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].

ILLUSTRATIVE CASE

A 26-year-old G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 26-year-old G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 26-year-old G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

THE CASE

A 34-year-old healthy woman presented to the breast surgical oncology clinic with skin changes to her left nipple after being referred by her primary care provider. She attributed the skin changes to shearing from breastfeeding her third child 5 years earlier. Physical examination revealed an erythematous and friable nipple with loss of protrusion (FIGURE 1). The patient reported routine bleeding from her nipple, but said the skin changes had remained stable and denied any breast masses. The patient’s last mammogram was 2.5 years earlier and had only been remarkable for bilateral benign calcifications.

THE DIAGNOSIS

A screening mammogram showed flattening and retraction of the left nipple, as well as suspicious left breast calcifications (BIRADS [Breast Imaging Reporting and Data System] 4 classification, FIGURE 2). A subsequent diagnostic mammogram showed a cluster of fine pleomorphic calcifications in the upper inner quadrant of the left breast (FIGURE 3). A stereotactic core needle biopsy was performed, and results confirmed a diagnosis of high-grade, estrogen receptor-negative, ductal carcinoma in situ (DCIS).

Subsequent work-up included a staging magnetic resonance imaging (MRI) and a left areola punch biopsy. MRI revealed an absence of a normal left nipple and extensive focal clumped non-mass enhancement in the area of the known DCIS (FIGURE 4). Biopsy results revealed enlarged atypical single cells within the epidermis. The cells stained positive for mucicarmine and cytokeratin 7 and negative for carcinoembryonic antigen and S-100 protein. This ruled out a pagetoid spread of melanoma and confirmed a diagnosis of Paget’s disease (PD) of the breast.

DISCUSSION

PD of the breast is a rare disorder (accounting for 0.5%-5% of all breast cancers) that is clinically characterized by erythematous, eczematous changes of the nipple-areolar complex (NAC).^1-7 PD is almost always unilateral and symptoms include pain, burning, and itching of the nipple, often with bloody nipple discharge.^1,3-8

PD can be mistaken for benign skin changes and diagnosed as dermatitis or eczema.^3,5 Because such changes often resolve temporarily with the use of topical corticosteroids or no treatment at all,² diagnosis is often delayed. PD of the breast is associated with underlying ductal carcinoma in 90% to 100% of cases,^1,2,5,8 so any skin pathology involving the nipple should be assumed to be PD until proven otherwise.

When no palpable mass is noted on physical exam, DCIS is usually found centrally behind the nipple.¹ In addition, lymph node involvement is noted in about 60% of cases.¹

Confirm the diagnosis with these tests

Diagnosis of PD of the breast is primarily clinical, with pathologic confirmation. All patients with clinically suspected PD should be evaluated using the following tests to determine the need for biopsy.

Mammography with magnification views of the NAC will show thickening, retraction, or flattening of the nipple, microcalcifications of the retroareolar region, and/or a subareolar mass.³ However, because breast tissue appears normal on mammography in 22% to 71% of patients,^1,5 the use of ultrasound and potentially MRI to delineate the extent of disease is warranted.

Ultrasound. While there are no characteristic findings on ultrasound, it can be used to detect dilation of the subareolar ducts, calcification, or a mass.⁴

MRI has a higher sensitivity for detection of occult disease.^2,5 MRI is also useful in the evaluation of axillary node asymmetry, which may indicate nodal involvement.²

Treatment is variable and has not been widely studied

Due to the rarity of PD, there are no randomized studies to point toward optimal treatment strategies.⁷ Treatment for PD is typically surgical and often involves mastectomy, with or without axillary node dissection.¹ Retrospective analyses have demonstrated that central lumpectomy (complete resection of the NAC and underlying disease) with radiation therapy has outcomes similar to mastectomy;² however, the cosmetic result is sometimes unfavorable.

In cases where there is no palpable mass nor mammographic findings of disease, breast conserving therapy may be considered. If chemotherapy is considered, it should be chosen based on the receptor profile of the disease and subsequent oncotype scoring.

The prognosis for patients with PD who are adequately treated and remain disease free after 5 years is excellent. These patients are likely to have achieved cure.²

Our patient underwent left simple mastectomy with sentinel node biopsy and tissue expander placement. Her postoperative course was uncomplicated, and she was discharged home on postoperative Day 1. On final pathology, the 2 sentinel nodes were disease free. The left mastectomy specimen was found to have high-grade DCIS with clear surgical margins. The area of involvement was found to be 3.5 cm × 3 cm in size and had clear skin margins. At follow-up one year later, the patient was doing well with no evidence of disease. She subsequently underwent implant insertion.

THE TAKEAWAY

This case highlights the unique progression of undiagnosed PD of the breast. It also highlights the importance of ruling out PD when skin changes involving the nipple are present, despite other possible explanations for those changes. This case in particular was complicated by a proximal history of breastfeeding, which erroneously provided an explanation and false reassurance for the primary care provider and patient.

Due to the common association of PD of the breast with underlying DCIS or invasive cancer, the most important aspect of care is early diagnostic work-up and appropriate referral. Primary care physicians have a unique role in obtaining appropriate early diagnostic tests (including mammogram and ultrasound) and making the necessary referral to a breast specialist in the presence of an abnormal physical exam involving the NAC, even in the absence of a palpable mass. In our patient’s case, punch biopsy of the NAC would have been appropriate at the first signs of friable, erythematous changes.

Tuberculosis (TB) remains a significant public health problem worldwide with an estimated 10.4 million new cases and 1.7 million deaths having occurred in 2016.¹ In that same year, there were 9287 new cases in the United States—the lowest number of TB cases on record.²

TB appears in one of 2 forms: active disease, which causes symptoms, morbidity, and mortality and is a source of transmission to others; and latent TB infection (LTBI), which is asymptomatic and noninfectious but can progress to active disease. The estimated prevalence of LTBI worldwide is 23%,³ although in the United States it is only about 5%.⁴ The proportion of those with LTBI who will develop active disease is estimated at 5% to 10% and is highly variable depending on risks.⁴

In the United States, about two-thirds of active TB cases occur among those who are foreign born, whose rate of active disease is 14.6/100,000.² Five countries account for more than half of foreign-born cases: Mexico, the Philippines, India, Vietnam, and China.²

Who should be tested?

A major public health strategy for controlling TB in the United States is targeted screening for LTBI and treatment to prevent progression to active disease. The US Preventive Services Task Force (USPSTF) recommends screening for LTBI in adults age 18 and older who are at high risk of TB infection.⁴ This is consistent with recommendations from the Centers for Disease Control and Prevention (CDC), although the CDC also recommends testing infants and children at high risk of infection, as well as all those at high risk for progression to active disease (TABLE 1^4-6).⁵

Two types of testing are available for TB screening: the TB skin test (TST) and the interferon-gamma release assay (IGRA). There are 2 IGRA test options: T-SPOT. TB (Oxford Immunotec) and QuantiFERON-TB Gold (Qiagen). The TST and IGRA each has advantages and disadvantages. The TST must be placed intradermally and read correctly, and the patient must return for the interpretation 48 to 72 hours after placement. Test interpretation depends on the patient’s risk category, with either a 5-mm, 10-mm, or 15-mm induration being classified as a positive result (TABLE 2⁷).

IGRA is a blood test that needs to be processed within a limited time frame and is more expensive than the TST. The USPSTF lists the sensitivity and specificity of each option as follows: TST, using a 10-mm cutoff, 79%, 97%; T-SPOT, 90%, 95%; QuantiFERON-TB Gold In-Tube, 80%, 97%.⁴

Which test to use?

Recently the CDC, the American Thoracic Society, and the Infectious Diseases Society of America jointly published revised recommendations on TB testing:⁸

• For children younger than 5 years, TST is the preferred option, although IGRA is acceptable in children older than 3 years of age.
• For individuals at high risk of infection but not at high risk of disease progression, IGRA is recommended if they have received a bacille Calmette-Guerin vaccine or are unlikely to return for TST interpretation.
• For others at high risk of infection but not at high risk of disease progression, IGRA is preferred but TST is acceptable.
• For those who have both a high risk of infection and a high risk of disease progression, evidence is insufficient to recommend one test over another; either type is acceptable.
• For those with neither high risk of infection nor high risk of disease progression, testing is not recommended. However, it may be required by law or for credentialing of some kind (eg, for some health professionals or those who work in schools or nursing homes). If this is the case, IGRA is suggested as the preferred test. If the test result is positive, performing a second test is advised (either TST or an alternative type of IGRA). Consider the individual to be infected only if the second test result is also positive.

If the risk is high for TB infection, but not for disease progression, test with an interferon-gamma release assay, particularly if the patient has been vaccinated or is unlikely to return for skin test interpretation.

If a TB screening result is positive, confirm or rule out active TB by asking about symptoms (cough, fever, weight loss) and performing a chest x-ray. If the radiograph shows signs of active TB, collect 3 sputum samples by induction for analysis by smear microscopy, culture, and, possibly, nucleic acid amplification and rifampin susceptibility testing. Consider consulting your local public health department for advice on, or assistance with, sample collection. Report LTBI to the local health department and seek advice on the appropriate tests and treatments.

Expanded treatment selections

With LTBI there are now 4 treatment options for patients and physicians to consider:⁹ isoniazid given daily or twice weekly for either 6 or 9 months; isoniazid and rifapentine given once weekly for 3 months; or rifampin given daily for 4 months. Factors influencing treatment selection include a patient’s age, concomitant conditions, and the likelihood of bacterial resistance. Free treatment for LTBI may be available; again, check with your local health department.

Tuberculosis (TB) remains a significant public health problem worldwide with an estimated 10.4 million new cases and 1.7 million deaths having occurred in 2016.¹ In that same year, there were 9287 new cases in the United States—the lowest number of TB cases on record.²

TB appears in one of 2 forms: active disease, which causes symptoms, morbidity, and mortality and is a source of transmission to others; and latent TB infection (LTBI), which is asymptomatic and noninfectious but can progress to active disease. The estimated prevalence of LTBI worldwide is 23%,³ although in the United States it is only about 5%.⁴ The proportion of those with LTBI who will develop active disease is estimated at 5% to 10% and is highly variable depending on risks.⁴

In the United States, about two-thirds of active TB cases occur among those who are foreign born, whose rate of active disease is 14.6/100,000.² Five countries account for more than half of foreign-born cases: Mexico, the Philippines, India, Vietnam, and China.²

Who should be tested?

A major public health strategy for controlling TB in the United States is targeted screening for LTBI and treatment to prevent progression to active disease. The US Preventive Services Task Force (USPSTF) recommends screening for LTBI in adults age 18 and older who are at high risk of TB infection.⁴ This is consistent with recommendations from the Centers for Disease Control and Prevention (CDC), although the CDC also recommends testing infants and children at high risk of infection, as well as all those at high risk for progression to active disease (TABLE 1^4-6).⁵

Two types of testing are available for TB screening: the TB skin test (TST) and the interferon-gamma release assay (IGRA). There are 2 IGRA test options: T-SPOT. TB (Oxford Immunotec) and QuantiFERON-TB Gold (Qiagen). The TST and IGRA each has advantages and disadvantages. The TST must be placed intradermally and read correctly, and the patient must return for the interpretation 48 to 72 hours after placement. Test interpretation depends on the patient’s risk category, with either a 5-mm, 10-mm, or 15-mm induration being classified as a positive result (TABLE 2⁷).

IGRA is a blood test that needs to be processed within a limited time frame and is more expensive than the TST. The USPSTF lists the sensitivity and specificity of each option as follows: TST, using a 10-mm cutoff, 79%, 97%; T-SPOT, 90%, 95%; QuantiFERON-TB Gold In-Tube, 80%, 97%.⁴

Which test to use?

Recently the CDC, the American Thoracic Society, and the Infectious Diseases Society of America jointly published revised recommendations on TB testing:⁸

• For children younger than 5 years, TST is the preferred option, although IGRA is acceptable in children older than 3 years of age.
• For individuals at high risk of infection but not at high risk of disease progression, IGRA is recommended if they have received a bacille Calmette-Guerin vaccine or are unlikely to return for TST interpretation.
• For others at high risk of infection but not at high risk of disease progression, IGRA is preferred but TST is acceptable.
• For those who have both a high risk of infection and a high risk of disease progression, evidence is insufficient to recommend one test over another; either type is acceptable.
• For those with neither high risk of infection nor high risk of disease progression, testing is not recommended. However, it may be required by law or for credentialing of some kind (eg, for some health professionals or those who work in schools or nursing homes). If this is the case, IGRA is suggested as the preferred test. If the test result is positive, performing a second test is advised (either TST or an alternative type of IGRA). Consider the individual to be infected only if the second test result is also positive.

If the risk is high for TB infection, but not for disease progression, test with an interferon-gamma release assay, particularly if the patient has been vaccinated or is unlikely to return for skin test interpretation.

If a TB screening result is positive, confirm or rule out active TB by asking about symptoms (cough, fever, weight loss) and performing a chest x-ray. If the radiograph shows signs of active TB, collect 3 sputum samples by induction for analysis by smear microscopy, culture, and, possibly, nucleic acid amplification and rifampin susceptibility testing. Consider consulting your local public health department for advice on, or assistance with, sample collection. Report LTBI to the local health department and seek advice on the appropriate tests and treatments.

Expanded treatment selections

With LTBI there are now 4 treatment options for patients and physicians to consider:⁹ isoniazid given daily or twice weekly for either 6 or 9 months; isoniazid and rifapentine given once weekly for 3 months; or rifampin given daily for 4 months. Factors influencing treatment selection include a patient’s age, concomitant conditions, and the likelihood of bacterial resistance. Free treatment for LTBI may be available; again, check with your local health department.

Tuberculosis (TB) remains a significant public health problem worldwide with an estimated 10.4 million new cases and 1.7 million deaths having occurred in 2016.¹ In that same year, there were 9287 new cases in the United States—the lowest number of TB cases on record.²

TB appears in one of 2 forms: active disease, which causes symptoms, morbidity, and mortality and is a source of transmission to others; and latent TB infection (LTBI), which is asymptomatic and noninfectious but can progress to active disease. The estimated prevalence of LTBI worldwide is 23%,³ although in the United States it is only about 5%.⁴ The proportion of those with LTBI who will develop active disease is estimated at 5% to 10% and is highly variable depending on risks.⁴

In the United States, about two-thirds of active TB cases occur among those who are foreign born, whose rate of active disease is 14.6/100,000.² Five countries account for more than half of foreign-born cases: Mexico, the Philippines, India, Vietnam, and China.²

Who should be tested?

A major public health strategy for controlling TB in the United States is targeted screening for LTBI and treatment to prevent progression to active disease. The US Preventive Services Task Force (USPSTF) recommends screening for LTBI in adults age 18 and older who are at high risk of TB infection.⁴ This is consistent with recommendations from the Centers for Disease Control and Prevention (CDC), although the CDC also recommends testing infants and children at high risk of infection, as well as all those at high risk for progression to active disease (TABLE 1^4-6).⁵

Two types of testing are available for TB screening: the TB skin test (TST) and the interferon-gamma release assay (IGRA). There are 2 IGRA test options: T-SPOT. TB (Oxford Immunotec) and QuantiFERON-TB Gold (Qiagen). The TST and IGRA each has advantages and disadvantages. The TST must be placed intradermally and read correctly, and the patient must return for the interpretation 48 to 72 hours after placement. Test interpretation depends on the patient’s risk category, with either a 5-mm, 10-mm, or 15-mm induration being classified as a positive result (TABLE 2⁷).

IGRA is a blood test that needs to be processed within a limited time frame and is more expensive than the TST. The USPSTF lists the sensitivity and specificity of each option as follows: TST, using a 10-mm cutoff, 79%, 97%; T-SPOT, 90%, 95%; QuantiFERON-TB Gold In-Tube, 80%, 97%.⁴

Which test to use?

Recently the CDC, the American Thoracic Society, and the Infectious Diseases Society of America jointly published revised recommendations on TB testing:⁸

• For children younger than 5 years, TST is the preferred option, although IGRA is acceptable in children older than 3 years of age.
• For individuals at high risk of infection but not at high risk of disease progression, IGRA is recommended if they have received a bacille Calmette-Guerin vaccine or are unlikely to return for TST interpretation.
• For others at high risk of infection but not at high risk of disease progression, IGRA is preferred but TST is acceptable.
• For those who have both a high risk of infection and a high risk of disease progression, evidence is insufficient to recommend one test over another; either type is acceptable.
• For those with neither high risk of infection nor high risk of disease progression, testing is not recommended. However, it may be required by law or for credentialing of some kind (eg, for some health professionals or those who work in schools or nursing homes). If this is the case, IGRA is suggested as the preferred test. If the test result is positive, performing a second test is advised (either TST or an alternative type of IGRA). Consider the individual to be infected only if the second test result is also positive.

If the risk is high for TB infection, but not for disease progression, test with an interferon-gamma release assay, particularly if the patient has been vaccinated or is unlikely to return for skin test interpretation.

If a TB screening result is positive, confirm or rule out active TB by asking about symptoms (cough, fever, weight loss) and performing a chest x-ray. If the radiograph shows signs of active TB, collect 3 sputum samples by induction for analysis by smear microscopy, culture, and, possibly, nucleic acid amplification and rifampin susceptibility testing. Consider consulting your local public health department for advice on, or assistance with, sample collection. Report LTBI to the local health department and seek advice on the appropriate tests and treatments.

Expanded treatment selections

With LTBI there are now 4 treatment options for patients and physicians to consider:⁹ isoniazid given daily or twice weekly for either 6 or 9 months; isoniazid and rifapentine given once weekly for 3 months; or rifampin given daily for 4 months. Factors influencing treatment selection include a patient’s age, concomitant conditions, and the likelihood of bacterial resistance. Free treatment for LTBI may be available; again, check with your local health department.

THE CASE

Lorna D* was seen by her primary care physician (PCP) as follow-up to a visit she made to the emergency department (ED). The 37 year old had gone to the ED 4 times in the previous year. Each time she presented with tachycardia, dyspnea, nausea, numbness in her extremities, and a fear that she was having a heart attack. In spite of negative work-ups at each visit (electrocardiogram, cardiac enzymes, complete blood count, toxicology screen, Holter monitoring), Ms. D was terrified that the ED doctors were missing something. She was still “rattled” by the chest pain and shortness of breath she had experienced. Mild symptoms were persisting and she was worried that she would have a heart attack and die without the treatment she believed she needed.

How would you proceed with this patient?

*The patient’s name has been changed to protect her privacy.

MANY PANIC ATTACKS PROMPT AN ED VISIT

Panic disorder (PD) is characterized by the spontaneous and unexpected occurrence of panic attacks, and by at least one month of persistent worry about having another attack or significant maladaptive behaviors related to the attack. Frequency of such attacks can vary from several a day to only a few per year. In a panic attack, an intense fear develops abruptly and peaks within 10 minutes of onset. At least 4 of the following 13 symptoms must accompany the attack, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5):¹

• palpitations, pounding heart, or accelerated heart rate
• sweating
• trembling or shaking
• sensations of shortness of breath or smothering
• feeling of choking
• chest pain or discomfort
• nausea or abdominal distress
• feeling dizzy, unsteady, lightheaded, or faint
• de-realization (feelings of unreality) or depersonalization (being detached from oneself)
• fear of losing control or going crazy
• fear of dying
• paresthesia (numbness or tingling sensations)
• chills or hot flushes.

Lifetime incidence rates of panic disorder are 1% to 3% for the general population.² A closer look at patients presenting to the ED with chest pain reveals that 17% to 25% meet criteria for panic disorder.^3,4 And an estimated 6% of individuals experiencing a panic attack present to their primary physician.⁵ Patients with panic disorder tend to use health care resources at a disproportionately high rate.⁶

An international review of panic disorder research suggests the average age of onset for PD is 32 years.⁷ Triggers can vary widely and no single stressor has been identified. The exact cause of PD is unknown, but a convergence of social and biological influences (including involvement of the amygdala) are implicated in its development.⁶ For individuals who have had a panic attack, 66.5% will have recurrent attacks.⁷ Lifetime prevalence of panic attacks is 13.2%.⁷

Differential goes far beyond myocardial infarction

Many medical conditions can mimic panic disorder symptoms: cardiovascular, pulmonary, and neurologic diseases; endocrine diseases (eg, hyperthyroidism); drug intoxication (eg, stimulants such as cocaine, amphetamines); drug withdrawal (eg, benzodiazepines, alcohol, sedative-hypnotics); and ingestion of excessive quantities of caffeine. Common comorbid medical disorders include asthma, coronary artery disease, cancer, thyroid disease, hypertension, ulcer, and migraine headaches.⁸

Spontaneous recurrences of panic may indicate panic disorder if the patient experiences at least 4 additional recognized symptoms.

When patients present with panic-like symptoms, suspect a possible medical condition when those symptoms include ataxia, altered mental status, or loss of bladder control, or when onset of panic symptoms occur later in life for a patient with no significant psychiatric history.

RULE OUT ORGANIC CAUSES

In addition to obtaining a complete history and doing a physical exam on patients with panic-like symptoms, you’ll also need to ensure that the following are done: a neurologic examination, standard laboratory testing (thyroid function, complete blood cell count, chemistry panel), and possible additional testing (eg, urine toxicology screen and D-dimer assay to exclude pulmonary embolism).

If organic causes are ruled out, focus on a psychiatric assessment:⁹

• history of the present illness (onset, symptoms, frequency, predisposing/precipitating factors)
• psychiatric history
• history of substance use
• family history of psychiatric disorders (especially anxiety disorders)
• social history (life events, including those preceding onset of panic; history of child abuse)
• medications
• mental status examination
• safety (panic disorder is associated with higher risk of suicidal ideation).

TREATMENT INCLUDES CBT AND MEDICATION

PD is a chronic disease with a variable course, but the long-term prognosis is good. PD is usually treated in an outpatient setting. Consider hospitalization if the patient is suicidal, if the potential for life-threatening withdrawal symptoms is high (as with alcohol or benzodiazepines), or if the symptoms are severely debilitating or attempted outpatient treatment is unsuccessful. Pharmacologic and psychotherapeutic interventions are used for PD (FIGURE⁹), although there is not enough evidence to recommend one vs the other or combination therapy vs monotherapy.⁹

CASE

For Ms. D, all medical test results came back negative, and the psychiatric assessment revealed that she met the DSM-5 criteria for panic disorder. Counting on the strength of their relationship, her physician talked to her about PD and discussed treatment options, which included counseling, medication, or both. Ms. D agreed to a referral for cognitive behavioral therapy (CBT) with a psychologist embedded at her physician’s primary care clinic and to begin taking medication. Her PCP started her on sertraline 25 mg/d.

In CBT, Ms. D’s psychologist taught her about “fight or flight” and explained that it was a normal physiologic response that could lead to panic. Ms. D. learned to approach her physical symptoms in a different way, and how to breathe in a way that slowed her panic reaction.

Consider SSRIs and SNRIs

First-line medication is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) due to the better tolerability and lower adverse effect profile of these classes compared with the tricyclic antidepressants or monoamine oxidase inhibitors. MAOIs are usually reserved for patients in whom multiple medication trials have failed.

Special considerations. American Psychiatric Association guidelines advise starting with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d (although many clinicians start lower, at 5 mg/d), to avoid hypersensitivity reactions. Gradually titrate the dose upward within 3 to 7 days after initiation until a therapeutic dose is reached over 2 to 6 weeks. Schedule follow-up visits for every one to 2 weeks at the beginning of treatment and every 2 to 4 weeks until the therapeutic dose is reached. Assess safety/suicidality at each visit.

To treat panic disorder with medication, start with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d.

Keep in mind that the onset of therapeutic effect is between 2 and 4 weeks, but that clinical response can take up to 8 to 12 weeks. Continue pharmacotherapy for at least one year. When discontinuing the medication, taper it slowly, and monitor the patient for withdrawal symptoms and recurrence of PD.⁹

Consider adding a benzodiazepine if symptoms are debilitating.⁹ Keep in mind, though, that the potential for addiction with these medications is high and they are intended to be used for only 4 to 12 weeks.⁸ Onset of action is within the first week, and a scheduled dosing regimen is preferred to giving the medication as needed. The starting dose (eg, clonazepam 0.25 mg bid)⁹ may be increased 3 to 5 days following initiation.

The evidence supports the use of CBT for panic disorder

CBT is an evidenced-based treatment for panic disorder.^10-13 Up to 75% of patients treated with CBT are panic free within 4 months.¹⁰ Other techniques proven effective are progressive muscle relaxation training, breathing retraining, psycho-education, exposure, and imagery.¹⁴

Treatment with medications and CBT either combined or used individually is effective in 80% to 90% of cases.¹⁵ CBT has been shown to decrease the likelihood of relapse in the year following treatment.¹⁵ Good premorbid functioning and a brief duration of symptoms increase the likelihood of a good prognosis.¹⁵

WHEN TO REFER TO A PSYCHIATRIST

Consider referral to a psychiatrist when patients have a comorbid psychiatric condition that complicates the clinical picture (eg, substance abuse disorder), if the diagnosis is uncertain, or if the patient does not respond to one or 2 adequate trials of medication and psychotherapy. Although psychiatric follow-up is sometimes difficult due to a lack of psychiatrist availability locally, it is a best-practice recommendation.

CASE

Ten days after Ms. D started the sertraline 25 mg/d, she called the PCP to report daily diarrhea. She stopped the sertraline on her own and asked for another medication. She also expressed her frustration with the severity of the symptoms. She was having 3 to 5 panic attacks daily and had been missing many days from work.

On the day of her follow-up PCP appointment, Ms. D also saw the psychologist. She reported that she’d been practicing relaxation breathing, tracking her panic attacks, limiting caffeine intake, and exercising regularly. But the attacks were still occurring.

The PCP switched her to paroxetine 10 mg/d and, due to the severity of the symptoms, prescribed clonazepam 0.5 mg bid. Two weeks later, Ms. D reported that she was feeling a little better, had returned to work, and was hopeful that she would be her “normal self again.” The PCP planned to encourage continuation of CBT, titrate the paroxetine to 20 to 40 mg/d based on symptoms, and to slowly taper the clonazepam toward discontinuation in the near future.

CORRESPONDENCE
Eric H. Berko, PhD, Case Western Reserve University School of Medicine, Department of Family Medicine, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-7878; [email protected].

THE CASE

Lorna D* was seen by her primary care physician (PCP) as follow-up to a visit she made to the emergency department (ED). The 37 year old had gone to the ED 4 times in the previous year. Each time she presented with tachycardia, dyspnea, nausea, numbness in her extremities, and a fear that she was having a heart attack. In spite of negative work-ups at each visit (electrocardiogram, cardiac enzymes, complete blood count, toxicology screen, Holter monitoring), Ms. D was terrified that the ED doctors were missing something. She was still “rattled” by the chest pain and shortness of breath she had experienced. Mild symptoms were persisting and she was worried that she would have a heart attack and die without the treatment she believed she needed.

How would you proceed with this patient?

*The patient’s name has been changed to protect her privacy.

MANY PANIC ATTACKS PROMPT AN ED VISIT

Panic disorder (PD) is characterized by the spontaneous and unexpected occurrence of panic attacks, and by at least one month of persistent worry about having another attack or significant maladaptive behaviors related to the attack. Frequency of such attacks can vary from several a day to only a few per year. In a panic attack, an intense fear develops abruptly and peaks within 10 minutes of onset. At least 4 of the following 13 symptoms must accompany the attack, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5):¹

• palpitations, pounding heart, or accelerated heart rate
• sweating
• trembling or shaking
• sensations of shortness of breath or smothering
• feeling of choking
• chest pain or discomfort
• nausea or abdominal distress
• feeling dizzy, unsteady, lightheaded, or faint
• de-realization (feelings of unreality) or depersonalization (being detached from oneself)
• fear of losing control or going crazy
• fear of dying
• paresthesia (numbness or tingling sensations)
• chills or hot flushes.

Lifetime incidence rates of panic disorder are 1% to 3% for the general population.² A closer look at patients presenting to the ED with chest pain reveals that 17% to 25% meet criteria for panic disorder.^3,4 And an estimated 6% of individuals experiencing a panic attack present to their primary physician.⁵ Patients with panic disorder tend to use health care resources at a disproportionately high rate.⁶

An international review of panic disorder research suggests the average age of onset for PD is 32 years.⁷ Triggers can vary widely and no single stressor has been identified. The exact cause of PD is unknown, but a convergence of social and biological influences (including involvement of the amygdala) are implicated in its development.⁶ For individuals who have had a panic attack, 66.5% will have recurrent attacks.⁷ Lifetime prevalence of panic attacks is 13.2%.⁷

Differential goes far beyond myocardial infarction

Many medical conditions can mimic panic disorder symptoms: cardiovascular, pulmonary, and neurologic diseases; endocrine diseases (eg, hyperthyroidism); drug intoxication (eg, stimulants such as cocaine, amphetamines); drug withdrawal (eg, benzodiazepines, alcohol, sedative-hypnotics); and ingestion of excessive quantities of caffeine. Common comorbid medical disorders include asthma, coronary artery disease, cancer, thyroid disease, hypertension, ulcer, and migraine headaches.⁸

Spontaneous recurrences of panic may indicate panic disorder if the patient experiences at least 4 additional recognized symptoms.

When patients present with panic-like symptoms, suspect a possible medical condition when those symptoms include ataxia, altered mental status, or loss of bladder control, or when onset of panic symptoms occur later in life for a patient with no significant psychiatric history.

RULE OUT ORGANIC CAUSES

In addition to obtaining a complete history and doing a physical exam on patients with panic-like symptoms, you’ll also need to ensure that the following are done: a neurologic examination, standard laboratory testing (thyroid function, complete blood cell count, chemistry panel), and possible additional testing (eg, urine toxicology screen and D-dimer assay to exclude pulmonary embolism).

If organic causes are ruled out, focus on a psychiatric assessment:⁹

• history of the present illness (onset, symptoms, frequency, predisposing/precipitating factors)
• psychiatric history
• history of substance use
• family history of psychiatric disorders (especially anxiety disorders)
• social history (life events, including those preceding onset of panic; history of child abuse)
• medications
• mental status examination
• safety (panic disorder is associated with higher risk of suicidal ideation).

TREATMENT INCLUDES CBT AND MEDICATION

PD is a chronic disease with a variable course, but the long-term prognosis is good. PD is usually treated in an outpatient setting. Consider hospitalization if the patient is suicidal, if the potential for life-threatening withdrawal symptoms is high (as with alcohol or benzodiazepines), or if the symptoms are severely debilitating or attempted outpatient treatment is unsuccessful. Pharmacologic and psychotherapeutic interventions are used for PD (FIGURE⁹), although there is not enough evidence to recommend one vs the other or combination therapy vs monotherapy.⁹

CASE

For Ms. D, all medical test results came back negative, and the psychiatric assessment revealed that she met the DSM-5 criteria for panic disorder. Counting on the strength of their relationship, her physician talked to her about PD and discussed treatment options, which included counseling, medication, or both. Ms. D agreed to a referral for cognitive behavioral therapy (CBT) with a psychologist embedded at her physician’s primary care clinic and to begin taking medication. Her PCP started her on sertraline 25 mg/d.

In CBT, Ms. D’s psychologist taught her about “fight or flight” and explained that it was a normal physiologic response that could lead to panic. Ms. D. learned to approach her physical symptoms in a different way, and how to breathe in a way that slowed her panic reaction.

Consider SSRIs and SNRIs

First-line medication is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) due to the better tolerability and lower adverse effect profile of these classes compared with the tricyclic antidepressants or monoamine oxidase inhibitors. MAOIs are usually reserved for patients in whom multiple medication trials have failed.

Special considerations. American Psychiatric Association guidelines advise starting with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d (although many clinicians start lower, at 5 mg/d), to avoid hypersensitivity reactions. Gradually titrate the dose upward within 3 to 7 days after initiation until a therapeutic dose is reached over 2 to 6 weeks. Schedule follow-up visits for every one to 2 weeks at the beginning of treatment and every 2 to 4 weeks until the therapeutic dose is reached. Assess safety/suicidality at each visit.

To treat panic disorder with medication, start with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d.

Keep in mind that the onset of therapeutic effect is between 2 and 4 weeks, but that clinical response can take up to 8 to 12 weeks. Continue pharmacotherapy for at least one year. When discontinuing the medication, taper it slowly, and monitor the patient for withdrawal symptoms and recurrence of PD.⁹

Consider adding a benzodiazepine if symptoms are debilitating.⁹ Keep in mind, though, that the potential for addiction with these medications is high and they are intended to be used for only 4 to 12 weeks.⁸ Onset of action is within the first week, and a scheduled dosing regimen is preferred to giving the medication as needed. The starting dose (eg, clonazepam 0.25 mg bid)⁹ may be increased 3 to 5 days following initiation.

The evidence supports the use of CBT for panic disorder

CBT is an evidenced-based treatment for panic disorder.^10-13 Up to 75% of patients treated with CBT are panic free within 4 months.¹⁰ Other techniques proven effective are progressive muscle relaxation training, breathing retraining, psycho-education, exposure, and imagery.¹⁴

Treatment with medications and CBT either combined or used individually is effective in 80% to 90% of cases.¹⁵ CBT has been shown to decrease the likelihood of relapse in the year following treatment.¹⁵ Good premorbid functioning and a brief duration of symptoms increase the likelihood of a good prognosis.¹⁵

WHEN TO REFER TO A PSYCHIATRIST

Consider referral to a psychiatrist when patients have a comorbid psychiatric condition that complicates the clinical picture (eg, substance abuse disorder), if the diagnosis is uncertain, or if the patient does not respond to one or 2 adequate trials of medication and psychotherapy. Although psychiatric follow-up is sometimes difficult due to a lack of psychiatrist availability locally, it is a best-practice recommendation.

CASE

Ten days after Ms. D started the sertraline 25 mg/d, she called the PCP to report daily diarrhea. She stopped the sertraline on her own and asked for another medication. She also expressed her frustration with the severity of the symptoms. She was having 3 to 5 panic attacks daily and had been missing many days from work.

On the day of her follow-up PCP appointment, Ms. D also saw the psychologist. She reported that she’d been practicing relaxation breathing, tracking her panic attacks, limiting caffeine intake, and exercising regularly. But the attacks were still occurring.

The PCP switched her to paroxetine 10 mg/d and, due to the severity of the symptoms, prescribed clonazepam 0.5 mg bid. Two weeks later, Ms. D reported that she was feeling a little better, had returned to work, and was hopeful that she would be her “normal self again.” The PCP planned to encourage continuation of CBT, titrate the paroxetine to 20 to 40 mg/d based on symptoms, and to slowly taper the clonazepam toward discontinuation in the near future.

CORRESPONDENCE
Eric H. Berko, PhD, Case Western Reserve University School of Medicine, Department of Family Medicine, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-7878; [email protected].

THE CASE

Lorna D* was seen by her primary care physician (PCP) as follow-up to a visit she made to the emergency department (ED). The 37 year old had gone to the ED 4 times in the previous year. Each time she presented with tachycardia, dyspnea, nausea, numbness in her extremities, and a fear that she was having a heart attack. In spite of negative work-ups at each visit (electrocardiogram, cardiac enzymes, complete blood count, toxicology screen, Holter monitoring), Ms. D was terrified that the ED doctors were missing something. She was still “rattled” by the chest pain and shortness of breath she had experienced. Mild symptoms were persisting and she was worried that she would have a heart attack and die without the treatment she believed she needed.

How would you proceed with this patient?

*The patient’s name has been changed to protect her privacy.

MANY PANIC ATTACKS PROMPT AN ED VISIT

Panic disorder (PD) is characterized by the spontaneous and unexpected occurrence of panic attacks, and by at least one month of persistent worry about having another attack or significant maladaptive behaviors related to the attack. Frequency of such attacks can vary from several a day to only a few per year. In a panic attack, an intense fear develops abruptly and peaks within 10 minutes of onset. At least 4 of the following 13 symptoms must accompany the attack, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5):¹

• palpitations, pounding heart, or accelerated heart rate
• sweating
• trembling or shaking
• sensations of shortness of breath or smothering
• feeling of choking
• chest pain or discomfort
• nausea or abdominal distress
• feeling dizzy, unsteady, lightheaded, or faint
• de-realization (feelings of unreality) or depersonalization (being detached from oneself)
• fear of losing control or going crazy
• fear of dying
• paresthesia (numbness or tingling sensations)
• chills or hot flushes.

Lifetime incidence rates of panic disorder are 1% to 3% for the general population.² A closer look at patients presenting to the ED with chest pain reveals that 17% to 25% meet criteria for panic disorder.^3,4 And an estimated 6% of individuals experiencing a panic attack present to their primary physician.⁵ Patients with panic disorder tend to use health care resources at a disproportionately high rate.⁶

An international review of panic disorder research suggests the average age of onset for PD is 32 years.⁷ Triggers can vary widely and no single stressor has been identified. The exact cause of PD is unknown, but a convergence of social and biological influences (including involvement of the amygdala) are implicated in its development.⁶ For individuals who have had a panic attack, 66.5% will have recurrent attacks.⁷ Lifetime prevalence of panic attacks is 13.2%.⁷

Differential goes far beyond myocardial infarction

Many medical conditions can mimic panic disorder symptoms: cardiovascular, pulmonary, and neurologic diseases; endocrine diseases (eg, hyperthyroidism); drug intoxication (eg, stimulants such as cocaine, amphetamines); drug withdrawal (eg, benzodiazepines, alcohol, sedative-hypnotics); and ingestion of excessive quantities of caffeine. Common comorbid medical disorders include asthma, coronary artery disease, cancer, thyroid disease, hypertension, ulcer, and migraine headaches.⁸

Spontaneous recurrences of panic may indicate panic disorder if the patient experiences at least 4 additional recognized symptoms.

When patients present with panic-like symptoms, suspect a possible medical condition when those symptoms include ataxia, altered mental status, or loss of bladder control, or when onset of panic symptoms occur later in life for a patient with no significant psychiatric history.

RULE OUT ORGANIC CAUSES

In addition to obtaining a complete history and doing a physical exam on patients with panic-like symptoms, you’ll also need to ensure that the following are done: a neurologic examination, standard laboratory testing (thyroid function, complete blood cell count, chemistry panel), and possible additional testing (eg, urine toxicology screen and D-dimer assay to exclude pulmonary embolism).

If organic causes are ruled out, focus on a psychiatric assessment:⁹

• history of the present illness (onset, symptoms, frequency, predisposing/precipitating factors)
• psychiatric history
• history of substance use
• family history of psychiatric disorders (especially anxiety disorders)
• social history (life events, including those preceding onset of panic; history of child abuse)
• medications
• mental status examination
• safety (panic disorder is associated with higher risk of suicidal ideation).

TREATMENT INCLUDES CBT AND MEDICATION

PD is a chronic disease with a variable course, but the long-term prognosis is good. PD is usually treated in an outpatient setting. Consider hospitalization if the patient is suicidal, if the potential for life-threatening withdrawal symptoms is high (as with alcohol or benzodiazepines), or if the symptoms are severely debilitating or attempted outpatient treatment is unsuccessful. Pharmacologic and psychotherapeutic interventions are used for PD (FIGURE⁹), although there is not enough evidence to recommend one vs the other or combination therapy vs monotherapy.⁹

CASE

For Ms. D, all medical test results came back negative, and the psychiatric assessment revealed that she met the DSM-5 criteria for panic disorder. Counting on the strength of their relationship, her physician talked to her about PD and discussed treatment options, which included counseling, medication, or both. Ms. D agreed to a referral for cognitive behavioral therapy (CBT) with a psychologist embedded at her physician’s primary care clinic and to begin taking medication. Her PCP started her on sertraline 25 mg/d.

In CBT, Ms. D’s psychologist taught her about “fight or flight” and explained that it was a normal physiologic response that could lead to panic. Ms. D. learned to approach her physical symptoms in a different way, and how to breathe in a way that slowed her panic reaction.

Consider SSRIs and SNRIs

First-line medication is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) due to the better tolerability and lower adverse effect profile of these classes compared with the tricyclic antidepressants or monoamine oxidase inhibitors. MAOIs are usually reserved for patients in whom multiple medication trials have failed.

Special considerations. American Psychiatric Association guidelines advise starting with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d (although many clinicians start lower, at 5 mg/d), to avoid hypersensitivity reactions. Gradually titrate the dose upward within 3 to 7 days after initiation until a therapeutic dose is reached over 2 to 6 weeks. Schedule follow-up visits for every one to 2 weeks at the beginning of treatment and every 2 to 4 weeks until the therapeutic dose is reached. Assess safety/suicidality at each visit.

To treat panic disorder with medication, start with a very low dose of an SSRI or SNRI, such as paroxetine 10 mg/d.

Keep in mind that the onset of therapeutic effect is between 2 and 4 weeks, but that clinical response can take up to 8 to 12 weeks. Continue pharmacotherapy for at least one year. When discontinuing the medication, taper it slowly, and monitor the patient for withdrawal symptoms and recurrence of PD.⁹

Consider adding a benzodiazepine if symptoms are debilitating.⁹ Keep in mind, though, that the potential for addiction with these medications is high and they are intended to be used for only 4 to 12 weeks.⁸ Onset of action is within the first week, and a scheduled dosing regimen is preferred to giving the medication as needed. The starting dose (eg, clonazepam 0.25 mg bid)⁹ may be increased 3 to 5 days following initiation.

The evidence supports the use of CBT for panic disorder

CBT is an evidenced-based treatment for panic disorder.^10-13 Up to 75% of patients treated with CBT are panic free within 4 months.¹⁰ Other techniques proven effective are progressive muscle relaxation training, breathing retraining, psycho-education, exposure, and imagery.¹⁴

Treatment with medications and CBT either combined or used individually is effective in 80% to 90% of cases.¹⁵ CBT has been shown to decrease the likelihood of relapse in the year following treatment.¹⁵ Good premorbid functioning and a brief duration of symptoms increase the likelihood of a good prognosis.¹⁵

WHEN TO REFER TO A PSYCHIATRIST

Consider referral to a psychiatrist when patients have a comorbid psychiatric condition that complicates the clinical picture (eg, substance abuse disorder), if the diagnosis is uncertain, or if the patient does not respond to one or 2 adequate trials of medication and psychotherapy. Although psychiatric follow-up is sometimes difficult due to a lack of psychiatrist availability locally, it is a best-practice recommendation.

CASE

Ten days after Ms. D started the sertraline 25 mg/d, she called the PCP to report daily diarrhea. She stopped the sertraline on her own and asked for another medication. She also expressed her frustration with the severity of the symptoms. She was having 3 to 5 panic attacks daily and had been missing many days from work.

On the day of her follow-up PCP appointment, Ms. D also saw the psychologist. She reported that she’d been practicing relaxation breathing, tracking her panic attacks, limiting caffeine intake, and exercising regularly. But the attacks were still occurring.

The PCP switched her to paroxetine 10 mg/d and, due to the severity of the symptoms, prescribed clonazepam 0.5 mg bid. Two weeks later, Ms. D reported that she was feeling a little better, had returned to work, and was hopeful that she would be her “normal self again.” The PCP planned to encourage continuation of CBT, titrate the paroxetine to 20 to 40 mg/d based on symptoms, and to slowly taper the clonazepam toward discontinuation in the near future.

CORRESPONDENCE
Eric H. Berko, PhD, Case Western Reserve University School of Medicine, Department of Family Medicine, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-7878; [email protected].