Pediatrics

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

Tinea incognito (TI) describes a dermatophytosis with often atypical clinical features attributed to prior use of topical corticosteroids or other immunomodulating agents. Tinea incognito may lack the scale and elevated margin typical of cutaneous dermatophytoses and can be mistaken for other pediatric cutaneous diseases, particularly atopic dermatitis. ¹ Given the prevalence of TI and its susceptibility to misdiagnosis, we conducted a retrospective medical record review of cases of pediatric dermatophytosis presenting from 2005 to 2016.

Methods

We reviewed medical records for patients younger than 18 years who had been seen at the Faculty Group Practice of the Ronald O. Perelman Department of Dermatology, New York University School of Medicine (New York, New York), between January 1, 2005, and October 21, 2016, using International Classification of Diseases, Ninth Revision (ICD-9) codes 110.0 (tinea capitis), 110.1 (onychomycosis/tinea unguium), 110.3 (tinea cruris), 110.4 (tinea pedis), 110.5 (tinea corporis), and 110.9 (tinea, unspecified site). Cases were included in this study if there was documentation of dermatophytosis previously treated with topical corticosteroids or calcineurin inhibitors as well as positive potassium hydroxide (KOH) preparation or fungal culture with dermatophyte growth obtained from lesions satisfying the first criterion. This study was approved by the New York University School of Medicine institutional review board (study no. S15-01388).

Statistical analyses were conducted in SPSS 19.0 for Windows. Categorical variables were assessed using the χ² test for independence and the Fisher exact test.

Results

A total of 464 cases were reviewed. A positive KOH preparation or dermatophyte fungal culture was documented in 83 cases. Of them, 29 (34.9%) were treated with topical steroids and/or calcineurin inhibitors prior to presentation to dermatology (Table). The mean age at presentation was 8 years. Duration of symptoms prior to presentation was recorded for 23 of 29 patients (79.3%). Of them, 6 (26.1%) experienced symptoms for 1 month or less, 12 (52.2%) for 1 to 6 months, and 5 (21.7%) for 6 months to 1 year.

Physical examination findings (Figure) were documented in all 29 cases. Annular lesions were noted in 24 patients (82.8%). Pustules were present in 5 patients (17.2%) and papules in 11 patients (37.9%). Fourteen patients (48.3%) had involvement of the face, 14 (48.3%) of the body (ie, trunk, extremities, or groin), and 3 (10.3%) of the scalp. Six patients (20.7%) demonstrated findings at more than one body site.

Females were more likely to demonstrate facial lesions (P=.02), while males were more likely to present with body lesions (P=.04). Of 26 patients diagnosed via fungal culture, 16 (55.2%) grew Trichophyton tonsurans, 4 (13.8%) grew Trichophyton rubrum, 3 (10.3%) grew Trichophyton mentagrophytes, 2 (6.9%) grew Microsporum canis, and 1 (3.4%) grew Microsporum gypseum. Treatment entailed oral medication in 18 cases (62.1%). Of them, 13 (72.2%) were treated with griseofulvin, 3 (16.7%) with fluconazole, and 2 (11.1%) with terbinafine. Topical antifungals were prescribed in the remaining 11 cases (37.9%); no further treatment was documented.

Comment

Since the initial description of TI, approximately 60 case reports and small series as well as several larger observational studies describing TI have been published. In our series of pediatric patients, 29 of 83 culture- or KOH-confirmed dermatophytosis cases (34.9%) were considered to be TI due to treatment with topical corticosteroids and/or calcineurin inhibitors prior to presentation. This high prevalence contrasts with the 5.6% prevalence reported in the only prior large case series examining TI in childhood.² These authors further reported that in their pediatric population, TI was significantly (odds ratio, 8.7; 95% CI, 4.7-16.1) more likely to occur on the face relative to other dermatophytoses and significantly (odds ratio, 0.014; 95% CI, 0.002-0.099) less likely to occur on the scalp.² We noted a significant association between female gender and facial symptoms as well as between male gender and truncal symptoms. Taken together, these findings suggest an increased likelihood of pediatric tinea faciei to be inappropriately treated, particularly in females.

Although TI treated with topical corticosteroids or calcineurin inhibitors can mimic other skin diseases, a majority of patients in our series demonstrated findings associated with classic tinea, such as annularity and scale. Further, we found that T tonsurans was the causative organism in most cases with T rubrum uncommonly seen, though it is the most prevalent dermatophyte observed worldwide and in 2 large TI case series.^3,4 Regional variation in dermatophytes may account for these differences. In our study, griseofulvin was used most frequently in TI treatment, though a systematic review of oral antifungals in tinea capitis supported terbinafine’s greater efficacy in patients infected with T tonsurans.⁵

Conclusion

Our case series demonstrated a 35% prevalence of TI cases in a population of children with confirmed dermatophytosis presenting to dermatologists at an American academic medical center. We hope that noting the high prevalence and manifold presentations of this disease will aid practitioners in maintaining clinical suspicion for dermatophytosis and thereby facilitate appropriate identification and treatment of TI.

Tinea incognito (TI) describes a dermatophytosis with often atypical clinical features attributed to prior use of topical corticosteroids or other immunomodulating agents. Tinea incognito may lack the scale and elevated margin typical of cutaneous dermatophytoses and can be mistaken for other pediatric cutaneous diseases, particularly atopic dermatitis. ¹ Given the prevalence of TI and its susceptibility to misdiagnosis, we conducted a retrospective medical record review of cases of pediatric dermatophytosis presenting from 2005 to 2016.

Methods

We reviewed medical records for patients younger than 18 years who had been seen at the Faculty Group Practice of the Ronald O. Perelman Department of Dermatology, New York University School of Medicine (New York, New York), between January 1, 2005, and October 21, 2016, using International Classification of Diseases, Ninth Revision (ICD-9) codes 110.0 (tinea capitis), 110.1 (onychomycosis/tinea unguium), 110.3 (tinea cruris), 110.4 (tinea pedis), 110.5 (tinea corporis), and 110.9 (tinea, unspecified site). Cases were included in this study if there was documentation of dermatophytosis previously treated with topical corticosteroids or calcineurin inhibitors as well as positive potassium hydroxide (KOH) preparation or fungal culture with dermatophyte growth obtained from lesions satisfying the first criterion. This study was approved by the New York University School of Medicine institutional review board (study no. S15-01388).

Statistical analyses were conducted in SPSS 19.0 for Windows. Categorical variables were assessed using the χ² test for independence and the Fisher exact test.

Results

A total of 464 cases were reviewed. A positive KOH preparation or dermatophyte fungal culture was documented in 83 cases. Of them, 29 (34.9%) were treated with topical steroids and/or calcineurin inhibitors prior to presentation to dermatology (Table). The mean age at presentation was 8 years. Duration of symptoms prior to presentation was recorded for 23 of 29 patients (79.3%). Of them, 6 (26.1%) experienced symptoms for 1 month or less, 12 (52.2%) for 1 to 6 months, and 5 (21.7%) for 6 months to 1 year.

Physical examination findings (Figure) were documented in all 29 cases. Annular lesions were noted in 24 patients (82.8%). Pustules were present in 5 patients (17.2%) and papules in 11 patients (37.9%). Fourteen patients (48.3%) had involvement of the face, 14 (48.3%) of the body (ie, trunk, extremities, or groin), and 3 (10.3%) of the scalp. Six patients (20.7%) demonstrated findings at more than one body site.

Females were more likely to demonstrate facial lesions (P=.02), while males were more likely to present with body lesions (P=.04). Of 26 patients diagnosed via fungal culture, 16 (55.2%) grew Trichophyton tonsurans, 4 (13.8%) grew Trichophyton rubrum, 3 (10.3%) grew Trichophyton mentagrophytes, 2 (6.9%) grew Microsporum canis, and 1 (3.4%) grew Microsporum gypseum. Treatment entailed oral medication in 18 cases (62.1%). Of them, 13 (72.2%) were treated with griseofulvin, 3 (16.7%) with fluconazole, and 2 (11.1%) with terbinafine. Topical antifungals were prescribed in the remaining 11 cases (37.9%); no further treatment was documented.

Comment

Since the initial description of TI, approximately 60 case reports and small series as well as several larger observational studies describing TI have been published. In our series of pediatric patients, 29 of 83 culture- or KOH-confirmed dermatophytosis cases (34.9%) were considered to be TI due to treatment with topical corticosteroids and/or calcineurin inhibitors prior to presentation. This high prevalence contrasts with the 5.6% prevalence reported in the only prior large case series examining TI in childhood.² These authors further reported that in their pediatric population, TI was significantly (odds ratio, 8.7; 95% CI, 4.7-16.1) more likely to occur on the face relative to other dermatophytoses and significantly (odds ratio, 0.014; 95% CI, 0.002-0.099) less likely to occur on the scalp.² We noted a significant association between female gender and facial symptoms as well as between male gender and truncal symptoms. Taken together, these findings suggest an increased likelihood of pediatric tinea faciei to be inappropriately treated, particularly in females.

Although TI treated with topical corticosteroids or calcineurin inhibitors can mimic other skin diseases, a majority of patients in our series demonstrated findings associated with classic tinea, such as annularity and scale. Further, we found that T tonsurans was the causative organism in most cases with T rubrum uncommonly seen, though it is the most prevalent dermatophyte observed worldwide and in 2 large TI case series.^3,4 Regional variation in dermatophytes may account for these differences. In our study, griseofulvin was used most frequently in TI treatment, though a systematic review of oral antifungals in tinea capitis supported terbinafine’s greater efficacy in patients infected with T tonsurans.⁵

Conclusion

Our case series demonstrated a 35% prevalence of TI cases in a population of children with confirmed dermatophytosis presenting to dermatologists at an American academic medical center. We hope that noting the high prevalence and manifold presentations of this disease will aid practitioners in maintaining clinical suspicion for dermatophytosis and thereby facilitate appropriate identification and treatment of TI.

Tinea incognito (TI) describes a dermatophytosis with often atypical clinical features attributed to prior use of topical corticosteroids or other immunomodulating agents. Tinea incognito may lack the scale and elevated margin typical of cutaneous dermatophytoses and can be mistaken for other pediatric cutaneous diseases, particularly atopic dermatitis. ¹ Given the prevalence of TI and its susceptibility to misdiagnosis, we conducted a retrospective medical record review of cases of pediatric dermatophytosis presenting from 2005 to 2016.

Methods

We reviewed medical records for patients younger than 18 years who had been seen at the Faculty Group Practice of the Ronald O. Perelman Department of Dermatology, New York University School of Medicine (New York, New York), between January 1, 2005, and October 21, 2016, using International Classification of Diseases, Ninth Revision (ICD-9) codes 110.0 (tinea capitis), 110.1 (onychomycosis/tinea unguium), 110.3 (tinea cruris), 110.4 (tinea pedis), 110.5 (tinea corporis), and 110.9 (tinea, unspecified site). Cases were included in this study if there was documentation of dermatophytosis previously treated with topical corticosteroids or calcineurin inhibitors as well as positive potassium hydroxide (KOH) preparation or fungal culture with dermatophyte growth obtained from lesions satisfying the first criterion. This study was approved by the New York University School of Medicine institutional review board (study no. S15-01388).

Statistical analyses were conducted in SPSS 19.0 for Windows. Categorical variables were assessed using the χ² test for independence and the Fisher exact test.

Results

A total of 464 cases were reviewed. A positive KOH preparation or dermatophyte fungal culture was documented in 83 cases. Of them, 29 (34.9%) were treated with topical steroids and/or calcineurin inhibitors prior to presentation to dermatology (Table). The mean age at presentation was 8 years. Duration of symptoms prior to presentation was recorded for 23 of 29 patients (79.3%). Of them, 6 (26.1%) experienced symptoms for 1 month or less, 12 (52.2%) for 1 to 6 months, and 5 (21.7%) for 6 months to 1 year.

Physical examination findings (Figure) were documented in all 29 cases. Annular lesions were noted in 24 patients (82.8%). Pustules were present in 5 patients (17.2%) and papules in 11 patients (37.9%). Fourteen patients (48.3%) had involvement of the face, 14 (48.3%) of the body (ie, trunk, extremities, or groin), and 3 (10.3%) of the scalp. Six patients (20.7%) demonstrated findings at more than one body site.

Females were more likely to demonstrate facial lesions (P=.02), while males were more likely to present with body lesions (P=.04). Of 26 patients diagnosed via fungal culture, 16 (55.2%) grew Trichophyton tonsurans, 4 (13.8%) grew Trichophyton rubrum, 3 (10.3%) grew Trichophyton mentagrophytes, 2 (6.9%) grew Microsporum canis, and 1 (3.4%) grew Microsporum gypseum. Treatment entailed oral medication in 18 cases (62.1%). Of them, 13 (72.2%) were treated with griseofulvin, 3 (16.7%) with fluconazole, and 2 (11.1%) with terbinafine. Topical antifungals were prescribed in the remaining 11 cases (37.9%); no further treatment was documented.

Comment

Since the initial description of TI, approximately 60 case reports and small series as well as several larger observational studies describing TI have been published. In our series of pediatric patients, 29 of 83 culture- or KOH-confirmed dermatophytosis cases (34.9%) were considered to be TI due to treatment with topical corticosteroids and/or calcineurin inhibitors prior to presentation. This high prevalence contrasts with the 5.6% prevalence reported in the only prior large case series examining TI in childhood.² These authors further reported that in their pediatric population, TI was significantly (odds ratio, 8.7; 95% CI, 4.7-16.1) more likely to occur on the face relative to other dermatophytoses and significantly (odds ratio, 0.014; 95% CI, 0.002-0.099) less likely to occur on the scalp.² We noted a significant association between female gender and facial symptoms as well as between male gender and truncal symptoms. Taken together, these findings suggest an increased likelihood of pediatric tinea faciei to be inappropriately treated, particularly in females.

Although TI treated with topical corticosteroids or calcineurin inhibitors can mimic other skin diseases, a majority of patients in our series demonstrated findings associated with classic tinea, such as annularity and scale. Further, we found that T tonsurans was the causative organism in most cases with T rubrum uncommonly seen, though it is the most prevalent dermatophyte observed worldwide and in 2 large TI case series.^3,4 Regional variation in dermatophytes may account for these differences. In our study, griseofulvin was used most frequently in TI treatment, though a systematic review of oral antifungals in tinea capitis supported terbinafine’s greater efficacy in patients infected with T tonsurans.⁵

Conclusion

Our case series demonstrated a 35% prevalence of TI cases in a population of children with confirmed dermatophytosis presenting to dermatologists at an American academic medical center. We hope that noting the high prevalence and manifold presentations of this disease will aid practitioners in maintaining clinical suspicion for dermatophytosis and thereby facilitate appropriate identification and treatment of TI.

Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.^1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.³

We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.

Case Report

A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.

Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A_1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.

Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.

The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.

Comment

Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.⁴ Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.^1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.¹ Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.

Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.⁵ The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.^6,7

Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.^2,6,7 Transmission does not occur from person to person.⁷ Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.^3,8-14

Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.¹⁴ Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.^3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.⁷ Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.^2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.⁴ Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.²

Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.^1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.¹⁹ To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.^4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.⁴

Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.⁷ Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.^1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.¹⁹

Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.⁴ Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.^1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.¹⁹ Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.¹⁹ Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.

Conclusion

Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.

Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.

Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.^1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.³

We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.

Case Report

A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.

Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A_1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.

Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.

The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.

Comment

Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.⁴ Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.^1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.¹ Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.

Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.⁵ The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.^6,7

Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.^2,6,7 Transmission does not occur from person to person.⁷ Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.^3,8-14

Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.¹⁴ Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.^3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.⁷ Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.^2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.⁴ Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.²

Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.^1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.¹⁹ To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.^4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.⁴

Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.⁷ Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.^1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.¹⁹

Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.⁴ Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.^1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.¹⁹ Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.¹⁹ Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.

Conclusion

Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.

Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.

Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.^1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.³

We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.

Case Report

A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.

Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A_1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.

Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.

The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.

Comment

Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.⁴ Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.^1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.¹ Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.

Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.⁵ The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.^6,7

Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.^2,6,7 Transmission does not occur from person to person.⁷ Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.^3,8-14

Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.¹⁴ Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.^3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.⁷ Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.^2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.⁴ Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.²

Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.^1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.¹⁹ To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.^4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.⁴

Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.⁷ Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.^1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.¹⁹

Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.⁴ Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.^1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.¹⁹ Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.¹⁹ Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.

Conclusion

Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.

Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.

Acute hemorrhagic edema of infancy (AHEI) is an uncommon leukocytoclastic vasculitis affecting children aged 6 to 24 months; Henoch-Schönlein purpura (HSP) is the most common misdiagnosis. The 2 entities should be differentiated, as HSP may have renal and gastrointestinal (GI) comorbidities that need serial follow-up, whereas AHEI follows a benign course without systemic sequelae. Patient history and physical examination are the most important factors in differentiating the 2 diseases; histopathologic and direct immunofluorescence (DIF) analyses may lend further diagnostic confidence.

We report the case of a 10-month-old previously healthy boy who presented with acute rash, edema, and low-grade fever in the setting of recent diarrhea. We differentiate between AHEI and HSP to help prevent misdiagnosis by health care providers.

Case Report

A 10-month-old previously healthy boy presented to the emergency department (ED) for evaluation of a rash and swelling of 4 days’ duration. He had nonbloody diarrhea 1 week prior; soon after, he developed bilateral lower leg edema and rash. On evaluation in a different ED, he had a low-grade fever (rectal temperature, 38.0°C) but normal blood work, including complete blood cell count, basic metabolic panel, and coagulation studies. The patient was discharged to outpatient follow-up with his pediatrician who reported normal urinalysis.

Due to progression of the rash, the patient presented to our ED 3 days after his initial ED assessment. Dermatology was consulted. At the time of presentation, he was afebrile but with GI upset and fussiness. His parents denied additional symptoms or blood in urine or stool. Physical examination revealed a nontoxic-appearing infant with scattered palpable, annular, purpuric papules coalescing into plaques on both legs and feet (Figure 1), with sparse petechiae noted on the lower abdomen. The cheeks had scattered purpuric papules and plaques bilaterally, a few with a small central crust (Figure 2), and the right superior helix had a faint purpuric macule. The hands had a few pink edematous coalescing papules.

Histopathologic analyses with hematoxylin and eosin staining (Figure 3) and DIF (Figure 4) were performed from within a representative purpuric plaque on the right hip. Direct immunofluorescence was performed to evaluate for an IgA vasculitis versus an alternative type of vasculitis. The hematoxylin and eosin–stained specimen demonstrated a dermal perivascular infiltrate involving superficial and deep vessels with neutrophils, karyorrhexis, and erythrocyte extravasation. The endothelium was intact, with a mild suggestion of fibrinoid change of the blood vessel walls. Direct immunofluorescence revealed granular deposition of IgA, C3, and fibrinogen in multiple dermal blood vessels. Combined, the specimens were interpreted as evolving IgA-associated leukocytoclastic vasculitis.

The case was reviewed with our 2 department pediatric dermatologists; a diagnosis of AHEI was made based on the clinical and supportive histopathological presentations. The patient’s parents chose active treatment with a 2-week taper of oral prednisone because of the patient’s discomfort with edema. No GI or adverse renal sequelae, including findings on urinalysis, were reported at 1-month hospital follow-up with dermatology and pediatrics.

Comment

Incidence and Clinical Characteristics
Acute hemorrhagic edema of infancy is an uncommon leukocytoclastic vasculitis first described in the United States by Snow¹ in 1913. Other names for the disorder include acute hemorrhagic edema of young children, cockade purpura and edema, Finkelstein disease, and Seidlmayer disease.² Boys are affected more often than girls, with most children presenting at 6 to 24 months of age. Most affected children experience a prodrome of simple respiratory tract illness (most common), diarrhea (as in our case), or urinary tract infection.² The exact pathophysiology behind AHEI is unknown, but it is thought to be an immune complex–mediated disease evidenced by the fact that infection, use of medication, or immunization precedes most cases.^3,4

Diagnosis
Acute hemorrhagic edema of infancy is diagnosed clinically, with or without the support of skin biopsy. It should be differentiated from HSP because of renal and GI sequelae that HSP portends compared to the benign course of AHEI.² Notably, some health care providers consider AHEI a benign variant of HSP.^2,3

Characteristically, AHEI patients are nontoxic-appearing infants with a low-grade fever who develop relatively large (1–5 cm) targetoid purpuric lesions and indurated nonpitting edema of the extremities.^2,5 Purpura in AHEI frequently occurs on the face, ears, and upper and lower extremities, whereas purpura in HSP most commonly presents on the buttocks and extensor legs with sparing of the face. Henoch-Schönlein purpura most often affects children aged 3 to 6 years compared to AHEI’s younger demographic (age <2 years).^4,5 Clinically, HSP presents with palpable purpura and 1 or more of the following features: diffuse abdominal pain, arthritis/arthralgia, renal involvement, and skin or renal biopsy showing predominant IgA deposition.^2,6

Both AHEI and HSP show leukocytoclastic vasculitis on histopathology.^2-4,6,7 Positive perivascular IgA staining on DIF is strongly associated with HSP, but nearly one-quarter of AHEI cases also show this deposition pattern^2,4,7; therefore, DIF alone cannot exclude a diagnosis of AHEI.

Differential Diagnosis
Alternative diagnoses to consider with AHEI include drug-induced vasculitis, erythema multiforme, HSP, Kawasaki disease, meningococcemia, nonaccidental skin bruising, Rocky Mountain spotted fever, septic vasculitis, and urticarial vasculitis (Table).^2-4,6-8

Treatment
Acute hemorrhagic edema of infancy is self-limited, with only rare reports of extracutaneous involvement. Supportive treatment is indicated because spontaneous recovery without sequelae is expected within 21 days.^2,3,6 If edema is symptomatic, as was the case with our patient, corticosteroids may shorten the disease course.³

Conclusion

Our case highlights the need to combine clinical history, physical examination, and histopathologic analysis to differentiate between AHEI and HSP, which is important for 2 reasons: (1) it helps with the decision to undertake active or observational treatment, and (2) it helps the clinician counsel the patient and guardians regarding potential associated renal and GI risks.

Acute hemorrhagic edema of infancy (AHEI) is an uncommon leukocytoclastic vasculitis affecting children aged 6 to 24 months; Henoch-Schönlein purpura (HSP) is the most common misdiagnosis. The 2 entities should be differentiated, as HSP may have renal and gastrointestinal (GI) comorbidities that need serial follow-up, whereas AHEI follows a benign course without systemic sequelae. Patient history and physical examination are the most important factors in differentiating the 2 diseases; histopathologic and direct immunofluorescence (DIF) analyses may lend further diagnostic confidence.

We report the case of a 10-month-old previously healthy boy who presented with acute rash, edema, and low-grade fever in the setting of recent diarrhea. We differentiate between AHEI and HSP to help prevent misdiagnosis by health care providers.

Case Report

A 10-month-old previously healthy boy presented to the emergency department (ED) for evaluation of a rash and swelling of 4 days’ duration. He had nonbloody diarrhea 1 week prior; soon after, he developed bilateral lower leg edema and rash. On evaluation in a different ED, he had a low-grade fever (rectal temperature, 38.0°C) but normal blood work, including complete blood cell count, basic metabolic panel, and coagulation studies. The patient was discharged to outpatient follow-up with his pediatrician who reported normal urinalysis.

Due to progression of the rash, the patient presented to our ED 3 days after his initial ED assessment. Dermatology was consulted. At the time of presentation, he was afebrile but with GI upset and fussiness. His parents denied additional symptoms or blood in urine or stool. Physical examination revealed a nontoxic-appearing infant with scattered palpable, annular, purpuric papules coalescing into plaques on both legs and feet (Figure 1), with sparse petechiae noted on the lower abdomen. The cheeks had scattered purpuric papules and plaques bilaterally, a few with a small central crust (Figure 2), and the right superior helix had a faint purpuric macule. The hands had a few pink edematous coalescing papules.

Histopathologic analyses with hematoxylin and eosin staining (Figure 3) and DIF (Figure 4) were performed from within a representative purpuric plaque on the right hip. Direct immunofluorescence was performed to evaluate for an IgA vasculitis versus an alternative type of vasculitis. The hematoxylin and eosin–stained specimen demonstrated a dermal perivascular infiltrate involving superficial and deep vessels with neutrophils, karyorrhexis, and erythrocyte extravasation. The endothelium was intact, with a mild suggestion of fibrinoid change of the blood vessel walls. Direct immunofluorescence revealed granular deposition of IgA, C3, and fibrinogen in multiple dermal blood vessels. Combined, the specimens were interpreted as evolving IgA-associated leukocytoclastic vasculitis.

The case was reviewed with our 2 department pediatric dermatologists; a diagnosis of AHEI was made based on the clinical and supportive histopathological presentations. The patient’s parents chose active treatment with a 2-week taper of oral prednisone because of the patient’s discomfort with edema. No GI or adverse renal sequelae, including findings on urinalysis, were reported at 1-month hospital follow-up with dermatology and pediatrics.

Comment

Incidence and Clinical Characteristics
Acute hemorrhagic edema of infancy is an uncommon leukocytoclastic vasculitis first described in the United States by Snow¹ in 1913. Other names for the disorder include acute hemorrhagic edema of young children, cockade purpura and edema, Finkelstein disease, and Seidlmayer disease.² Boys are affected more often than girls, with most children presenting at 6 to 24 months of age. Most affected children experience a prodrome of simple respiratory tract illness (most common), diarrhea (as in our case), or urinary tract infection.² The exact pathophysiology behind AHEI is unknown, but it is thought to be an immune complex–mediated disease evidenced by the fact that infection, use of medication, or immunization precedes most cases.^3,4

Diagnosis
Acute hemorrhagic edema of infancy is diagnosed clinically, with or without the support of skin biopsy. It should be differentiated from HSP because of renal and GI sequelae that HSP portends compared to the benign course of AHEI.² Notably, some health care providers consider AHEI a benign variant of HSP.^2,3

Characteristically, AHEI patients are nontoxic-appearing infants with a low-grade fever who develop relatively large (1–5 cm) targetoid purpuric lesions and indurated nonpitting edema of the extremities.^2,5 Purpura in AHEI frequently occurs on the face, ears, and upper and lower extremities, whereas purpura in HSP most commonly presents on the buttocks and extensor legs with sparing of the face. Henoch-Schönlein purpura most often affects children aged 3 to 6 years compared to AHEI’s younger demographic (age <2 years).^4,5 Clinically, HSP presents with palpable purpura and 1 or more of the following features: diffuse abdominal pain, arthritis/arthralgia, renal involvement, and skin or renal biopsy showing predominant IgA deposition.^2,6

Both AHEI and HSP show leukocytoclastic vasculitis on histopathology.^2-4,6,7 Positive perivascular IgA staining on DIF is strongly associated with HSP, but nearly one-quarter of AHEI cases also show this deposition pattern^2,4,7; therefore, DIF alone cannot exclude a diagnosis of AHEI.

Differential Diagnosis
Alternative diagnoses to consider with AHEI include drug-induced vasculitis, erythema multiforme, HSP, Kawasaki disease, meningococcemia, nonaccidental skin bruising, Rocky Mountain spotted fever, septic vasculitis, and urticarial vasculitis (Table).^2-4,6-8

Treatment
Acute hemorrhagic edema of infancy is self-limited, with only rare reports of extracutaneous involvement. Supportive treatment is indicated because spontaneous recovery without sequelae is expected within 21 days.^2,3,6 If edema is symptomatic, as was the case with our patient, corticosteroids may shorten the disease course.³

Conclusion

Our case highlights the need to combine clinical history, physical examination, and histopathologic analysis to differentiate between AHEI and HSP, which is important for 2 reasons: (1) it helps with the decision to undertake active or observational treatment, and (2) it helps the clinician counsel the patient and guardians regarding potential associated renal and GI risks.

Acute hemorrhagic edema of infancy (AHEI) is an uncommon leukocytoclastic vasculitis affecting children aged 6 to 24 months; Henoch-Schönlein purpura (HSP) is the most common misdiagnosis. The 2 entities should be differentiated, as HSP may have renal and gastrointestinal (GI) comorbidities that need serial follow-up, whereas AHEI follows a benign course without systemic sequelae. Patient history and physical examination are the most important factors in differentiating the 2 diseases; histopathologic and direct immunofluorescence (DIF) analyses may lend further diagnostic confidence.

We report the case of a 10-month-old previously healthy boy who presented with acute rash, edema, and low-grade fever in the setting of recent diarrhea. We differentiate between AHEI and HSP to help prevent misdiagnosis by health care providers.

Case Report

A 10-month-old previously healthy boy presented to the emergency department (ED) for evaluation of a rash and swelling of 4 days’ duration. He had nonbloody diarrhea 1 week prior; soon after, he developed bilateral lower leg edema and rash. On evaluation in a different ED, he had a low-grade fever (rectal temperature, 38.0°C) but normal blood work, including complete blood cell count, basic metabolic panel, and coagulation studies. The patient was discharged to outpatient follow-up with his pediatrician who reported normal urinalysis.

Due to progression of the rash, the patient presented to our ED 3 days after his initial ED assessment. Dermatology was consulted. At the time of presentation, he was afebrile but with GI upset and fussiness. His parents denied additional symptoms or blood in urine or stool. Physical examination revealed a nontoxic-appearing infant with scattered palpable, annular, purpuric papules coalescing into plaques on both legs and feet (Figure 1), with sparse petechiae noted on the lower abdomen. The cheeks had scattered purpuric papules and plaques bilaterally, a few with a small central crust (Figure 2), and the right superior helix had a faint purpuric macule. The hands had a few pink edematous coalescing papules.

Histopathologic analyses with hematoxylin and eosin staining (Figure 3) and DIF (Figure 4) were performed from within a representative purpuric plaque on the right hip. Direct immunofluorescence was performed to evaluate for an IgA vasculitis versus an alternative type of vasculitis. The hematoxylin and eosin–stained specimen demonstrated a dermal perivascular infiltrate involving superficial and deep vessels with neutrophils, karyorrhexis, and erythrocyte extravasation. The endothelium was intact, with a mild suggestion of fibrinoid change of the blood vessel walls. Direct immunofluorescence revealed granular deposition of IgA, C3, and fibrinogen in multiple dermal blood vessels. Combined, the specimens were interpreted as evolving IgA-associated leukocytoclastic vasculitis.

The case was reviewed with our 2 department pediatric dermatologists; a diagnosis of AHEI was made based on the clinical and supportive histopathological presentations. The patient’s parents chose active treatment with a 2-week taper of oral prednisone because of the patient’s discomfort with edema. No GI or adverse renal sequelae, including findings on urinalysis, were reported at 1-month hospital follow-up with dermatology and pediatrics.

Comment

Incidence and Clinical Characteristics
Acute hemorrhagic edema of infancy is an uncommon leukocytoclastic vasculitis first described in the United States by Snow¹ in 1913. Other names for the disorder include acute hemorrhagic edema of young children, cockade purpura and edema, Finkelstein disease, and Seidlmayer disease.² Boys are affected more often than girls, with most children presenting at 6 to 24 months of age. Most affected children experience a prodrome of simple respiratory tract illness (most common), diarrhea (as in our case), or urinary tract infection.² The exact pathophysiology behind AHEI is unknown, but it is thought to be an immune complex–mediated disease evidenced by the fact that infection, use of medication, or immunization precedes most cases.^3,4

Diagnosis
Acute hemorrhagic edema of infancy is diagnosed clinically, with or without the support of skin biopsy. It should be differentiated from HSP because of renal and GI sequelae that HSP portends compared to the benign course of AHEI.² Notably, some health care providers consider AHEI a benign variant of HSP.^2,3

Characteristically, AHEI patients are nontoxic-appearing infants with a low-grade fever who develop relatively large (1–5 cm) targetoid purpuric lesions and indurated nonpitting edema of the extremities.^2,5 Purpura in AHEI frequently occurs on the face, ears, and upper and lower extremities, whereas purpura in HSP most commonly presents on the buttocks and extensor legs with sparing of the face. Henoch-Schönlein purpura most often affects children aged 3 to 6 years compared to AHEI’s younger demographic (age <2 years).^4,5 Clinically, HSP presents with palpable purpura and 1 or more of the following features: diffuse abdominal pain, arthritis/arthralgia, renal involvement, and skin or renal biopsy showing predominant IgA deposition.^2,6

Both AHEI and HSP show leukocytoclastic vasculitis on histopathology.^2-4,6,7 Positive perivascular IgA staining on DIF is strongly associated with HSP, but nearly one-quarter of AHEI cases also show this deposition pattern^2,4,7; therefore, DIF alone cannot exclude a diagnosis of AHEI.

Differential Diagnosis
Alternative diagnoses to consider with AHEI include drug-induced vasculitis, erythema multiforme, HSP, Kawasaki disease, meningococcemia, nonaccidental skin bruising, Rocky Mountain spotted fever, septic vasculitis, and urticarial vasculitis (Table).^2-4,6-8

Treatment
Acute hemorrhagic edema of infancy is self-limited, with only rare reports of extracutaneous involvement. Supportive treatment is indicated because spontaneous recovery without sequelae is expected within 21 days.^2,3,6 If edema is symptomatic, as was the case with our patient, corticosteroids may shorten the disease course.³

Conclusion

Our case highlights the need to combine clinical history, physical examination, and histopathologic analysis to differentiate between AHEI and HSP, which is important for 2 reasons: (1) it helps with the decision to undertake active or observational treatment, and (2) it helps the clinician counsel the patient and guardians regarding potential associated renal and GI risks.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.^1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.^6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,^13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.^12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.²⁴

Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.

Incidence of CVA6

Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.^7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.²⁶ According to one study, “[n]early every Chinese city showed a sharp rise in [CVA6].”²⁷

The incidence of CVA6 also has been increasing in other areas.²⁸ In Spain, CVA6 overtook CVA16 as the dominant cause of HFMD during 2011 and 2012 outbreaks.²⁹ From 2011 to 2012, there was a CVA6-associated HFMD outbreak in North America, with 63 cases reported to the Centers for Disease Control and Prevention (CDC), including 15 adult cases, with approximately 50% having been exposed to children with HFMD.⁹ In 2014, a Minnesota college with approximately 1000 students reported 9 suspected cases of HFMD to the Minnesota Department of Health. Coxsackievirus A6 was isolated, sequenced, and identified by the CDC in 5 of 9 patients (age range, 19–47 years).⁹

In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.⁷ Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.⁷

Presentation

Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1). Skin lesions often are painful and spread to a wider distribution than typical of HFMD, which can include the face, proximal extremities, lips, perianal and groin skin, scalp, and dorsal feet and hands (Figure 2). These areas are classically spared in the prototypical presentation of HFMD in children.^2,6,24,30-33 Vesicles that are typically football shaped (Figure 3) are a diagnostic clue of the disease. After patients have recovered from the disease, they can have delayed-onset palmar and plantar desquamation that usually presents 1 to 3 weeks after the disease. Additionally, another postsyndrome finding is onychomadesis, or detachment of the nail plate from the nail matrix.^6,34-37 This process likely occurs due to direct cytopathic effect to the nail matrix from the viral infection.^24,37 Blistering may be severe and can form hemorrhagic bullae.²⁴ Although cutaneous findings are more severe, neurologic involvement actually is more rare in the CVA6 strain compared to other viral strains known to cause HFMD, specifically EV71. One study found only 2.4% of 141 patients infected with CVA6 had central nervous system involvement, specifically aseptic meningitis or encephalitis.^21,24

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

Photograph courtesy of Lauren Snitzer, MD (Houston, Texas).

In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.^24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.²⁴

Clinical Diagnosis

Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.⁶ In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.⁴⁰ In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.^6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.^6,41 CD3⁺ and CD8⁺ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.⁶

Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.^41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.⁴³ This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.²⁴ Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.^2,24

Treatment

Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.²⁴

Genetic Analysis

Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.⁴⁴ These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.^27,44

Conclusion

With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

Case Report

An 11-year-old boy presented with atraumatic thickening of the skin on the bilateral distal and proximal interphalangeal joints of 1 year’s duration. The patient also noted small bumps of unknown duration across the bilateral palms and soles with prominence on the lateral aspects. The patient previously used over-the-counter topical wart removal treatment and topical salicylic acid with minimal improvement. The patient reported no pertinent medical or surgical history, although there was a family history of Alport syndrome, predominantly in male relatives. The patient’s father and paternal grandfather were noted to have similar lesions on the palms.

On physical examination, multiple pink to flesh-colored hyperkeratotic plaques were noted over the proximal and distal interphalangeal joints of the bilateral hands (Figure 1A). Upon close inspection, there were small flesh-colored and slightly translucent papules in a linear distribution on the palmar surfaces of the hands (Figure 2A) with predominance on the thenar and hypothenar eminences. The flexural creases of the bilateral wrists also revealed linear flesh-colored papules. The same small flesh-colored and translucent papules also were noted on the plantar surfaces of the bilateral feet (Figure 2B).

A biopsy was obtained from one of the small translucent papules on the left palm. Hematoxylin and eosin–stained sections revealed elevated compact orthokeratosis with an underlying central epidermal dell (Figure 3). A diagnosis of marginal papular keratoderma was made and further elastin staining was completed. Elastin stains showed marked thinning of the elastin fibers throughout the reticular dermis. Many elastin fibers in the reticular dermis demonstrated a fine arborizing pattern that normally is only evident in the papillary dermis (Figure 4). Acrokeratoelastoidosis (AKE) was diagnosed histopathologically, and knuckle pads were diagnosed clinically.

Because the patient was asymptomatic, he did not want treatment of AKE. He had marked improvement of the knuckle pads after 1 month with daily application of urea cream 10% (Figure 1B), and intermittent use was required for maintenance.

Comment

Etiology
Acrokeratoelastoidosis was first described in 1953 and is considered a type of palmoplantar marginal papular keratoderma.¹ There is overlap within the marginal papular keratodermas that makes precise diagnosis difficult within this group. The marginal papular keratodermas on the palms and soles are a group of disorders that include AKE, focal acral hyperkeratosis (FAH), mosaic acral keratosis, degenerative collagenous plaques on the hands, and digital papular calcific elastosis. These diseases are similar in clinical and histopathological features; some argue these diseases are the same entity.²

Acrokeratoelastoidosis has been hypothesized to originate from altered elastic fiber synthesis from fibroblasts.³ Because AKE is rare, most cases of common knuckle pads do not coexist with AKE; therefore, it is unknown if the underlying etiology remains the same for both entities. Unlike AKE, knuckle pads are often associated with Dupuytren contractures, repetitive trauma, or friction to the area.^1,2

Presentation
Acrokeratoelastoidosis is a rare disease with onset in childhood or young adulthood. Childhood cases are inherited in an autosomal-dominant fashion.¹ Adulthood onset suggests a sporadic form of inheritance. Acrokeratoelastoidosis has no gender or racial predilection.⁴ It presents over the thenar and hypothenar eminences, as well as the lateral digits, calcaneal tendon, and dorsal digits.¹ Most often, AKE occurs symmetrically along the border separating the ventral and dorsal aspects on the palms and soles. These lesions present as small, firm, translucent papules that align linearly on the ventral-dorsal palmoplantar junction in a pattern resembling paving stones.¹ Coalescence of papules into plaques has been reported. Extension of lesions to the dorsal and palmar surfaces can occur. Small circumscribed callosities may develop over the metacarpophalangeal and interphalangeal joints resembling knuckle pads.²

Histopathology
Histopathologically, AKE is distinguished by elastorrhexis—thinning, fragmenting, and rarefaction of elastin fibers—in the epidermis and reticular dermis layers.³ Acrokeratoelastoidosis also presents with orthokeratosis overlying a cuplike epithelial depression and possible epithelial acanthosis.^2,5 Many cases exhibit hypergranulosis at the base of the epidermal dell. Dense basophilic granules may be seen in the peripheral cytoplasm of fibroblast cells coming from the hypothesized defect in elastin secretion.^1,3,4

Differential Diagnosis
The main differential diagnosis of AKE is FAH. Clinically and histopathologically they appear identical; both diseases have cuplike epidermal depressions with overlying orthohyperkeratosis and prominent hypergranulosis.⁵ The elastin stains, Verhoeff-van Gieson or acid orcein stain, are imperative for distinguishing these two diseases. Although AKE demonstrates elastorrhexis and reduced elastic fibers, FAH reveals no alteration of elastic fibers. It has been suggested that FAH is a clinical variant of AKE and should be titled AKE without elastorrhexis.¹

Treatment
Acrokeratoelastoidosis is asymptomatic except for mild palmoplantar hyperhidrosis and typically does not require treatment⁴; however, the condition can be of cosmetic concern for patients. Lesions can be treated topically with keratolytics such as tretinoin and salicylic acid. A wide variety of systemic treatments including methotrexate, prednisolone, dapsone, and acitretin have been reported with variable clinical response.^2-4 Copresenting knuckle pads can be treated with urea cream, salicylic acid cream, or intralesional corticosteroids.¹

Photo from Pexels

The latest edition of the national palliative care guidelines provides new clinical strategies relevant to hematology practice in the United States, according to a physician-researcher specializing in hematology.

The Clinical Practice Guidelines for Quality Palliative Care, 4th edition, represents a “blueprint for what it looks like to provide high-quality, comprehensive palliative care to people with serious illness,” said Thomas W. LeBlanc, MD, a physician-researcher at Duke University School of Medicine in Durham, North Carolina.

However, unlike previous editions, this update to the guidelines emphasizes the importance of palliative care provided by both primary care and specialty care clinicians.

“Part of this report is about trying to raise the game of everybody in medicine and provide a higher basic level of primary palliative care to all people with serious illness, but then also to figure out who has higher levels of needs where the specialists should be applied, since they are a scarce resource,” Dr. LeBlanc said.

The latest edition helps establish a foundation for gold standard palliative care for people living with serious illness, regardless of diagnosis, prognosis, setting, or age, according to The National Coalition for Hospice and Palliative Care, which published the clinical practice guidelines.

The update was developed by the National Consensus Project for Quality Palliative Care (NCP), which includes 16 national organizations with palliative care and hospice expertise, and is endorsed by more than 80 national organizations, including the American Society of Hematology.

One key reason for the update, according to NCP, was to acknowledge that today’s healthcare system may not be meeting patients’ palliative care needs.

Specifically, the guidelines call on clinicians who don’t practice palliative care to integrate palliative care principles into their routine assessment of seriously ill patients with conditions such as heart failure, lung disease, and cancer.

That differs from the way palliative care is traditionally practiced, in which specially trained doctors, nurses, and other specialists provide that support.

An issue with that traditional model is a shortage of specialized clinicians to meet palliative care needs, said Dr. LeBlanc, whose clinical practice and research focuses on palliative care needs of patients with hematologic malignancies.

“Palliative care has matured as a field such that we are now actually facing workforce shortage issues and really fundamental questions about who really needs us the most and how we increase our reach to improve the lives of more patients and families facing serious illness,” he said.

That’s a major driver behind the emphasis in the latest guidelines on providing palliative care in the community, coordinating care, and dealing with care transitions, Dr. LeBlanc added.

“I hope that this document will help to demonstrate the value and the need for palliative care specialists and for improvements in primary care in the care of patients with hematologic diseases in general,” he said. “To me, this adds increasing legitimacy to this whole field.”

Photo from Pexels

The latest edition of the national palliative care guidelines provides new clinical strategies relevant to hematology practice in the United States, according to a physician-researcher specializing in hematology.

The Clinical Practice Guidelines for Quality Palliative Care, 4th edition, represents a “blueprint for what it looks like to provide high-quality, comprehensive palliative care to people with serious illness,” said Thomas W. LeBlanc, MD, a physician-researcher at Duke University School of Medicine in Durham, North Carolina.

However, unlike previous editions, this update to the guidelines emphasizes the importance of palliative care provided by both primary care and specialty care clinicians.

“Part of this report is about trying to raise the game of everybody in medicine and provide a higher basic level of primary palliative care to all people with serious illness, but then also to figure out who has higher levels of needs where the specialists should be applied, since they are a scarce resource,” Dr. LeBlanc said.

The latest edition helps establish a foundation for gold standard palliative care for people living with serious illness, regardless of diagnosis, prognosis, setting, or age, according to The National Coalition for Hospice and Palliative Care, which published the clinical practice guidelines.

The update was developed by the National Consensus Project for Quality Palliative Care (NCP), which includes 16 national organizations with palliative care and hospice expertise, and is endorsed by more than 80 national organizations, including the American Society of Hematology.

One key reason for the update, according to NCP, was to acknowledge that today’s healthcare system may not be meeting patients’ palliative care needs.

Specifically, the guidelines call on clinicians who don’t practice palliative care to integrate palliative care principles into their routine assessment of seriously ill patients with conditions such as heart failure, lung disease, and cancer.

That differs from the way palliative care is traditionally practiced, in which specially trained doctors, nurses, and other specialists provide that support.

An issue with that traditional model is a shortage of specialized clinicians to meet palliative care needs, said Dr. LeBlanc, whose clinical practice and research focuses on palliative care needs of patients with hematologic malignancies.

“Palliative care has matured as a field such that we are now actually facing workforce shortage issues and really fundamental questions about who really needs us the most and how we increase our reach to improve the lives of more patients and families facing serious illness,” he said.

That’s a major driver behind the emphasis in the latest guidelines on providing palliative care in the community, coordinating care, and dealing with care transitions, Dr. LeBlanc added.

“I hope that this document will help to demonstrate the value and the need for palliative care specialists and for improvements in primary care in the care of patients with hematologic diseases in general,” he said. “To me, this adds increasing legitimacy to this whole field.”

Photo from Pexels

The latest edition of the national palliative care guidelines provides new clinical strategies relevant to hematology practice in the United States, according to a physician-researcher specializing in hematology.

The Clinical Practice Guidelines for Quality Palliative Care, 4th edition, represents a “blueprint for what it looks like to provide high-quality, comprehensive palliative care to people with serious illness,” said Thomas W. LeBlanc, MD, a physician-researcher at Duke University School of Medicine in Durham, North Carolina.

However, unlike previous editions, this update to the guidelines emphasizes the importance of palliative care provided by both primary care and specialty care clinicians.

“Part of this report is about trying to raise the game of everybody in medicine and provide a higher basic level of primary palliative care to all people with serious illness, but then also to figure out who has higher levels of needs where the specialists should be applied, since they are a scarce resource,” Dr. LeBlanc said.

The latest edition helps establish a foundation for gold standard palliative care for people living with serious illness, regardless of diagnosis, prognosis, setting, or age, according to The National Coalition for Hospice and Palliative Care, which published the clinical practice guidelines.

The update was developed by the National Consensus Project for Quality Palliative Care (NCP), which includes 16 national organizations with palliative care and hospice expertise, and is endorsed by more than 80 national organizations, including the American Society of Hematology.

One key reason for the update, according to NCP, was to acknowledge that today’s healthcare system may not be meeting patients’ palliative care needs.

Specifically, the guidelines call on clinicians who don’t practice palliative care to integrate palliative care principles into their routine assessment of seriously ill patients with conditions such as heart failure, lung disease, and cancer.

That differs from the way palliative care is traditionally practiced, in which specially trained doctors, nurses, and other specialists provide that support.

An issue with that traditional model is a shortage of specialized clinicians to meet palliative care needs, said Dr. LeBlanc, whose clinical practice and research focuses on palliative care needs of patients with hematologic malignancies.

“Palliative care has matured as a field such that we are now actually facing workforce shortage issues and really fundamental questions about who really needs us the most and how we increase our reach to improve the lives of more patients and families facing serious illness,” he said.

That’s a major driver behind the emphasis in the latest guidelines on providing palliative care in the community, coordinating care, and dealing with care transitions, Dr. LeBlanc added.

“I hope that this document will help to demonstrate the value and the need for palliative care specialists and for improvements in primary care in the care of patients with hematologic diseases in general,” he said. “To me, this adds increasing legitimacy to this whole field.”

A 15-year-old Caucasian boy presented for evaluation of an asymptomatic brown patch on his right shoulder. While the patient’s mother first noticed the patch when he was 5 years old, the discolored area had recently been expanding in size and had developed hypertrichosis. The patient was otherwise healthy; he took no medications and denied any symptoms or history of trauma to the area. None of his siblings were similarly affected.

A physical examination revealed a well-demarcated hyperpigmented patch with an irregularly shaped border and an increased number of terminal hairs (FIGURE 1). The affected area was not indurated, and there were no muscular or skeletal abnormalities on inspection. Examination of the patch under a dermatoscope revealed islands of reticular (lattice-like) hyperpigmentation, focal hypopigmentation, and prominent follicles (FIGURE 2).

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

 

 

DIAGNOSIS: Becker melanosis

Becker melanosis (also called Becker’s nevus or Becker’s pigmentary hamartoma) is an organoid hamartoma that is most common among males.¹ This benign area of hyperpigmentation typically manifests as a circumscribed patch with an irregular border on the upper trunk, shoulders, or upper arms of young men. Becker melanosis is usually acquired and typically comes to medical attention around the time of puberty, although there may be a history of discoloration (as was true in this case).

A diagnosis that’s usually made clinically

Androgenic origin. Because of the male predominance and association with hypertrichosis (and for that matter, acne), androgens have been thought to play a role in the development of Becker melanosis.² The condition affects about 1 in 200 young men.¹ To date, no specific gene defect has been identified.

Becker melanosis is a benign condition marked by hyperpigmentation and hypertrichosis.

Underlying hypoplasia of the breast or musculoskeletal abnormalities are uncommonly associated with Becker melanosis. When these abnormalities are present, the condition is known as Becker’s nevus syndrome.³

Look for the pattern. Becker melanosis is associated with homogenous brown patches with perifollicular hypopigmentation, sometimes with a faint reticular pattern.^4,5 The diagnosis can usually be made clinically, but a skin biopsy can be helpful to confirm questionable cases. Dermoscopy can also assist in diagnosis. In this case, our patient’s presentation was typical, and additional studies were not needed.

Other causes of hyperpigmentation

The differential diagnosis includes other localized disorders associated with hyperpigmentation (TABLE^1,3,4).

Continue to: Morphea

Morphea represents a thickening of collagen bundles in the skin. Although morphea can affect the shoulder and trunk, as Becker melanosis does, lesions of morphea feel firm to the touch and are not associated with hypertrichosis.

Localized post-inflammatory hyperpigmentation occurs following a traumatic event, such as a burn, or a prior dermatosis, such as zoster. Careful history-taking can uncover an antecedent inflammatory condition. Post-inflammatory pigment changes do not typically result in hypertrichosis.

Café-au-lait macules can manifest as isolated areas of discoloration. These macules can be an important indicator of neurofibromatosis, a genetic disorder in which tumors grow in the nervous system. Melanocytic hamartomas of the iris (Lisch nodules), axillary freckling (Crowe’s sign), or multiple cutaneous neurofibromas serve as additional clues to neurofibromatosis. In ambiguous cases, a skin biopsy can help differentiate a café au lait macule from Becker melanosis.

To treat or not to treat?

No treatment other than reassurance is needed in most cases of Becker melanosis, as it is a benign condition. Protecting the area from sunlight can minimize darkening and contrast with the surrounding skin. Electrolysis and laser therapy can be used to treat the associated hypertrichosis; laser therapy can also reduce the hyperpigmentation. Nonablative fractional resurfacing accompanied by laser hair removal is also reported to be of value.⁶

Our patient was satisfied with reassurance of the benign nature of the condition and did not elect treatment.

CORRESPONDENCE
Matthew F. Helm, MD, 500 University Drive, Suite 4300, Department of Dermatology, HU14, UPC II, Hershey, PA 17033-2360; Mhelm2@pennstatehealth.psu.edu

A 15-year-old Caucasian boy presented for evaluation of an asymptomatic brown patch on his right shoulder. While the patient’s mother first noticed the patch when he was 5 years old, the discolored area had recently been expanding in size and had developed hypertrichosis. The patient was otherwise healthy; he took no medications and denied any symptoms or history of trauma to the area. None of his siblings were similarly affected.

A physical examination revealed a well-demarcated hyperpigmented patch with an irregularly shaped border and an increased number of terminal hairs (FIGURE 1). The affected area was not indurated, and there were no muscular or skeletal abnormalities on inspection. Examination of the patch under a dermatoscope revealed islands of reticular (lattice-like) hyperpigmentation, focal hypopigmentation, and prominent follicles (FIGURE 2).

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

 

 

DIAGNOSIS: Becker melanosis

Becker melanosis (also called Becker’s nevus or Becker’s pigmentary hamartoma) is an organoid hamartoma that is most common among males.¹ This benign area of hyperpigmentation typically manifests as a circumscribed patch with an irregular border on the upper trunk, shoulders, or upper arms of young men. Becker melanosis is usually acquired and typically comes to medical attention around the time of puberty, although there may be a history of discoloration (as was true in this case).

A diagnosis that’s usually made clinically

Androgenic origin. Because of the male predominance and association with hypertrichosis (and for that matter, acne), androgens have been thought to play a role in the development of Becker melanosis.² The condition affects about 1 in 200 young men.¹ To date, no specific gene defect has been identified.

Becker melanosis is a benign condition marked by hyperpigmentation and hypertrichosis.

Underlying hypoplasia of the breast or musculoskeletal abnormalities are uncommonly associated with Becker melanosis. When these abnormalities are present, the condition is known as Becker’s nevus syndrome.³

Look for the pattern. Becker melanosis is associated with homogenous brown patches with perifollicular hypopigmentation, sometimes with a faint reticular pattern.^4,5 The diagnosis can usually be made clinically, but a skin biopsy can be helpful to confirm questionable cases. Dermoscopy can also assist in diagnosis. In this case, our patient’s presentation was typical, and additional studies were not needed.

Other causes of hyperpigmentation

The differential diagnosis includes other localized disorders associated with hyperpigmentation (TABLE^1,3,4).

Continue to: Morphea

Morphea represents a thickening of collagen bundles in the skin. Although morphea can affect the shoulder and trunk, as Becker melanosis does, lesions of morphea feel firm to the touch and are not associated with hypertrichosis.

Localized post-inflammatory hyperpigmentation occurs following a traumatic event, such as a burn, or a prior dermatosis, such as zoster. Careful history-taking can uncover an antecedent inflammatory condition. Post-inflammatory pigment changes do not typically result in hypertrichosis.

Café-au-lait macules can manifest as isolated areas of discoloration. These macules can be an important indicator of neurofibromatosis, a genetic disorder in which tumors grow in the nervous system. Melanocytic hamartomas of the iris (Lisch nodules), axillary freckling (Crowe’s sign), or multiple cutaneous neurofibromas serve as additional clues to neurofibromatosis. In ambiguous cases, a skin biopsy can help differentiate a café au lait macule from Becker melanosis.

To treat or not to treat?

No treatment other than reassurance is needed in most cases of Becker melanosis, as it is a benign condition. Protecting the area from sunlight can minimize darkening and contrast with the surrounding skin. Electrolysis and laser therapy can be used to treat the associated hypertrichosis; laser therapy can also reduce the hyperpigmentation. Nonablative fractional resurfacing accompanied by laser hair removal is also reported to be of value.⁶

Our patient was satisfied with reassurance of the benign nature of the condition and did not elect treatment.

CORRESPONDENCE
Matthew F. Helm, MD, 500 University Drive, Suite 4300, Department of Dermatology, HU14, UPC II, Hershey, PA 17033-2360; Mhelm2@pennstatehealth.psu.edu

A 15-year-old Caucasian boy presented for evaluation of an asymptomatic brown patch on his right shoulder. While the patient’s mother first noticed the patch when he was 5 years old, the discolored area had recently been expanding in size and had developed hypertrichosis. The patient was otherwise healthy; he took no medications and denied any symptoms or history of trauma to the area. None of his siblings were similarly affected.

A physical examination revealed a well-demarcated hyperpigmented patch with an irregularly shaped border and an increased number of terminal hairs (FIGURE 1). The affected area was not indurated, and there were no muscular or skeletal abnormalities on inspection. Examination of the patch under a dermatoscope revealed islands of reticular (lattice-like) hyperpigmentation, focal hypopigmentation, and prominent follicles (FIGURE 2).

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

 

 

DIAGNOSIS: Becker melanosis

Becker melanosis (also called Becker’s nevus or Becker’s pigmentary hamartoma) is an organoid hamartoma that is most common among males.¹ This benign area of hyperpigmentation typically manifests as a circumscribed patch with an irregular border on the upper trunk, shoulders, or upper arms of young men. Becker melanosis is usually acquired and typically comes to medical attention around the time of puberty, although there may be a history of discoloration (as was true in this case).

A diagnosis that’s usually made clinically

Androgenic origin. Because of the male predominance and association with hypertrichosis (and for that matter, acne), androgens have been thought to play a role in the development of Becker melanosis.² The condition affects about 1 in 200 young men.¹ To date, no specific gene defect has been identified.

Becker melanosis is a benign condition marked by hyperpigmentation and hypertrichosis.

Underlying hypoplasia of the breast or musculoskeletal abnormalities are uncommonly associated with Becker melanosis. When these abnormalities are present, the condition is known as Becker’s nevus syndrome.³

Look for the pattern. Becker melanosis is associated with homogenous brown patches with perifollicular hypopigmentation, sometimes with a faint reticular pattern.^4,5 The diagnosis can usually be made clinically, but a skin biopsy can be helpful to confirm questionable cases. Dermoscopy can also assist in diagnosis. In this case, our patient’s presentation was typical, and additional studies were not needed.

Other causes of hyperpigmentation

The differential diagnosis includes other localized disorders associated with hyperpigmentation (TABLE^1,3,4).

Continue to: Morphea

Morphea represents a thickening of collagen bundles in the skin. Although morphea can affect the shoulder and trunk, as Becker melanosis does, lesions of morphea feel firm to the touch and are not associated with hypertrichosis.

Localized post-inflammatory hyperpigmentation occurs following a traumatic event, such as a burn, or a prior dermatosis, such as zoster. Careful history-taking can uncover an antecedent inflammatory condition. Post-inflammatory pigment changes do not typically result in hypertrichosis.

Café-au-lait macules can manifest as isolated areas of discoloration. These macules can be an important indicator of neurofibromatosis, a genetic disorder in which tumors grow in the nervous system. Melanocytic hamartomas of the iris (Lisch nodules), axillary freckling (Crowe’s sign), or multiple cutaneous neurofibromas serve as additional clues to neurofibromatosis. In ambiguous cases, a skin biopsy can help differentiate a café au lait macule from Becker melanosis.

To treat or not to treat?

No treatment other than reassurance is needed in most cases of Becker melanosis, as it is a benign condition. Protecting the area from sunlight can minimize darkening and contrast with the surrounding skin. Electrolysis and laser therapy can be used to treat the associated hypertrichosis; laser therapy can also reduce the hyperpigmentation. Nonablative fractional resurfacing accompanied by laser hair removal is also reported to be of value.⁶

Our patient was satisfied with reassurance of the benign nature of the condition and did not elect treatment.

CORRESPONDENCE
Matthew F. Helm, MD, 500 University Drive, Suite 4300, Department of Dermatology, HU14, UPC II, Hershey, PA 17033-2360; Mhelm2@pennstatehealth.psu.edu

Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; ajstille@uic.edu.

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; ajstille@uic.edu.

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; ajstille@uic.edu.

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.