and Mortality Weekly Report, the study is the first of its kind to look at all 50 U.S. states and the District of Columbia.

The study found that among those most likely to get great sleep were married or have a job, with 67% and 65%, respectively saying they get enough. Only 56% of divorced adults said they get enough sleep, and just over half of jobless adults sleep seven hours a night regularly. Among the best sleepers were college graduates, with 72% reporting seven hours or more.

The study found geographical differences as well as ethnic disparities. Hawaiian residents get less sleep than those living in South Dakota, the study found. Non-Hispanic whites sleep better than non-Hispanic black residents, with 67% and 54%, respectively.

ATLANTA (Reuters) - Did you get enough sleep last night? If not, you are not alone. More than one out of three American adults do not get enough sleep, according to a study released Thursday from the U.S. Centers for Disease Control and Prevention.

"That's a big problem," says Dr. Nancy Collop, director of the Emory Sleep Center at Emory University School of Medicine in Atlanta, who is familiar with the study. "You don't function as well, your ability to pay attention is reduced, and it can have serious, long term side effects. It can change your metabolism for the worse."

At least seven hours of sleep is considered healthy for an adults aged 18 to 60, according to the American Academy of Sleep Medicine and the Sleep Research Society. The CDC analyzed data from a 2014 survey of 444,306 adults and found roughly 65% of respondents reported getting that amount of

sleep.

"Lifestyle changes such as going to bed at the same time each night; rising at the same time each morning; and turning off or removing televisions, computers, mobile devices from the bedroom, can help people get the healthy sleep they need," said Dr. Wayne Giles, director of the CDC's Division of Population Health, in a statement.

Getting less than seven hours a night is associated with an increased risk of obesity, diabetes, high blood pressure, heart disease, stroke and frequent mental distress, the study shows. Published in the CDC's Morbidity and Mortality Weekly Report, the study is the first of its kind to look at all 50 U.S. states and the District of Columbia.

The study found that among those most likely to get great sleep were married or have a job, with 67% and 65%, respectively saying they get enough. Only 56% of divorced adults said they get enough sleep, and just over half of jobless adults sleep seven hours a night regularly. Among the best sleepers were college graduates, with 72% reporting seven hours or more.

The study found geographical differences as well as ethnic disparities. Hawaiian residents get less sleep than those living in South Dakota, the study found. Non-Hispanic whites sleep better than non-Hispanic black residents, with 67% and 54%, respectively.

Lab mice

Photo by Aaron Logan

New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.

“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”

Dr Grabow and her colleagues described this work in Cell Reports.

Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.

So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.

In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.

However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.

Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.

And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.

The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.

“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.

“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”

Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.

“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”

“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”

Lab mice

Photo by Aaron Logan

New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.

“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”

Dr Grabow and her colleagues described this work in Cell Reports.

Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.

So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.

In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.

However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.

Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.

And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.

The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.

“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.

“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”

Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.

“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”

“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”

Lab mice

Photo by Aaron Logan

New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.

“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”

Dr Grabow and her colleagues described this work in Cell Reports.

Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.

So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.

In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.

However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.

Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.

And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.

The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.

“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.

“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”

Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.

“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”

“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”

Sleeping newborn

Photo by Vera Kratochvil

Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.

The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.

The team reported these findings in Anesthesiology.

“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.

“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”

The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.

To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.

Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.

The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.

Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.

“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.

“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”

“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”

“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . .  in blood samples collected from these patients.”

Sleeping newborn

Photo by Vera Kratochvil

Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.

The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.

The team reported these findings in Anesthesiology.

“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.

“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”

The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.

To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.

Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.

The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.

Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.

“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.

“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”

“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”

“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . .  in blood samples collected from these patients.”

Sleeping newborn

Photo by Vera Kratochvil

Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.

The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.

The team reported these findings in Anesthesiology.

“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.

“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”

The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.

To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.

Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.

The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.

Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.

“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.

“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”

“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”

“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . .  in blood samples collected from these patients.”

Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”