Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.

In the October, 2017 audiocast, “Statins for primary prevention of CVD: To start or not to start?” Dr. Doug Campos-Outcalt drew an incorrect conclusion when he used himself as an example to demonstrate the application of recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and the US Preventive Services Task Force. He indicated that he would qualify for starting low- to moderate-dose statins under both sets of recommendations when, in fact, he would qualify only under the ACC/AHA recommendations. The audio file has been revised to reflect the proper conclusion.

In the October, 2017 audiocast, “Statins for primary prevention of CVD: To start or not to start?” Dr. Doug Campos-Outcalt drew an incorrect conclusion when he used himself as an example to demonstrate the application of recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and the US Preventive Services Task Force. He indicated that he would qualify for starting low- to moderate-dose statins under both sets of recommendations when, in fact, he would qualify only under the ACC/AHA recommendations. The audio file has been revised to reflect the proper conclusion.

In the October, 2017 audiocast, “Statins for primary prevention of CVD: To start or not to start?” Dr. Doug Campos-Outcalt drew an incorrect conclusion when he used himself as an example to demonstrate the application of recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and the US Preventive Services Task Force. He indicated that he would qualify for starting low- to moderate-dose statins under both sets of recommendations when, in fact, he would qualify only under the ACC/AHA recommendations. The audio file has been revised to reflect the proper conclusion.

Resources

1. US Food and Drug Administration. Shingrix. Available at: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm581491.htm. Accessed November 17, 2017.
2. Hales CM, Harpaz R, Ortego-Sanchez I, et al. Update on recommendations for the use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63:729-731.
3. Centers for Disease Control and Prevention. Herpes Zoster Work Group Activity Update. June 21, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-06/zoster-01-belongia.pdf. Accessed October 27, 2017.
4. Centers for Disease Control and Prevention. Vaccination. Available at: https://www.cdc.gov/shingles/vaccination.html. Accessed November 17, 2017.
5. Meeting of the Advisory Committee on Immunization Practices (ACIP). Atlanta, Ga; October 25-26, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/agenda-archive/agenda-2017-10.pdf. Accessed November 20, 2017.

Resources

1. US Food and Drug Administration. Shingrix. Available at: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm581491.htm. Accessed November 17, 2017.
2. Hales CM, Harpaz R, Ortego-Sanchez I, et al. Update on recommendations for the use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63:729-731.
3. Centers for Disease Control and Prevention. Herpes Zoster Work Group Activity Update. June 21, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-06/zoster-01-belongia.pdf. Accessed October 27, 2017.
4. Centers for Disease Control and Prevention. Vaccination. Available at: https://www.cdc.gov/shingles/vaccination.html. Accessed November 17, 2017.
5. Meeting of the Advisory Committee on Immunization Practices (ACIP). Atlanta, Ga; October 25-26, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/agenda-archive/agenda-2017-10.pdf. Accessed November 20, 2017.

Resources

1. US Food and Drug Administration. Shingrix. Available at: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm581491.htm. Accessed November 17, 2017.
2. Hales CM, Harpaz R, Ortego-Sanchez I, et al. Update on recommendations for the use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63:729-731.
3. Centers for Disease Control and Prevention. Herpes Zoster Work Group Activity Update. June 21, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-06/zoster-01-belongia.pdf. Accessed October 27, 2017.
4. Centers for Disease Control and Prevention. Vaccination. Available at: https://www.cdc.gov/shingles/vaccination.html. Accessed November 17, 2017.
5. Meeting of the Advisory Committee on Immunization Practices (ACIP). Atlanta, Ga; October 25-26, 2017. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/agenda-archive/agenda-2017-10.pdf. Accessed November 20, 2017.

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

THE CASE

A 67-year-old man presented to the hospital with subacute loss of vision in his left eye. The visual changes began 2 weeks earlier, with a central area of visual loss that had since progressed to near complete vision loss in the left eye.

Physical examination revealed patchy alopecia, a scaling and hyperkeratotic rash of his hands and feet (FIGURE 1), and blanching, erythematous plaques with associated scaling on the scrotum and glans penis. Ophthalmologic examination revealed 1/200 vision in his left eye with a large plaque occupying a substantial portion of the superior quadrant, smaller perifoveal plaques in both of his eyes, and a small infiltrate above the left optic nerve head (FIGURE 2). The patient also described fatigue, loss of taste, and an unintentional weight loss of 7 to 10 kg over the previous 6 months. He had seen his primary care provider 3 months prior for a burning sensation and scaling rash on his feet and hands, and was prescribed a topical steroid.

The patient’s social history was relevant for intermittent condom use with 6 lifetime female partners, but it was negative for new sexual partners, sexual contact with men, intravenous drug use, tattoos, blood transfusions, or travel outside the state. His medical history was significant for hypertension.

Routine laboratory tests were remarkable for an elevated erythrocyte sedimentation rate of 53 mm/hr (normal: 0-15 mm/hr) and a C-reactive protein of 5.3 mg/dL (normal: <0.5 mg/dL). Lumbar puncture revealed a white blood cell count of 133 cells/mcL (normal: 0-5 cells/mcL) with 87% lymphocytes and protein elevated to 63 mg/dL (normal: 15-40 mg/dL).

Other tests were ordered and included a serum fourth-generation ELISA to screen for human immunodeficiency virus (HIV)-1 and HIV-2, a cerebrospinal fluid venereal disease research laboratory (CSF-VDRL) test, a syphilis IgG screen and reflexive rapid plasma reagin (RPR) quantitation, and tests for cytomegalovirus antibodies, antinuclear antibody, rheumatoid factor, and Toxoplasma antibodies. Punch biopsy of the patient’s palmar skin changes was also performed; Steiner stain and spirochete immunohistochemical stain were applied to the sample. Magnetic resonance imaging of the brain and orbit was unremarkable.

THE DIAGNOSIS

The patient’s HIV screening test came back positive and was followed by confirmation of HIV-1 antibody, with an HIV viral load of 61,000 copies/mL and a CD4 count of 383 cells/mm³. The CSF-VDRL test and serum syphilis IgG were also positive, and the RPR titer was 1:16. The Steiner and spirochete immunohistochemical stains confirmed the presence of treponemes in the epidermis (FIGURE 3). Taken together, these findings confirmed a unifying diagnosis of ocular syphilis and syphilitic keratoderma with concomitant HIV.

DISCUSSION

After reaching an all-time low in the mid-1990s, several recent reports indicate that the incidence of syphilis is again increasing in North America.^1-3 In the United States, annual incidence rates have increased from 2.1/100,000 in 2000 to 5.3/100,000 in 2013.³ The increase has been most notable in younger men, men who have sex with men (MSM), and those with HIV infection.¹

A 2015 Centers for Disease Control and Prevention advisory highlights an unusual collection of cases of ocular syphilis, predominantly in HIV-infected MSM, from California and Washington.⁴ Disease sequelae in this outbreak have resulted in blindness.

A recent increase of syphilis in the United States has been most notable in younger men, men who have sex with men, and those with HIV infection.

HIV coinfection has been reported in 27.5% of males and 12.4% of females with new diagnoses of syphilis.¹ Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.^1,5,6 Cutaneous findings such as malignant syphilis (characterized by ulcerating, pustular, or rupioid lesions), as well as other atypical rashes mimicking eczema, leprosy, mycosis fungoides, or keratoderma blenorrhagicum, may all be more common in those with HIV coinfection.⁶ Ageusia or dysgeusia is rare in syphilis, and to our knowledge has only been described with concomitant oral lesions.⁷

MANAGEMENT

Our patient was treated with a continuous daily infusion of 20 million units of penicillin G for 14 days, one drop of 1% ocular prednisolone in each eye 4 times daily for 4 weeks, one drop of 2% cyclopentoate in each eye 2 times daily for 4 weeks, and 60 mg/d of oral prednisone tapered over 3 months. For the HIV infection, he was started on antiretroviral therapy soon after diagnosis.

Patients with HIV are more likely to have asymptomatic primary syphilitic infection, and may have an earlier onset of secondary syphilis and neurosyphilis.

Within 48 hours of initiating penicillin, he reported a marked improvement in vision and regained the ability to taste. After one week of therapy, near resolution of the palmoplantar rash was noted and the patient was discharged on hospital Day 8. At a 3-month follow-up visit, he was asymptomatic, with return of normal sensation. Repeat ophthalmologic examination showed no evidence of disease.

THE TAKEAWAY

This case complements other sporadic reports of symptoms of ocular and cutaneous syphilis serving as the initial presentation of HIV infection.^5,8,9 Risk-factor based screening for HIV often leads to missed diagnoses, and early recognition of this constellation of symptoms may aid in prompt diagnosis and treatment of syphilis and HIV.¹⁰

EVIDENCE SUMMARY

A systematic review analyzed 30 predominantly US studies with more than 8000 patients published between 1990 and 2012 (4 RCTs, 7 nonrandomized clinical trials, 13 before/after intervention trials, and 6 evaluation studies) to evaluate interventions that decreased parental vaccine refusal and hesitancy.¹ Interventions included: change in state law, changes in state and school policies, and family-centered education initiatives.

Four studies that evaluated the impact of state laws concerning personal exemption (in addition to religious exemption) consistently found that total nonmedical exemption rates were higher in states that allowed personal exemptions. One nationwide survey found that total nonmedical exemption rates were 2.54 times higher (95% confidence interval [CI], 1.68-3.83) in states that allowed personal exemption than in states where only religious nonmedical exemption was allowed.

Fifteen studies evaluated the impact of educational initiatives on parental attitude towards vaccination; 8 of them reported statistically significant changes. None of the studies demonstrated a change in vaccination rates, however. Citing the generally low quality of the studies, the review authors concluded that they didn’t have convincing evidence that educational interventions reduced vaccine hesitancy.

Herd immunity is an iffy motivator

A systematic review analyzed 29 studies from western nations (17 qualitative and 12 quantitative, 4650 patients) regarding willingness to immunize children for the benefit of the community.² Of the 17 qualitative studies, only 2 (164 patients) identified benefit to others as a motivating factor in parents’ decisions to immunize their children. In the 12 quantitative studies, a wide range of parents (1% to 60%) rated the concept of benefit to others as a reason for immunization. Overall, approximately one-third of parents listed herd immunity as a motivating reason. The authors concluded that the high heterogeneity of the studies made it unclear whether herd immunity was a motivating factor in childhood immunizations.

Multifaceted interventions, education, and tailored approaches may all work

A systematic review of international studies published between 2007 and 2013 investigated interventions to increase uptake of routinely recommended immunizations in groups with vaccine hesitancy and reduced use.³ Authors identified 189 articles (trial types and number of patients not given) that provided outcome measures.

Interventions that resulted in at least a 25% increase in vaccine uptake were primarily multifaceted, including elements of: targeting undervaccinated populations, improving access or convenience, educational initiatives, and mandates. Interventions that produced a greater than 20% increase in knowledge were generally educational interventions embedded in routine processes such as clinic visits.

The authors noted wide variation between studies in effect size, settings, and target populations. They concluded that interventions tailored to specific populations and concerns were likely to work best.

Corrective information doesn’t help with the most worried parents

A subsequent RCT tested whether correcting the myth that the flu vaccine can give people the flu would reduce belief in the misconception, increase perceptions that the flu vaccine is safe, and increase vaccination intent.⁴ Respondents to a national online poll of 1000 people received one of 3 interventions: correctional education (information debunking the myth), risk education (information about the risks of influenza infection), or no additional education.

Although about a third of parents cite herd immunity as a motivation to vaccinate, its efficacy in addressing vaccine hesitancy isn't clear.

Corrective information about the flu vaccine reduced the false belief that the vaccine can cause the flu by 15% to 20% and that the flu vaccine is unsafe by 5% to 10% (data from graphs; P<.05 for both effects). However, corrective information actually decreased parental intention to vaccinate among the group most concerned about the adverse effects of the vaccine (data from graph and text: +5% in the low-concern group vs −18% in the high-concern group; P<.05).

A presumptive approach works—but at a cost

A subsequent observational study videotaped 111 patient-provider vaccine discussions.⁵ Researchers categorized the initiation of the vaccine discussion as presumptive (eg, “We have to do some shots.”) or participatory (eg, “What do you want to do about shots?”). Using a presumptive style was more likely to result in acceptance of all recommended vaccines by the end of the visit (90% vs 17%; P<.05), but it decreased the chance of a highly rated visit experience (63% vs 95%; P<.05).

RECOMMENDATIONS

The 2015 Centers for Disease Control and Prevention (CDC) Pink Book recommends a combination of strategies, aimed at both providers and the public, for increasing and maintaining high immunization rates. The Pink Book advises providers to be ready to address vaccine safety concerns raised by parents.⁶

In a 2012 guideline, the CDC encouraged providers to listen attentively, be ready with scientific information and reliable resources, and use appropriate anecdotes in communicating with vaccine-hesitant parents.⁷ The guideline recommended against excluding families who refuse vaccination from the practice.

EVIDENCE SUMMARY

A systematic review analyzed 30 predominantly US studies with more than 8000 patients published between 1990 and 2012 (4 RCTs, 7 nonrandomized clinical trials, 13 before/after intervention trials, and 6 evaluation studies) to evaluate interventions that decreased parental vaccine refusal and hesitancy.¹ Interventions included: change in state law, changes in state and school policies, and family-centered education initiatives.

Four studies that evaluated the impact of state laws concerning personal exemption (in addition to religious exemption) consistently found that total nonmedical exemption rates were higher in states that allowed personal exemptions. One nationwide survey found that total nonmedical exemption rates were 2.54 times higher (95% confidence interval [CI], 1.68-3.83) in states that allowed personal exemption than in states where only religious nonmedical exemption was allowed.

Fifteen studies evaluated the impact of educational initiatives on parental attitude towards vaccination; 8 of them reported statistically significant changes. None of the studies demonstrated a change in vaccination rates, however. Citing the generally low quality of the studies, the review authors concluded that they didn’t have convincing evidence that educational interventions reduced vaccine hesitancy.

Herd immunity is an iffy motivator

A systematic review analyzed 29 studies from western nations (17 qualitative and 12 quantitative, 4650 patients) regarding willingness to immunize children for the benefit of the community.² Of the 17 qualitative studies, only 2 (164 patients) identified benefit to others as a motivating factor in parents’ decisions to immunize their children. In the 12 quantitative studies, a wide range of parents (1% to 60%) rated the concept of benefit to others as a reason for immunization. Overall, approximately one-third of parents listed herd immunity as a motivating reason. The authors concluded that the high heterogeneity of the studies made it unclear whether herd immunity was a motivating factor in childhood immunizations.

Multifaceted interventions, education, and tailored approaches may all work

A systematic review of international studies published between 2007 and 2013 investigated interventions to increase uptake of routinely recommended immunizations in groups with vaccine hesitancy and reduced use.³ Authors identified 189 articles (trial types and number of patients not given) that provided outcome measures.

Interventions that resulted in at least a 25% increase in vaccine uptake were primarily multifaceted, including elements of: targeting undervaccinated populations, improving access or convenience, educational initiatives, and mandates. Interventions that produced a greater than 20% increase in knowledge were generally educational interventions embedded in routine processes such as clinic visits.

The authors noted wide variation between studies in effect size, settings, and target populations. They concluded that interventions tailored to specific populations and concerns were likely to work best.

Corrective information doesn’t help with the most worried parents

A subsequent RCT tested whether correcting the myth that the flu vaccine can give people the flu would reduce belief in the misconception, increase perceptions that the flu vaccine is safe, and increase vaccination intent.⁴ Respondents to a national online poll of 1000 people received one of 3 interventions: correctional education (information debunking the myth), risk education (information about the risks of influenza infection), or no additional education.

Although about a third of parents cite herd immunity as a motivation to vaccinate, its efficacy in addressing vaccine hesitancy isn't clear.

Corrective information about the flu vaccine reduced the false belief that the vaccine can cause the flu by 15% to 20% and that the flu vaccine is unsafe by 5% to 10% (data from graphs; P<.05 for both effects). However, corrective information actually decreased parental intention to vaccinate among the group most concerned about the adverse effects of the vaccine (data from graph and text: +5% in the low-concern group vs −18% in the high-concern group; P<.05).

A presumptive approach works—but at a cost

A subsequent observational study videotaped 111 patient-provider vaccine discussions.⁵ Researchers categorized the initiation of the vaccine discussion as presumptive (eg, “We have to do some shots.”) or participatory (eg, “What do you want to do about shots?”). Using a presumptive style was more likely to result in acceptance of all recommended vaccines by the end of the visit (90% vs 17%; P<.05), but it decreased the chance of a highly rated visit experience (63% vs 95%; P<.05).

RECOMMENDATIONS

The 2015 Centers for Disease Control and Prevention (CDC) Pink Book recommends a combination of strategies, aimed at both providers and the public, for increasing and maintaining high immunization rates. The Pink Book advises providers to be ready to address vaccine safety concerns raised by parents.⁶

In a 2012 guideline, the CDC encouraged providers to listen attentively, be ready with scientific information and reliable resources, and use appropriate anecdotes in communicating with vaccine-hesitant parents.⁷ The guideline recommended against excluding families who refuse vaccination from the practice.

EVIDENCE SUMMARY

A systematic review analyzed 30 predominantly US studies with more than 8000 patients published between 1990 and 2012 (4 RCTs, 7 nonrandomized clinical trials, 13 before/after intervention trials, and 6 evaluation studies) to evaluate interventions that decreased parental vaccine refusal and hesitancy.¹ Interventions included: change in state law, changes in state and school policies, and family-centered education initiatives.

Four studies that evaluated the impact of state laws concerning personal exemption (in addition to religious exemption) consistently found that total nonmedical exemption rates were higher in states that allowed personal exemptions. One nationwide survey found that total nonmedical exemption rates were 2.54 times higher (95% confidence interval [CI], 1.68-3.83) in states that allowed personal exemption than in states where only religious nonmedical exemption was allowed.

Fifteen studies evaluated the impact of educational initiatives on parental attitude towards vaccination; 8 of them reported statistically significant changes. None of the studies demonstrated a change in vaccination rates, however. Citing the generally low quality of the studies, the review authors concluded that they didn’t have convincing evidence that educational interventions reduced vaccine hesitancy.

Herd immunity is an iffy motivator

A systematic review analyzed 29 studies from western nations (17 qualitative and 12 quantitative, 4650 patients) regarding willingness to immunize children for the benefit of the community.² Of the 17 qualitative studies, only 2 (164 patients) identified benefit to others as a motivating factor in parents’ decisions to immunize their children. In the 12 quantitative studies, a wide range of parents (1% to 60%) rated the concept of benefit to others as a reason for immunization. Overall, approximately one-third of parents listed herd immunity as a motivating reason. The authors concluded that the high heterogeneity of the studies made it unclear whether herd immunity was a motivating factor in childhood immunizations.

Multifaceted interventions, education, and tailored approaches may all work

A systematic review of international studies published between 2007 and 2013 investigated interventions to increase uptake of routinely recommended immunizations in groups with vaccine hesitancy and reduced use.³ Authors identified 189 articles (trial types and number of patients not given) that provided outcome measures.

Interventions that resulted in at least a 25% increase in vaccine uptake were primarily multifaceted, including elements of: targeting undervaccinated populations, improving access or convenience, educational initiatives, and mandates. Interventions that produced a greater than 20% increase in knowledge were generally educational interventions embedded in routine processes such as clinic visits.

The authors noted wide variation between studies in effect size, settings, and target populations. They concluded that interventions tailored to specific populations and concerns were likely to work best.

Corrective information doesn’t help with the most worried parents

A subsequent RCT tested whether correcting the myth that the flu vaccine can give people the flu would reduce belief in the misconception, increase perceptions that the flu vaccine is safe, and increase vaccination intent.⁴ Respondents to a national online poll of 1000 people received one of 3 interventions: correctional education (information debunking the myth), risk education (information about the risks of influenza infection), or no additional education.

Although about a third of parents cite herd immunity as a motivation to vaccinate, its efficacy in addressing vaccine hesitancy isn't clear.

Corrective information about the flu vaccine reduced the false belief that the vaccine can cause the flu by 15% to 20% and that the flu vaccine is unsafe by 5% to 10% (data from graphs; P<.05 for both effects). However, corrective information actually decreased parental intention to vaccinate among the group most concerned about the adverse effects of the vaccine (data from graph and text: +5% in the low-concern group vs −18% in the high-concern group; P<.05).

A presumptive approach works—but at a cost

A subsequent observational study videotaped 111 patient-provider vaccine discussions.⁵ Researchers categorized the initiation of the vaccine discussion as presumptive (eg, “We have to do some shots.”) or participatory (eg, “What do you want to do about shots?”). Using a presumptive style was more likely to result in acceptance of all recommended vaccines by the end of the visit (90% vs 17%; P<.05), but it decreased the chance of a highly rated visit experience (63% vs 95%; P<.05).

RECOMMENDATIONS

The 2015 Centers for Disease Control and Prevention (CDC) Pink Book recommends a combination of strategies, aimed at both providers and the public, for increasing and maintaining high immunization rates. The Pink Book advises providers to be ready to address vaccine safety concerns raised by parents.⁶

In a 2012 guideline, the CDC encouraged providers to listen attentively, be ready with scientific information and reliable resources, and use appropriate anecdotes in communicating with vaccine-hesitant parents.⁷ The guideline recommended against excluding families who refuse vaccination from the practice.

A 70-year-old Caucasian man presented with a longstanding history of numerous nontender, fleshy, skin-colored papules on his trunk, ranging from 3 to 8 mm in size (FIGURE). They were noted incidentally during an examination of unrelated nonhealing lesions on the patient’s left cheek. He said the lesions on his trunk first appeared when he was 28 years old and had continued to grow in size and number. The patient said his son had at least one similar lesion on his upper back, but otherwise there was no family history of these lesions.

A biopsy was performed on one of the nodules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Segmental neurofibromatosis

Dermatopathologic evaluation of the tissue sample indicated that the lesion was a neurofibroma, and clinical correlation fine-tuned the diagnosis to segmental neurofibromatosis (NF). The diagnosis of segmental NF is clinical with biopsy to confirm the lesions are neurofibromas. Segmental NF is a mosaic form of neurofibromatosis type 1 (NF1) that results from a postzygotic mutation of the NF1 gene. While NF1 is a relatively common neurocutaneous disorder that occurs with a frequency of one in 3000,¹ segmental NF is more rare, with an estimated prevalence of one in 40,000.²

NF1 often follows an autosomal dominant inheritance pattern, although up to 50% of patients with NF1 arise de novo from spontaneous mutations.³ NF1 is characterized by multiple café-au-lait macules, axillary freckling, neurofibromas, and Lisch nodules (pigmented iris hamartomas).

The distribution of neurofibromas with segmental NF is usually limited to one dermatome.

Systemic findings that are associated with NF1 include malignant peripheral nerve sheath tumors, optic gliomas, and vasculopathy.³ While patients with segmental NF may exhibit some of these same findings, the distribution of neurofibromas is often limited to one dermatome. Additionally, patients with segmental NF typically do not exhibit extracutaneous lesions, systemic involvement, or a family history of NF.

Rule out these dermatomal lesions

This case highlights a unique pattern of neoplasm development along a dermatome, an area of skin where innervation derives from a single spinal nerve. Symptoms that follow a dermatome often point to a pathology involving the related nerve root.

This differs from Blaschko lines, which form a specific surface pattern that is believed to reflect the migration of embryonic skin cells. Blaschko lines do not follow any known vascular, nervous, or lymphatic structures of the skin. Interestingly, when patients with segmental NF have associated pigmentary lesions, such as café-au-lait macules, these lesions may border Blaschko lines.

Herpes zoster, also known as shingles, is the most common infectious process that presents in a dermatomal pattern. Herpes zoster is caused by reactivation of the varicella-zoster virus, which lies within the dorsal root ganglion of a spinal nerve. This condition commonly results in a dermatomal distribution of vesicles/bullae on an erythematous base.

Neoplasms—including common cutaneous malignancies, such as basal cell carcinoma, as well as rare benign cutaneous conditions, such as cutaneous schwannoma, may have a distribution similar to that of segmental NF. A biopsy can help distinguish the diagnosis. See the TABLE⁴ for a complete differential diagnosis for dermatomally distributed nodules.

Classifying neurofibromatosis

It’s important to classify the type of NF in order to get a better handle on the patient’s prognosis and to facilitate genetic counseling. In particular, the much more common NF1 comes with an increased risk of systemic findings such as malignant peripheral nerve sheath tumors, optic gliomas, other gliomas, and leukemia. Few patients with segmental NF, on the other hand, will have these systemic findings.⁴ Segmental NF treatment typically focuses on symptomatic management or cosmetic concerns.

Our patient did not have any of the systemic complications that occasionally occur with segmental NF as discussed above, so no medical treatment was required. We informed him that the cutaneous and subcutaneous neurofibromas do not require removal unless there is pain, bleeding, disfigurement, or signs of malignant transformation. Our patient was not interested in removal of the nodules for cosmetic reasons, so we recommended follow-up as needed.

CORRESPONDENCE
Thomas M. Beachkofsky, MD, FAAD, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, 3551 Roger Brooke Dr, Fort Sam Houston, TX 78234; [email protected].

A 70-year-old Caucasian man presented with a longstanding history of numerous nontender, fleshy, skin-colored papules on his trunk, ranging from 3 to 8 mm in size (FIGURE). They were noted incidentally during an examination of unrelated nonhealing lesions on the patient’s left cheek. He said the lesions on his trunk first appeared when he was 28 years old and had continued to grow in size and number. The patient said his son had at least one similar lesion on his upper back, but otherwise there was no family history of these lesions.

A biopsy was performed on one of the nodules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Segmental neurofibromatosis

Dermatopathologic evaluation of the tissue sample indicated that the lesion was a neurofibroma, and clinical correlation fine-tuned the diagnosis to segmental neurofibromatosis (NF). The diagnosis of segmental NF is clinical with biopsy to confirm the lesions are neurofibromas. Segmental NF is a mosaic form of neurofibromatosis type 1 (NF1) that results from a postzygotic mutation of the NF1 gene. While NF1 is a relatively common neurocutaneous disorder that occurs with a frequency of one in 3000,¹ segmental NF is more rare, with an estimated prevalence of one in 40,000.²

NF1 often follows an autosomal dominant inheritance pattern, although up to 50% of patients with NF1 arise de novo from spontaneous mutations.³ NF1 is characterized by multiple café-au-lait macules, axillary freckling, neurofibromas, and Lisch nodules (pigmented iris hamartomas).

The distribution of neurofibromas with segmental NF is usually limited to one dermatome.

Systemic findings that are associated with NF1 include malignant peripheral nerve sheath tumors, optic gliomas, and vasculopathy.³ While patients with segmental NF may exhibit some of these same findings, the distribution of neurofibromas is often limited to one dermatome. Additionally, patients with segmental NF typically do not exhibit extracutaneous lesions, systemic involvement, or a family history of NF.

Rule out these dermatomal lesions

This case highlights a unique pattern of neoplasm development along a dermatome, an area of skin where innervation derives from a single spinal nerve. Symptoms that follow a dermatome often point to a pathology involving the related nerve root.

This differs from Blaschko lines, which form a specific surface pattern that is believed to reflect the migration of embryonic skin cells. Blaschko lines do not follow any known vascular, nervous, or lymphatic structures of the skin. Interestingly, when patients with segmental NF have associated pigmentary lesions, such as café-au-lait macules, these lesions may border Blaschko lines.

Herpes zoster, also known as shingles, is the most common infectious process that presents in a dermatomal pattern. Herpes zoster is caused by reactivation of the varicella-zoster virus, which lies within the dorsal root ganglion of a spinal nerve. This condition commonly results in a dermatomal distribution of vesicles/bullae on an erythematous base.

Neoplasms—including common cutaneous malignancies, such as basal cell carcinoma, as well as rare benign cutaneous conditions, such as cutaneous schwannoma, may have a distribution similar to that of segmental NF. A biopsy can help distinguish the diagnosis. See the TABLE⁴ for a complete differential diagnosis for dermatomally distributed nodules.

Classifying neurofibromatosis

It’s important to classify the type of NF in order to get a better handle on the patient’s prognosis and to facilitate genetic counseling. In particular, the much more common NF1 comes with an increased risk of systemic findings such as malignant peripheral nerve sheath tumors, optic gliomas, other gliomas, and leukemia. Few patients with segmental NF, on the other hand, will have these systemic findings.⁴ Segmental NF treatment typically focuses on symptomatic management or cosmetic concerns.

Our patient did not have any of the systemic complications that occasionally occur with segmental NF as discussed above, so no medical treatment was required. We informed him that the cutaneous and subcutaneous neurofibromas do not require removal unless there is pain, bleeding, disfigurement, or signs of malignant transformation. Our patient was not interested in removal of the nodules for cosmetic reasons, so we recommended follow-up as needed.

CORRESPONDENCE
Thomas M. Beachkofsky, MD, FAAD, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, 3551 Roger Brooke Dr, Fort Sam Houston, TX 78234; [email protected].

A 70-year-old Caucasian man presented with a longstanding history of numerous nontender, fleshy, skin-colored papules on his trunk, ranging from 3 to 8 mm in size (FIGURE). They were noted incidentally during an examination of unrelated nonhealing lesions on the patient’s left cheek. He said the lesions on his trunk first appeared when he was 28 years old and had continued to grow in size and number. The patient said his son had at least one similar lesion on his upper back, but otherwise there was no family history of these lesions.

A biopsy was performed on one of the nodules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Segmental neurofibromatosis

Dermatopathologic evaluation of the tissue sample indicated that the lesion was a neurofibroma, and clinical correlation fine-tuned the diagnosis to segmental neurofibromatosis (NF). The diagnosis of segmental NF is clinical with biopsy to confirm the lesions are neurofibromas. Segmental NF is a mosaic form of neurofibromatosis type 1 (NF1) that results from a postzygotic mutation of the NF1 gene. While NF1 is a relatively common neurocutaneous disorder that occurs with a frequency of one in 3000,¹ segmental NF is more rare, with an estimated prevalence of one in 40,000.²

NF1 often follows an autosomal dominant inheritance pattern, although up to 50% of patients with NF1 arise de novo from spontaneous mutations.³ NF1 is characterized by multiple café-au-lait macules, axillary freckling, neurofibromas, and Lisch nodules (pigmented iris hamartomas).

The distribution of neurofibromas with segmental NF is usually limited to one dermatome.

Systemic findings that are associated with NF1 include malignant peripheral nerve sheath tumors, optic gliomas, and vasculopathy.³ While patients with segmental NF may exhibit some of these same findings, the distribution of neurofibromas is often limited to one dermatome. Additionally, patients with segmental NF typically do not exhibit extracutaneous lesions, systemic involvement, or a family history of NF.

Rule out these dermatomal lesions

This case highlights a unique pattern of neoplasm development along a dermatome, an area of skin where innervation derives from a single spinal nerve. Symptoms that follow a dermatome often point to a pathology involving the related nerve root.

This differs from Blaschko lines, which form a specific surface pattern that is believed to reflect the migration of embryonic skin cells. Blaschko lines do not follow any known vascular, nervous, or lymphatic structures of the skin. Interestingly, when patients with segmental NF have associated pigmentary lesions, such as café-au-lait macules, these lesions may border Blaschko lines.

Herpes zoster, also known as shingles, is the most common infectious process that presents in a dermatomal pattern. Herpes zoster is caused by reactivation of the varicella-zoster virus, which lies within the dorsal root ganglion of a spinal nerve. This condition commonly results in a dermatomal distribution of vesicles/bullae on an erythematous base.

Neoplasms—including common cutaneous malignancies, such as basal cell carcinoma, as well as rare benign cutaneous conditions, such as cutaneous schwannoma, may have a distribution similar to that of segmental NF. A biopsy can help distinguish the diagnosis. See the TABLE⁴ for a complete differential diagnosis for dermatomally distributed nodules.

Classifying neurofibromatosis

It’s important to classify the type of NF in order to get a better handle on the patient’s prognosis and to facilitate genetic counseling. In particular, the much more common NF1 comes with an increased risk of systemic findings such as malignant peripheral nerve sheath tumors, optic gliomas, other gliomas, and leukemia. Few patients with segmental NF, on the other hand, will have these systemic findings.⁴ Segmental NF treatment typically focuses on symptomatic management or cosmetic concerns.

Our patient did not have any of the systemic complications that occasionally occur with segmental NF as discussed above, so no medical treatment was required. We informed him that the cutaneous and subcutaneous neurofibromas do not require removal unless there is pain, bleeding, disfigurement, or signs of malignant transformation. Our patient was not interested in removal of the nodules for cosmetic reasons, so we recommended follow-up as needed.

CORRESPONDENCE
Thomas M. Beachkofsky, MD, FAAD, San Antonio Uniformed Services Health Education Consortium, Brooke Army Medical Center, 3551 Roger Brooke Dr, Fort Sam Houston, TX 78234; [email protected].