THE COMPARISON

A Pink scaling plaques and erythematous erosions in the antecubital fossae of a 6-year-old White boy.

B Violaceous, hyperpigmented, nummular plaques on the back and extensor surface of the right arm of a 16-month-old Black girl.

C Atopic dermatitis and follicular prominence/accentuation on the neck of a young Black girl.

Epidemiology

People of African descent have the highest atopic dermatitis prevalence and severity.

Key clinical features in people with darker skin tones include:

• follicular prominence
• papular morphology
• prurigo nodules
• hyperpigmented, violaceous-brown or gray plaques instead of erythematous plaques
• lichenification
• treatment resistant.^1,2

Worth noting

Postinflammatory hyperpigmentation and postinflammatory hypopigmentation may be more distressing to the patient/family than the atopic dermatitis itself.

Health disparity highlight

In the United States, patients with skin of color are more likely to be hospitalized with severe atopic dermatitis, have more substantial out-of-pocket costs, be underinsured, and have an increased number of missed days of work. Limited access to outpatient health care plays a role in exacerbating this health disparity.^3,4

THE COMPARISON

A Pink scaling plaques and erythematous erosions in the antecubital fossae of a 6-year-old White boy.

B Violaceous, hyperpigmented, nummular plaques on the back and extensor surface of the right arm of a 16-month-old Black girl.

C Atopic dermatitis and follicular prominence/accentuation on the neck of a young Black girl.

Epidemiology

People of African descent have the highest atopic dermatitis prevalence and severity.

Key clinical features in people with darker skin tones include:

• follicular prominence
• papular morphology
• prurigo nodules
• hyperpigmented, violaceous-brown or gray plaques instead of erythematous plaques
• lichenification
• treatment resistant.^1,2

Worth noting

Postinflammatory hyperpigmentation and postinflammatory hypopigmentation may be more distressing to the patient/family than the atopic dermatitis itself.

Health disparity highlight

In the United States, patients with skin of color are more likely to be hospitalized with severe atopic dermatitis, have more substantial out-of-pocket costs, be underinsured, and have an increased number of missed days of work. Limited access to outpatient health care plays a role in exacerbating this health disparity.^3,4

THE COMPARISON

A Pink scaling plaques and erythematous erosions in the antecubital fossae of a 6-year-old White boy.

B Violaceous, hyperpigmented, nummular plaques on the back and extensor surface of the right arm of a 16-month-old Black girl.

C Atopic dermatitis and follicular prominence/accentuation on the neck of a young Black girl.

Epidemiology

People of African descent have the highest atopic dermatitis prevalence and severity.

Key clinical features in people with darker skin tones include:

• follicular prominence
• papular morphology
• prurigo nodules
• hyperpigmented, violaceous-brown or gray plaques instead of erythematous plaques
• lichenification
• treatment resistant.^1,2

Worth noting

Postinflammatory hyperpigmentation and postinflammatory hypopigmentation may be more distressing to the patient/family than the atopic dermatitis itself.

Health disparity highlight

In the United States, patients with skin of color are more likely to be hospitalized with severe atopic dermatitis, have more substantial out-of-pocket costs, be underinsured, and have an increased number of missed days of work. Limited access to outpatient health care plays a role in exacerbating this health disparity.^3,4

To the Editor:

Argyria is a rare disease caused by chronic exposure to products with high silver content (eg, oral ingestion, inhalation, percutaneous absorption). With time, the blood levels of silver surpass the body’s renal and hepatic excretory capacities that lead to silver granules being deposited in the skin and internal organs, including the liver, spleen, adrenal glands, and bone marrow.¹ The cutaneous deposition results in a blue or blue-gray pigmentation of the skin, mucous membranes, and nails. Intervals of exposure that span from 8 months to 5 years prior to symptom onset have been described in the literature.² The discoloration that results often is permanent, with no established way of effectively removing silver deposits from the tissue.³

A 22-year-old autistic man, who was completely dependent on his mother’s care, presented to the emergency department with a primary concern of abdominal pain. The mother reported that he was indicating abdominal pain by motioning to his stomach for the last 5 days. The mother also reported he did not have a bowel movement during this time, and she noticed his hands were shaking. Prior to presentation, the mother had given him 2 enemas and had him on a 3-day strict liquid fast consisting of water, lemon juice, cayenne pepper, honey, and orange juice. Notably, the mother had a strong history of using naturopathic remedies for treatment of her son’s ailments.

On admission, the patient was stable. There was a 2-point decrease in the patient’s body mass index over the last month. Initial serum electrolytes were highly abnormal with a serum sodium level of 124 mEq/L (reference range, 135–145 mEq/L), blood urea nitrogen of 3 mg/dL (reference range, 7–20 mg/dL), creatinine of 0.77 mg/dL (reference range, 0.74–1.35 mg/dL), and lactic acid of 2.1 mEq/L (reference range, 0.5–1 mEq/L). Serum osmolality was 272 mOsm/kg (reference range, 275–295 mOsm/kg). Urine osmolality was 114 mOsm/kg (reference range, 500–850 mOsm/kg) with a low-normal urine sodium level of 41 mmol/24 hr (reference range, 40–220 mmol/24 hr). Abnormalities were felt to be secondary to malnutrition from the strict liquid diet (blood urea nitrogen and creatinine ratio of 3:1 suggestive of notable protein calorie malnutrition). The patient was given 1 L of normal saline in the emergency department, with further fluids held so as not to increase serum sodium level too rapidly. A regular diet was started.

Physical examination revealed dry mucosal membranes but otherwise was unremarkable. Active bowel sounds were noted, as well as a soft, nontender, and nondistended abdomen; however, when examining the patient’s hands for reported shaking, a distinct abnormality of the nails was noticed. The patient had slate blue discoloration of the lunula, along with hyperpigmented violaceous discoloration of the proximal nail bed on all 10 fingernails (Figure 1). No abnormalities were seen on the toenails. The mother had a distinct bluish gray discoloration of the face as well as similar nail findings (Figure 2), strongly suggestive of colloidal silver use. An urgent serum silver level was ordered on the patient as well as a heavy metal panel. The mother was found applying numerous “natural remedies” to the patient’s skin while in the hospital, including a liquid spray and lotion, both in unmarked bottles. At that time, the mother was informed that no external supplements should be applied to her son. The serum silver level was elevated substantially at 94.3 ng/mL (reference range, <1.0 ng/mL). When the mother was confronted, she initially denied use of silver but later admitted to notable silver content in the cream she was applying to her son’s skin. The mother reported that she read online that colloidal silver had been historically used to cure numerous ailments and she was ordering products from an online company. She was counseled on the dangers of both topical application and ingestion of silver, and all supplements were removed from the home.

Initial differential diagnoses for altered nail pigmentation include drug-induced causes, systemic diseases, cyanosis, and exposure to metals.⁷ The most commonly indicated medications resulting in blue nail pigment changes include antimalarials, minocycline, zidovudine, and phenothiazine. Systemic diseases that may cause blue nail color change include Wilson disease, hemochromatosis, Addison disease, methemoglobinemia, and alkaptonuria.⁷ Metals include gold, mercury, arsenic, bismuth, lead, and silver.⁴ After a thorough review of the patient’s medications and lack of support for any underlying disease process, contact with metals, particularly silver, was ranked highly on our differential list. In support of this theory, the mother’s bluish gray facial skin led to high clinical suspicion that she was ingesting colloidal silver and also was exposing her son to silver.

Treatment of argyria is challenging but first and foremost involves discontinuation of the source of chronic silver exposure. Unfortunately, the discoloration of generalized argyria often is permanent. Sunscreen can be used to help prevent any further darkening of pigment. The pigment in localized argyria has been reported to slowly fade with time, and there also have been reports of successful treatment using a low-fluence Q-switched 1064-nm Nd:YAG laser.⁸

To the Editor:

Argyria is a rare disease caused by chronic exposure to products with high silver content (eg, oral ingestion, inhalation, percutaneous absorption). With time, the blood levels of silver surpass the body’s renal and hepatic excretory capacities that lead to silver granules being deposited in the skin and internal organs, including the liver, spleen, adrenal glands, and bone marrow.¹ The cutaneous deposition results in a blue or blue-gray pigmentation of the skin, mucous membranes, and nails. Intervals of exposure that span from 8 months to 5 years prior to symptom onset have been described in the literature.² The discoloration that results often is permanent, with no established way of effectively removing silver deposits from the tissue.³

A 22-year-old autistic man, who was completely dependent on his mother’s care, presented to the emergency department with a primary concern of abdominal pain. The mother reported that he was indicating abdominal pain by motioning to his stomach for the last 5 days. The mother also reported he did not have a bowel movement during this time, and she noticed his hands were shaking. Prior to presentation, the mother had given him 2 enemas and had him on a 3-day strict liquid fast consisting of water, lemon juice, cayenne pepper, honey, and orange juice. Notably, the mother had a strong history of using naturopathic remedies for treatment of her son’s ailments.

On admission, the patient was stable. There was a 2-point decrease in the patient’s body mass index over the last month. Initial serum electrolytes were highly abnormal with a serum sodium level of 124 mEq/L (reference range, 135–145 mEq/L), blood urea nitrogen of 3 mg/dL (reference range, 7–20 mg/dL), creatinine of 0.77 mg/dL (reference range, 0.74–1.35 mg/dL), and lactic acid of 2.1 mEq/L (reference range, 0.5–1 mEq/L). Serum osmolality was 272 mOsm/kg (reference range, 275–295 mOsm/kg). Urine osmolality was 114 mOsm/kg (reference range, 500–850 mOsm/kg) with a low-normal urine sodium level of 41 mmol/24 hr (reference range, 40–220 mmol/24 hr). Abnormalities were felt to be secondary to malnutrition from the strict liquid diet (blood urea nitrogen and creatinine ratio of 3:1 suggestive of notable protein calorie malnutrition). The patient was given 1 L of normal saline in the emergency department, with further fluids held so as not to increase serum sodium level too rapidly. A regular diet was started.

Physical examination revealed dry mucosal membranes but otherwise was unremarkable. Active bowel sounds were noted, as well as a soft, nontender, and nondistended abdomen; however, when examining the patient’s hands for reported shaking, a distinct abnormality of the nails was noticed. The patient had slate blue discoloration of the lunula, along with hyperpigmented violaceous discoloration of the proximal nail bed on all 10 fingernails (Figure 1). No abnormalities were seen on the toenails. The mother had a distinct bluish gray discoloration of the face as well as similar nail findings (Figure 2), strongly suggestive of colloidal silver use. An urgent serum silver level was ordered on the patient as well as a heavy metal panel. The mother was found applying numerous “natural remedies” to the patient’s skin while in the hospital, including a liquid spray and lotion, both in unmarked bottles. At that time, the mother was informed that no external supplements should be applied to her son. The serum silver level was elevated substantially at 94.3 ng/mL (reference range, <1.0 ng/mL). When the mother was confronted, she initially denied use of silver but later admitted to notable silver content in the cream she was applying to her son’s skin. The mother reported that she read online that colloidal silver had been historically used to cure numerous ailments and she was ordering products from an online company. She was counseled on the dangers of both topical application and ingestion of silver, and all supplements were removed from the home.

Initial differential diagnoses for altered nail pigmentation include drug-induced causes, systemic diseases, cyanosis, and exposure to metals.⁷ The most commonly indicated medications resulting in blue nail pigment changes include antimalarials, minocycline, zidovudine, and phenothiazine. Systemic diseases that may cause blue nail color change include Wilson disease, hemochromatosis, Addison disease, methemoglobinemia, and alkaptonuria.⁷ Metals include gold, mercury, arsenic, bismuth, lead, and silver.⁴ After a thorough review of the patient’s medications and lack of support for any underlying disease process, contact with metals, particularly silver, was ranked highly on our differential list. In support of this theory, the mother’s bluish gray facial skin led to high clinical suspicion that she was ingesting colloidal silver and also was exposing her son to silver.

Treatment of argyria is challenging but first and foremost involves discontinuation of the source of chronic silver exposure. Unfortunately, the discoloration of generalized argyria often is permanent. Sunscreen can be used to help prevent any further darkening of pigment. The pigment in localized argyria has been reported to slowly fade with time, and there also have been reports of successful treatment using a low-fluence Q-switched 1064-nm Nd:YAG laser.⁸

To the Editor:

Argyria is a rare disease caused by chronic exposure to products with high silver content (eg, oral ingestion, inhalation, percutaneous absorption). With time, the blood levels of silver surpass the body’s renal and hepatic excretory capacities that lead to silver granules being deposited in the skin and internal organs, including the liver, spleen, adrenal glands, and bone marrow.¹ The cutaneous deposition results in a blue or blue-gray pigmentation of the skin, mucous membranes, and nails. Intervals of exposure that span from 8 months to 5 years prior to symptom onset have been described in the literature.² The discoloration that results often is permanent, with no established way of effectively removing silver deposits from the tissue.³

A 22-year-old autistic man, who was completely dependent on his mother’s care, presented to the emergency department with a primary concern of abdominal pain. The mother reported that he was indicating abdominal pain by motioning to his stomach for the last 5 days. The mother also reported he did not have a bowel movement during this time, and she noticed his hands were shaking. Prior to presentation, the mother had given him 2 enemas and had him on a 3-day strict liquid fast consisting of water, lemon juice, cayenne pepper, honey, and orange juice. Notably, the mother had a strong history of using naturopathic remedies for treatment of her son’s ailments.

On admission, the patient was stable. There was a 2-point decrease in the patient’s body mass index over the last month. Initial serum electrolytes were highly abnormal with a serum sodium level of 124 mEq/L (reference range, 135–145 mEq/L), blood urea nitrogen of 3 mg/dL (reference range, 7–20 mg/dL), creatinine of 0.77 mg/dL (reference range, 0.74–1.35 mg/dL), and lactic acid of 2.1 mEq/L (reference range, 0.5–1 mEq/L). Serum osmolality was 272 mOsm/kg (reference range, 275–295 mOsm/kg). Urine osmolality was 114 mOsm/kg (reference range, 500–850 mOsm/kg) with a low-normal urine sodium level of 41 mmol/24 hr (reference range, 40–220 mmol/24 hr). Abnormalities were felt to be secondary to malnutrition from the strict liquid diet (blood urea nitrogen and creatinine ratio of 3:1 suggestive of notable protein calorie malnutrition). The patient was given 1 L of normal saline in the emergency department, with further fluids held so as not to increase serum sodium level too rapidly. A regular diet was started.

Physical examination revealed dry mucosal membranes but otherwise was unremarkable. Active bowel sounds were noted, as well as a soft, nontender, and nondistended abdomen; however, when examining the patient’s hands for reported shaking, a distinct abnormality of the nails was noticed. The patient had slate blue discoloration of the lunula, along with hyperpigmented violaceous discoloration of the proximal nail bed on all 10 fingernails (Figure 1). No abnormalities were seen on the toenails. The mother had a distinct bluish gray discoloration of the face as well as similar nail findings (Figure 2), strongly suggestive of colloidal silver use. An urgent serum silver level was ordered on the patient as well as a heavy metal panel. The mother was found applying numerous “natural remedies” to the patient’s skin while in the hospital, including a liquid spray and lotion, both in unmarked bottles. At that time, the mother was informed that no external supplements should be applied to her son. The serum silver level was elevated substantially at 94.3 ng/mL (reference range, <1.0 ng/mL). When the mother was confronted, she initially denied use of silver but later admitted to notable silver content in the cream she was applying to her son’s skin. The mother reported that she read online that colloidal silver had been historically used to cure numerous ailments and she was ordering products from an online company. She was counseled on the dangers of both topical application and ingestion of silver, and all supplements were removed from the home.

Initial differential diagnoses for altered nail pigmentation include drug-induced causes, systemic diseases, cyanosis, and exposure to metals.⁷ The most commonly indicated medications resulting in blue nail pigment changes include antimalarials, minocycline, zidovudine, and phenothiazine. Systemic diseases that may cause blue nail color change include Wilson disease, hemochromatosis, Addison disease, methemoglobinemia, and alkaptonuria.⁷ Metals include gold, mercury, arsenic, bismuth, lead, and silver.⁴ After a thorough review of the patient’s medications and lack of support for any underlying disease process, contact with metals, particularly silver, was ranked highly on our differential list. In support of this theory, the mother’s bluish gray facial skin led to high clinical suspicion that she was ingesting colloidal silver and also was exposing her son to silver.

Treatment of argyria is challenging but first and foremost involves discontinuation of the source of chronic silver exposure. Unfortunately, the discoloration of generalized argyria often is permanent. Sunscreen can be used to help prevent any further darkening of pigment. The pigment in localized argyria has been reported to slowly fade with time, and there also have been reports of successful treatment using a low-fluence Q-switched 1064-nm Nd:YAG laser.⁸

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

THE CASE

A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.

The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.

The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.

Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).

THE DIAGNOSIS

An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.

DISCUSSION

POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.¹

Case reports have shown an association between SSRIs and syncope. SSRIs have also been tied to increased heart rate variability.

The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.^2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.

Continue to: Syncope could indicate a larger cardiovascular problem

The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.

Unintended adverse effects

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.⁴ However, case reports have shown an association between SSRIs and syncope.^4-6 SSRIs have also been tied to increased heart rate variability.⁷

Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.

Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.

THE TAKEAWAY

We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.

CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; [email protected]

THE CASE

A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.

The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.

The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.

Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).

THE DIAGNOSIS

An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.

DISCUSSION

POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.¹

Case reports have shown an association between SSRIs and syncope. SSRIs have also been tied to increased heart rate variability.

The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.^2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.

Continue to: Syncope could indicate a larger cardiovascular problem

The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.

Unintended adverse effects

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.⁴ However, case reports have shown an association between SSRIs and syncope.^4-6 SSRIs have also been tied to increased heart rate variability.⁷

Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.

Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.

THE TAKEAWAY

We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.

CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; [email protected]

THE CASE

A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.

The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.

The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.

Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).

THE DIAGNOSIS

An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.

DISCUSSION

POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.¹

Case reports have shown an association between SSRIs and syncope. SSRIs have also been tied to increased heart rate variability.

The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.^2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.

Continue to: Syncope could indicate a larger cardiovascular problem

The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.

Unintended adverse effects

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.⁴ However, case reports have shown an association between SSRIs and syncope.^4-6 SSRIs have also been tied to increased heart rate variability.⁷

Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.

Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.

THE TAKEAWAY

We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.

CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; [email protected]

Skin and soft-tissue infections, frequently encountered in primary care, range from the uncomplicated erysipelas to the life-threatening necrotizing fasciitis. This review draws from the latest evidence and guidelines to help guide the care you provide to patients with cellulitis, orbital cellulitis, erysipelas, folliculitis, furuncles, carbuncles, abscesses, and necrotizing fasciitis.

Cellulitis

Cellulitis, an infection of the deep dermal and subcutaneous layers of the skin, has become increasingly common in recent years, with both incidence and hospitalization rates rising.¹ Cellulitis occurs when pathogens enter the dermis through breaks in the skin barrier due to cutaneous fungal infections, trauma, pressure sores, venous stasis, or inflammation. The diagnosis is often made clinically based on characteristic skin findings—classically an acute, poorly demarcated area of erythema, warmth, swelling, and tenderness. Lymphangitic streaking and local lymphadenopathy may also be present. Infection often occurs on an extremity (although it can be found on other areas of the body) and is usually unilateral. Fever may or may not be present.²

Likely responsible microorganisms. Staphylococcus aureus and Group A streptococci (often Streptococcus pyogenes) are common culprits. One systematic review that examined cultures taken of intact skin in cellulitis patients found S aureus to be about twice as common as S pyogenes, with both bacteria accounting for a little more than 70% of cases. Of the remaining positive cultures, the most common organisms were alpha-­hemolytic streptococcus, group B streptococcus, Pseudomonas aeruginosa, Clostridium perfringens, Escherichia coli, Pasteurella multocida, and Proteus mirabilis.³ Similarly, a systematic review of bacteremia in patients with cellulitis and erysipelas found that S pyogenes, other beta-hemolytic strep, and S aureus account for about 70% of cases (although S aureus was responsible for just 14%), with the remainder of cases caused by gram-negative organisms such as E coli and P aeruginosa.⁴

Treatment considerations. Strict treatment guidelines for cellulitis are lacking, but general consensus encourages the use of antibiotics and occasionally surgery. For mild and moderate cases of cellulitis, prescribe oral and parenteral antibiotics to cover for streptococci and methicillin-susceptible S aureus, respectively. Expand coverage to include vancomycin if nasal colonization shows methicillin-resistant S aureus (MRSA) or if you otherwise suspect prior MRSA exposure. Expanded coverage will also be needed if there is severe nonpurulent infection associated with penetrating trauma or a history of intravenous drug use, or the patient meets criteria for systemic inflammatory response syndrome. If patients are severely compromised (eg, neutropenic), it is reasonable to further add broad-spectrum coverage (eg, intravenous piperacillin-­tazobactam or carbapenem). Typical duration of treatment is 5 to 7 days, although this should be extended if there is no clinical improvement.

For orbital cellulitis, choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.

Generally, cellulitis can be managed in the outpatient setting, although hospitalization is recommended if there are concerns for deep or necrotizing infection, if patients are nonadherent to therapy or are immunocompromised, or if outpatient therapy has failed.⁵ Furthermore, in an observational study of 606 adult patients, prior episodes of cellulitis, venous insufficiency, and immunosuppression were all independently associated with poorer clinical outcomes.² Also treat underlying predisposing factors such as edema, obesity, eczema, venous insufficiency, and toe web abnormalities such as fissures, scaling, or maceration.⁵ Consider the use of prophylactic antibiotics for patients who have had 3 to 4 episodes of cellulitis despite attempts to treat predisposing conditions. Prophylactic antibiotic regimens include penicillin or erythromycin orally and penicillin G benzathine intramuscularly.⁵ Antibiotic regimens are summarized in the TABLE.⁵

Orbital cellulitis

Orbital cellulitis is an infection of the tissues posterior to the orbital septum.^6,7 Periorbital, or preseptal, cellulitis occurs anterior to the orbital septum and is the more common of the 2 infections—84% compared with 16% for orbital cellulitis.⁶ However, orbital cellulitis, which affects mainly children at a median age of 7 years,⁶ must be detected and treated early due to the potential for serious complications such as cavernous sinus thrombosis, meningitis, intracranial abscess, and vision loss.⁷ Chemosis (conjunctival edema) and diplopia are more commonly associated with orbital cellulitis and are seldom seen with preseptal cellulitis.

Predominant causative organisms are S pneumoniae, Moraxella catarrhalis, non-typeable Haemophilus influenzae, and group A streptococcus. The most common mechanism of infection is tracking from periorbital structures (eg, paranasal and ethmoid sinusitis). Other causes include orbital trauma/fracture, periorbital surgery, and bacterial endocarditis. Clinically, patients present with limited ocular motility and proptosis associated with inflamed conjunctiva, orbital pain, headache, malaise, fever, eyelid edema, and possible decrease in visual acuity. The diagnosis is often made clinically and confirmed with orbital computed tomography (CT) with contrast, which can assist in ruling out intracranial involvement such as abscess.

Continue to: Antibiotic therapy

Antibiotic therapy, generally administered intravenously, is recommended for at least 3 days or until orbital symptoms begin to resolve. Choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.⁸ For instance, a regimen may include vancomycin for MRSA coverage, a third-generation cephalosporin, or metronidazole for anaerobic coverage if there is concern about intracranial involvement. Surgical intervention is often reserved for patients with inadequate response to antibiotic therapy, necessitating biopsy for pathogen identification, as well as drainage of large abscesses refractory to antibiotics.

Erysipelas

Erysipelas, a related yet distinct form of cellulitis, is a bacterial infection of the superficial dermis and hypodermis and is commonly caused by group A streptococcus.^5,9 Other less common organisms include S aureus, P aeruginosa, and enterobacteria. Erysipelas predominantly affects the lower extremities unilaterally (~90%); the arms and the face are the next most common locations. In addition to the rapid onset of well-demarcated erythema, pain, and swelling, patients may have fever and regional lymphadenopathy. Risk factors include portal of entry (eg, tinea pedis, ulceration), lymphedema, and diabetes. Complications of erysipelas include bullae from edema, abscess formation, and, rarely, bacteremia.

When clinical exam alone is inconclusive when evaluating skin and softtissue infections in children and adolescents, consider using ultrasound to improve diagnostic accuracy.

Antibiotic treatment regimens include penicillin G, macrolides (reserved for those with penicillin allergies), fluoroquinolones, and cephalosporins, with duration of treatment ranging from 10 to 14 days depending on infection severity. Fever, pain, and erythema generally improve within 48 to 72 hours of antibiotic therapy. If there is no improvement, consider alternative diagnoses, such as necrotizing fasciitis. Recurrence rates following the initial episode of erysipelas are estimated at 10% of patients at 6 months and 30% at 3 years.¹⁰

Folliculitis

Inflammation of hair follicles is characterized by superficial inflammation with the development of perifollicular papules or pustules on an erythematous base.^11,12 Folliculitis most commonly affects the face, scalp, thighs, buttocks, axillae, and inguinal areas.¹³ It may be caused by infection, an inflammatory reaction, or physical injury. Diagnosis is typically based on the patient’s history and physical examination.

Bacteria are the most common cause of infection, although fungi, viruses, and other entities can cause folliculitis. S aureus (methicillin sensitive or methicillin resistant) is the most common pathogen; in the past, superficial pustular folliculitis attributed to S aureus was referred to as Bockhart impetigo. Folliculitis secondary to P aeruginosa, often seen after exposure to contaminated water or hot tubs, is frequently referred to as “hot tub folliculitis.” Malassezia, a reported cause of fungal folliculitis, tends to occur in adolescents of either sex and men with high sebum production, is common in tropical climates, and can be associated with HIV or immunosuppression.^11,12,14

Continue to: Differential diagnosis...

Differential diagnosis of folliculitis includes pseudofolliculitis barbae, eosinophilic folliculitis, keratosis pilaris, acne vulgaris, candidiasis, contact dermatitis, impetigo, and miliaria.¹³ Pseudofolliculitis barbae is an inflammatory reaction to shaving, more commonly seen in darkly pigmented skin. Pseudofolliculitis develops when the hair shaft penetrates the wall of the follicle or directly enters the epidermis.

Initial treatment for mild disease includes the elimination of predisposing factors such as occlusion, moisture, and abrasion. The area should be kept clean and dry, avoiding friction. For localized disease, prescribe topical clindamycin, mupirocin ointment, or benzoyl peroxide. If symptoms fail to respond, prescribe a 7-day course of antibiotic that targets methicillin-sensitive S aureus—eg, cephalexin or dicloxacillin. Also consider doxycycline, which has anti-inflammatory effects and is effective against MRSA. For refractory lesions, ­trimethoprim-sulfamethoxazole, clindamycin, or minocycline may be useful. If you suspect pseudomonas, consider giving ciprofloxacin for 10 to 14 days for persistent lesions or if the patient is immunocompromised.^13,15 Consider obtaining bacterial, fungal, or viral cultures for lesions that fail to respond to initial treatment.

Do not routinely order cultures or prescribe antibiotics for uncomplicated abscesses.

Furuncles/carbuncles/abscesses

A furuncle, commonly referred to as a boil, is an infected hair follicle that becomes enclosed, creating a collection of pus. A carbuncle is a collection of furuncles that converge and drain through a single opening. An abscess is a localized collection of pus arising from within the dermis that can extend within deeper tissues.⁵ Furuncles, carbuncles, and abscesses are managed similarly with drainage and consideration for MRSA risk factors.

S aureus is the most common cause of these infections; 59% of skin abscesses are due to community-acquired MRSA.¹⁶ Anaerobes may contribute to the polymicrobial flora of skin abscesses.¹⁷ Risk factors for MRSA infection include a history of previous MRSA infection, diabetes, dialysis or renal failure, placement of an indwelling catheter or medical device, injection drug use, incarceration, close contact with a person with known MRSA infection or colonization, long-term care residence, hospitalization or surgery within the past 12 months, and high prevalence of MRSA in the community.⁵

Ultrasound improves diagnostic accuracy. One study showed that when a clinical exam alone was inconclusive in evaluating skin and soft-tissue infections in children and adolescents, an ultrasound-assisted examination improved diagnostic accuracy.¹⁸ Sensitivity of the clinical examination was 43.7%, compared with 77.6% for the clinical examination plus ultrasound.¹⁸

Continue to: Incision and drainage first

Incision and drainage first. Ultrasound-guided needle aspiration, however, has not improved treatment efficacy compared with incision and drainage,¹⁹ the mainstay approach for abscesses.¹⁷ The procedure to drain a furuncle, carbuncle, or abscess should include the expression of all purulent material and the removal of all loculations if possible. Wound culture is recommended during incision and drainage per current guidelines.⁵ Simple dry dressings are convenient and effective, although some wounds may require packing. Tap water (that is potable) is suitable for wound cleansing. However, there is no strong evidence that irrigating wounds increases healing or reduces infection.²⁰

Routine use of antibiotics is not recommended for simple cutaneous abscesses.^5,17,21 Evidence has been conflicting regarding empiric antibiotic coverage of MRSA following incision and drainage.^22-25 Guidelines recommend considering the initiation of antibiotics if there are multiple abscesses, gangrene, surrounding cellulitis, or systemic signs of infection, or if the host is immunocompromised.⁵

If MRSA is suspected, recommended antibiotic coverage includes trimethoprim-­sulfamethoxazole, clindamycin, doxycycline, or minocycline.⁵ If MRSA is identified, treatment options include dicloxacillin or cephalexin. For severe infections persisting after incision and drainage, in addition to oral antibiotic therapy, consider intravenous antibiotic options for MRSA: cefazolin, clindamycin, linezolid, nafcillin, telavancin, or vancomycin.⁵

Necrotizing fasciitis

Necrotizing fasciitis is a rare but potentially deadly infection of the skin and soft tissue. It progresses rapidly and spreads along fascial planes, leading to the necrosis of the superficial fascia. The infection often is more extensive than is indicated by superficial signs. Prompt diagnosis is imperative as necrotizing fasciitis is a surgical emergency.^5,26 In the United States, 500 to 1500 cases of necrotizing fasciitis occur each year.²⁷ Risk factors for necrotizing fasciitis include diabetes, peripheral vascular disease, malignancy, obesity, cirrhosis, renal failure, injection drug use, chronic corticosteroid therapy, alcohol abuse, malnutrition, and iatrogenic immunosuppression.^26,28

Monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.

Necrotizing fasciitis may be polymicrobial or monomicrobial. Polymicrobial infection, also referred to as type I, is often due to multiple bacteria that originate from the bowel flora, typically including a mix of anaerobic and aerobic organisms. On average, there can be 5 infecting organisms identified per wound, although in some cases up to 15 organisms have been identified in a single wound.⁵ Type I infection is often associated with tissue injury, abscess, or abdominal surgery. The majority of cases of necrotizing fasciitis are polymicrobial.^27,28

Continue to: Monomicrobial infection...

Monomicrobial infection, also referred to as type II, is often due to group A streptococcus, S aureus, vibrio spp, Aeromonas hyrophilio, or an anaerobic streptococci like peptostreptococcus spp. Typically monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.^5,26,29,30

Clinical presentation. In the early stages of disease, patients commonly complain of flu-like symptoms and extreme pain that is out of proportion to findings on the exam. Additional warning signs include fevers and other symptoms of toxicity such as tachycardia, hypotension, nausea, vomiting, and diarrhea. Later in the course, symptoms may localize to the affected area and include erythema, tense swelling, development of blisters or bullae, blackish blue discoloration of the skin, severe pain, and loss of sensation. In some cases involving gas-forming bacteria, tissue crepitus may be noted on exam.^5,27-31

Rely on clinical judgment to hasten surgical intervention. Laboratory or imaging findings may augment clinical judgment. But if you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery. Blood tests that may aid in the diagnosis of necrotizing fasciitis include a complete blood count with differential; coagulation studies; a comprehensive metabolic panel; assays of lactate, C-reactive protein (CRP), and creatinine kinase; and blood cultures. Most often, patients with necrotizing fasciitis will have leukocytosis or leukopenia, evidence of hemolysis, thrombocytopenia, acute renal failure, and significantly elevated CRP.

If you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery.

On any imaging modality, indications of necrotizing fasciitis are inflammatory infiltration of the deep fascia on the affected side that is absent on the contralateral side, and the presence of subcutaneous air (which is a specific but rare finding). Imaging modalities may include CT or magnetic resonance imaging. A definitive diagnosis can only be made with surgical exploration of the involved area. Definitive microbiologic diagnosis will require culture of organisms from affected tissue or blood.^5,26,30,31

First address any hemodynamic instability (hypotension is frequently encountered), followed by urgent surgical exploration, debridement of the wound, and antimicrobial therapy. Antibiotic treatment should align with probable pathogens and treatment should be continued until repeated surgical debridement is no longer necessary, clinical improvement is evident, and 48 to 72 hours have passed since defervescence. A reasonable initial empiric regimen in adults would include an agent that is effective against group A streptococcus, gram-negative pathogens, and anaerobes, such as a carbapenem or a beta-lactam-­beta-lactamase inhibitor such as piperacillin-­tazobactam. Additionally, include an agent that targets MRSA, such as vancomycin, linezolid, or clindamycin.⁵

CORRESPONDENCE
Karl T. Clebak, MD, Department of Family and Community Medicine Residency Program, Penn State Health M.S. Hershey Medical Center, 500 University Drive, H154/C1613, Hershey, PA 17033; [email protected]

Skin and soft-tissue infections, frequently encountered in primary care, range from the uncomplicated erysipelas to the life-threatening necrotizing fasciitis. This review draws from the latest evidence and guidelines to help guide the care you provide to patients with cellulitis, orbital cellulitis, erysipelas, folliculitis, furuncles, carbuncles, abscesses, and necrotizing fasciitis.

Cellulitis

Cellulitis, an infection of the deep dermal and subcutaneous layers of the skin, has become increasingly common in recent years, with both incidence and hospitalization rates rising.¹ Cellulitis occurs when pathogens enter the dermis through breaks in the skin barrier due to cutaneous fungal infections, trauma, pressure sores, venous stasis, or inflammation. The diagnosis is often made clinically based on characteristic skin findings—classically an acute, poorly demarcated area of erythema, warmth, swelling, and tenderness. Lymphangitic streaking and local lymphadenopathy may also be present. Infection often occurs on an extremity (although it can be found on other areas of the body) and is usually unilateral. Fever may or may not be present.²

Likely responsible microorganisms. Staphylococcus aureus and Group A streptococci (often Streptococcus pyogenes) are common culprits. One systematic review that examined cultures taken of intact skin in cellulitis patients found S aureus to be about twice as common as S pyogenes, with both bacteria accounting for a little more than 70% of cases. Of the remaining positive cultures, the most common organisms were alpha-­hemolytic streptococcus, group B streptococcus, Pseudomonas aeruginosa, Clostridium perfringens, Escherichia coli, Pasteurella multocida, and Proteus mirabilis.³ Similarly, a systematic review of bacteremia in patients with cellulitis and erysipelas found that S pyogenes, other beta-hemolytic strep, and S aureus account for about 70% of cases (although S aureus was responsible for just 14%), with the remainder of cases caused by gram-negative organisms such as E coli and P aeruginosa.⁴

Treatment considerations. Strict treatment guidelines for cellulitis are lacking, but general consensus encourages the use of antibiotics and occasionally surgery. For mild and moderate cases of cellulitis, prescribe oral and parenteral antibiotics to cover for streptococci and methicillin-susceptible S aureus, respectively. Expand coverage to include vancomycin if nasal colonization shows methicillin-resistant S aureus (MRSA) or if you otherwise suspect prior MRSA exposure. Expanded coverage will also be needed if there is severe nonpurulent infection associated with penetrating trauma or a history of intravenous drug use, or the patient meets criteria for systemic inflammatory response syndrome. If patients are severely compromised (eg, neutropenic), it is reasonable to further add broad-spectrum coverage (eg, intravenous piperacillin-­tazobactam or carbapenem). Typical duration of treatment is 5 to 7 days, although this should be extended if there is no clinical improvement.

For orbital cellulitis, choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.

Generally, cellulitis can be managed in the outpatient setting, although hospitalization is recommended if there are concerns for deep or necrotizing infection, if patients are nonadherent to therapy or are immunocompromised, or if outpatient therapy has failed.⁵ Furthermore, in an observational study of 606 adult patients, prior episodes of cellulitis, venous insufficiency, and immunosuppression were all independently associated with poorer clinical outcomes.² Also treat underlying predisposing factors such as edema, obesity, eczema, venous insufficiency, and toe web abnormalities such as fissures, scaling, or maceration.⁵ Consider the use of prophylactic antibiotics for patients who have had 3 to 4 episodes of cellulitis despite attempts to treat predisposing conditions. Prophylactic antibiotic regimens include penicillin or erythromycin orally and penicillin G benzathine intramuscularly.⁵ Antibiotic regimens are summarized in the TABLE.⁵

Orbital cellulitis

Orbital cellulitis is an infection of the tissues posterior to the orbital septum.^6,7 Periorbital, or preseptal, cellulitis occurs anterior to the orbital septum and is the more common of the 2 infections—84% compared with 16% for orbital cellulitis.⁶ However, orbital cellulitis, which affects mainly children at a median age of 7 years,⁶ must be detected and treated early due to the potential for serious complications such as cavernous sinus thrombosis, meningitis, intracranial abscess, and vision loss.⁷ Chemosis (conjunctival edema) and diplopia are more commonly associated with orbital cellulitis and are seldom seen with preseptal cellulitis.

Predominant causative organisms are S pneumoniae, Moraxella catarrhalis, non-typeable Haemophilus influenzae, and group A streptococcus. The most common mechanism of infection is tracking from periorbital structures (eg, paranasal and ethmoid sinusitis). Other causes include orbital trauma/fracture, periorbital surgery, and bacterial endocarditis. Clinically, patients present with limited ocular motility and proptosis associated with inflamed conjunctiva, orbital pain, headache, malaise, fever, eyelid edema, and possible decrease in visual acuity. The diagnosis is often made clinically and confirmed with orbital computed tomography (CT) with contrast, which can assist in ruling out intracranial involvement such as abscess.

Continue to: Antibiotic therapy

Antibiotic therapy, generally administered intravenously, is recommended for at least 3 days or until orbital symptoms begin to resolve. Choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.⁸ For instance, a regimen may include vancomycin for MRSA coverage, a third-generation cephalosporin, or metronidazole for anaerobic coverage if there is concern about intracranial involvement. Surgical intervention is often reserved for patients with inadequate response to antibiotic therapy, necessitating biopsy for pathogen identification, as well as drainage of large abscesses refractory to antibiotics.

Erysipelas

Erysipelas, a related yet distinct form of cellulitis, is a bacterial infection of the superficial dermis and hypodermis and is commonly caused by group A streptococcus.^5,9 Other less common organisms include S aureus, P aeruginosa, and enterobacteria. Erysipelas predominantly affects the lower extremities unilaterally (~90%); the arms and the face are the next most common locations. In addition to the rapid onset of well-demarcated erythema, pain, and swelling, patients may have fever and regional lymphadenopathy. Risk factors include portal of entry (eg, tinea pedis, ulceration), lymphedema, and diabetes. Complications of erysipelas include bullae from edema, abscess formation, and, rarely, bacteremia.

When clinical exam alone is inconclusive when evaluating skin and softtissue infections in children and adolescents, consider using ultrasound to improve diagnostic accuracy.

Antibiotic treatment regimens include penicillin G, macrolides (reserved for those with penicillin allergies), fluoroquinolones, and cephalosporins, with duration of treatment ranging from 10 to 14 days depending on infection severity. Fever, pain, and erythema generally improve within 48 to 72 hours of antibiotic therapy. If there is no improvement, consider alternative diagnoses, such as necrotizing fasciitis. Recurrence rates following the initial episode of erysipelas are estimated at 10% of patients at 6 months and 30% at 3 years.¹⁰

Folliculitis

Inflammation of hair follicles is characterized by superficial inflammation with the development of perifollicular papules or pustules on an erythematous base.^11,12 Folliculitis most commonly affects the face, scalp, thighs, buttocks, axillae, and inguinal areas.¹³ It may be caused by infection, an inflammatory reaction, or physical injury. Diagnosis is typically based on the patient’s history and physical examination.

Bacteria are the most common cause of infection, although fungi, viruses, and other entities can cause folliculitis. S aureus (methicillin sensitive or methicillin resistant) is the most common pathogen; in the past, superficial pustular folliculitis attributed to S aureus was referred to as Bockhart impetigo. Folliculitis secondary to P aeruginosa, often seen after exposure to contaminated water or hot tubs, is frequently referred to as “hot tub folliculitis.” Malassezia, a reported cause of fungal folliculitis, tends to occur in adolescents of either sex and men with high sebum production, is common in tropical climates, and can be associated with HIV or immunosuppression.^11,12,14

Continue to: Differential diagnosis...

Differential diagnosis of folliculitis includes pseudofolliculitis barbae, eosinophilic folliculitis, keratosis pilaris, acne vulgaris, candidiasis, contact dermatitis, impetigo, and miliaria.¹³ Pseudofolliculitis barbae is an inflammatory reaction to shaving, more commonly seen in darkly pigmented skin. Pseudofolliculitis develops when the hair shaft penetrates the wall of the follicle or directly enters the epidermis.

Initial treatment for mild disease includes the elimination of predisposing factors such as occlusion, moisture, and abrasion. The area should be kept clean and dry, avoiding friction. For localized disease, prescribe topical clindamycin, mupirocin ointment, or benzoyl peroxide. If symptoms fail to respond, prescribe a 7-day course of antibiotic that targets methicillin-sensitive S aureus—eg, cephalexin or dicloxacillin. Also consider doxycycline, which has anti-inflammatory effects and is effective against MRSA. For refractory lesions, ­trimethoprim-sulfamethoxazole, clindamycin, or minocycline may be useful. If you suspect pseudomonas, consider giving ciprofloxacin for 10 to 14 days for persistent lesions or if the patient is immunocompromised.^13,15 Consider obtaining bacterial, fungal, or viral cultures for lesions that fail to respond to initial treatment.

Do not routinely order cultures or prescribe antibiotics for uncomplicated abscesses.

Furuncles/carbuncles/abscesses

A furuncle, commonly referred to as a boil, is an infected hair follicle that becomes enclosed, creating a collection of pus. A carbuncle is a collection of furuncles that converge and drain through a single opening. An abscess is a localized collection of pus arising from within the dermis that can extend within deeper tissues.⁵ Furuncles, carbuncles, and abscesses are managed similarly with drainage and consideration for MRSA risk factors.

S aureus is the most common cause of these infections; 59% of skin abscesses are due to community-acquired MRSA.¹⁶ Anaerobes may contribute to the polymicrobial flora of skin abscesses.¹⁷ Risk factors for MRSA infection include a history of previous MRSA infection, diabetes, dialysis or renal failure, placement of an indwelling catheter or medical device, injection drug use, incarceration, close contact with a person with known MRSA infection or colonization, long-term care residence, hospitalization or surgery within the past 12 months, and high prevalence of MRSA in the community.⁵

Ultrasound improves diagnostic accuracy. One study showed that when a clinical exam alone was inconclusive in evaluating skin and soft-tissue infections in children and adolescents, an ultrasound-assisted examination improved diagnostic accuracy.¹⁸ Sensitivity of the clinical examination was 43.7%, compared with 77.6% for the clinical examination plus ultrasound.¹⁸

Continue to: Incision and drainage first

Incision and drainage first. Ultrasound-guided needle aspiration, however, has not improved treatment efficacy compared with incision and drainage,¹⁹ the mainstay approach for abscesses.¹⁷ The procedure to drain a furuncle, carbuncle, or abscess should include the expression of all purulent material and the removal of all loculations if possible. Wound culture is recommended during incision and drainage per current guidelines.⁵ Simple dry dressings are convenient and effective, although some wounds may require packing. Tap water (that is potable) is suitable for wound cleansing. However, there is no strong evidence that irrigating wounds increases healing or reduces infection.²⁰

Routine use of antibiotics is not recommended for simple cutaneous abscesses.^5,17,21 Evidence has been conflicting regarding empiric antibiotic coverage of MRSA following incision and drainage.^22-25 Guidelines recommend considering the initiation of antibiotics if there are multiple abscesses, gangrene, surrounding cellulitis, or systemic signs of infection, or if the host is immunocompromised.⁵

If MRSA is suspected, recommended antibiotic coverage includes trimethoprim-­sulfamethoxazole, clindamycin, doxycycline, or minocycline.⁵ If MRSA is identified, treatment options include dicloxacillin or cephalexin. For severe infections persisting after incision and drainage, in addition to oral antibiotic therapy, consider intravenous antibiotic options for MRSA: cefazolin, clindamycin, linezolid, nafcillin, telavancin, or vancomycin.⁵

Necrotizing fasciitis

Necrotizing fasciitis is a rare but potentially deadly infection of the skin and soft tissue. It progresses rapidly and spreads along fascial planes, leading to the necrosis of the superficial fascia. The infection often is more extensive than is indicated by superficial signs. Prompt diagnosis is imperative as necrotizing fasciitis is a surgical emergency.^5,26 In the United States, 500 to 1500 cases of necrotizing fasciitis occur each year.²⁷ Risk factors for necrotizing fasciitis include diabetes, peripheral vascular disease, malignancy, obesity, cirrhosis, renal failure, injection drug use, chronic corticosteroid therapy, alcohol abuse, malnutrition, and iatrogenic immunosuppression.^26,28

Monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.

Necrotizing fasciitis may be polymicrobial or monomicrobial. Polymicrobial infection, also referred to as type I, is often due to multiple bacteria that originate from the bowel flora, typically including a mix of anaerobic and aerobic organisms. On average, there can be 5 infecting organisms identified per wound, although in some cases up to 15 organisms have been identified in a single wound.⁵ Type I infection is often associated with tissue injury, abscess, or abdominal surgery. The majority of cases of necrotizing fasciitis are polymicrobial.^27,28

Continue to: Monomicrobial infection...

Monomicrobial infection, also referred to as type II, is often due to group A streptococcus, S aureus, vibrio spp, Aeromonas hyrophilio, or an anaerobic streptococci like peptostreptococcus spp. Typically monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.^5,26,29,30

Clinical presentation. In the early stages of disease, patients commonly complain of flu-like symptoms and extreme pain that is out of proportion to findings on the exam. Additional warning signs include fevers and other symptoms of toxicity such as tachycardia, hypotension, nausea, vomiting, and diarrhea. Later in the course, symptoms may localize to the affected area and include erythema, tense swelling, development of blisters or bullae, blackish blue discoloration of the skin, severe pain, and loss of sensation. In some cases involving gas-forming bacteria, tissue crepitus may be noted on exam.^5,27-31

Rely on clinical judgment to hasten surgical intervention. Laboratory or imaging findings may augment clinical judgment. But if you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery. Blood tests that may aid in the diagnosis of necrotizing fasciitis include a complete blood count with differential; coagulation studies; a comprehensive metabolic panel; assays of lactate, C-reactive protein (CRP), and creatinine kinase; and blood cultures. Most often, patients with necrotizing fasciitis will have leukocytosis or leukopenia, evidence of hemolysis, thrombocytopenia, acute renal failure, and significantly elevated CRP.

If you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery.

On any imaging modality, indications of necrotizing fasciitis are inflammatory infiltration of the deep fascia on the affected side that is absent on the contralateral side, and the presence of subcutaneous air (which is a specific but rare finding). Imaging modalities may include CT or magnetic resonance imaging. A definitive diagnosis can only be made with surgical exploration of the involved area. Definitive microbiologic diagnosis will require culture of organisms from affected tissue or blood.^5,26,30,31

First address any hemodynamic instability (hypotension is frequently encountered), followed by urgent surgical exploration, debridement of the wound, and antimicrobial therapy. Antibiotic treatment should align with probable pathogens and treatment should be continued until repeated surgical debridement is no longer necessary, clinical improvement is evident, and 48 to 72 hours have passed since defervescence. A reasonable initial empiric regimen in adults would include an agent that is effective against group A streptococcus, gram-negative pathogens, and anaerobes, such as a carbapenem or a beta-lactam-­beta-lactamase inhibitor such as piperacillin-­tazobactam. Additionally, include an agent that targets MRSA, such as vancomycin, linezolid, or clindamycin.⁵

CORRESPONDENCE
Karl T. Clebak, MD, Department of Family and Community Medicine Residency Program, Penn State Health M.S. Hershey Medical Center, 500 University Drive, H154/C1613, Hershey, PA 17033; [email protected]

Skin and soft-tissue infections, frequently encountered in primary care, range from the uncomplicated erysipelas to the life-threatening necrotizing fasciitis. This review draws from the latest evidence and guidelines to help guide the care you provide to patients with cellulitis, orbital cellulitis, erysipelas, folliculitis, furuncles, carbuncles, abscesses, and necrotizing fasciitis.

Cellulitis

Cellulitis, an infection of the deep dermal and subcutaneous layers of the skin, has become increasingly common in recent years, with both incidence and hospitalization rates rising.¹ Cellulitis occurs when pathogens enter the dermis through breaks in the skin barrier due to cutaneous fungal infections, trauma, pressure sores, venous stasis, or inflammation. The diagnosis is often made clinically based on characteristic skin findings—classically an acute, poorly demarcated area of erythema, warmth, swelling, and tenderness. Lymphangitic streaking and local lymphadenopathy may also be present. Infection often occurs on an extremity (although it can be found on other areas of the body) and is usually unilateral. Fever may or may not be present.²

Likely responsible microorganisms. Staphylococcus aureus and Group A streptococci (often Streptococcus pyogenes) are common culprits. One systematic review that examined cultures taken of intact skin in cellulitis patients found S aureus to be about twice as common as S pyogenes, with both bacteria accounting for a little more than 70% of cases. Of the remaining positive cultures, the most common organisms were alpha-­hemolytic streptococcus, group B streptococcus, Pseudomonas aeruginosa, Clostridium perfringens, Escherichia coli, Pasteurella multocida, and Proteus mirabilis.³ Similarly, a systematic review of bacteremia in patients with cellulitis and erysipelas found that S pyogenes, other beta-hemolytic strep, and S aureus account for about 70% of cases (although S aureus was responsible for just 14%), with the remainder of cases caused by gram-negative organisms such as E coli and P aeruginosa.⁴

Treatment considerations. Strict treatment guidelines for cellulitis are lacking, but general consensus encourages the use of antibiotics and occasionally surgery. For mild and moderate cases of cellulitis, prescribe oral and parenteral antibiotics to cover for streptococci and methicillin-susceptible S aureus, respectively. Expand coverage to include vancomycin if nasal colonization shows methicillin-resistant S aureus (MRSA) or if you otherwise suspect prior MRSA exposure. Expanded coverage will also be needed if there is severe nonpurulent infection associated with penetrating trauma or a history of intravenous drug use, or the patient meets criteria for systemic inflammatory response syndrome. If patients are severely compromised (eg, neutropenic), it is reasonable to further add broad-spectrum coverage (eg, intravenous piperacillin-­tazobactam or carbapenem). Typical duration of treatment is 5 to 7 days, although this should be extended if there is no clinical improvement.

For orbital cellulitis, choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.

Generally, cellulitis can be managed in the outpatient setting, although hospitalization is recommended if there are concerns for deep or necrotizing infection, if patients are nonadherent to therapy or are immunocompromised, or if outpatient therapy has failed.⁵ Furthermore, in an observational study of 606 adult patients, prior episodes of cellulitis, venous insufficiency, and immunosuppression were all independently associated with poorer clinical outcomes.² Also treat underlying predisposing factors such as edema, obesity, eczema, venous insufficiency, and toe web abnormalities such as fissures, scaling, or maceration.⁵ Consider the use of prophylactic antibiotics for patients who have had 3 to 4 episodes of cellulitis despite attempts to treat predisposing conditions. Prophylactic antibiotic regimens include penicillin or erythromycin orally and penicillin G benzathine intramuscularly.⁵ Antibiotic regimens are summarized in the TABLE.⁵

Orbital cellulitis

Orbital cellulitis is an infection of the tissues posterior to the orbital septum.^6,7 Periorbital, or preseptal, cellulitis occurs anterior to the orbital septum and is the more common of the 2 infections—84% compared with 16% for orbital cellulitis.⁶ However, orbital cellulitis, which affects mainly children at a median age of 7 years,⁶ must be detected and treated early due to the potential for serious complications such as cavernous sinus thrombosis, meningitis, intracranial abscess, and vision loss.⁷ Chemosis (conjunctival edema) and diplopia are more commonly associated with orbital cellulitis and are seldom seen with preseptal cellulitis.

Predominant causative organisms are S pneumoniae, Moraxella catarrhalis, non-typeable Haemophilus influenzae, and group A streptococcus. The most common mechanism of infection is tracking from periorbital structures (eg, paranasal and ethmoid sinusitis). Other causes include orbital trauma/fracture, periorbital surgery, and bacterial endocarditis. Clinically, patients present with limited ocular motility and proptosis associated with inflamed conjunctiva, orbital pain, headache, malaise, fever, eyelid edema, and possible decrease in visual acuity. The diagnosis is often made clinically and confirmed with orbital computed tomography (CT) with contrast, which can assist in ruling out intracranial involvement such as abscess.

Continue to: Antibiotic therapy

Antibiotic therapy, generally administered intravenously, is recommended for at least 3 days or until orbital symptoms begin to resolve. Choose antibiotics effective against sinusitis-related pathogens (eg, S pneumoniae, H influenzae, M catarrhalis), S aureus, and anaerobes.⁸ For instance, a regimen may include vancomycin for MRSA coverage, a third-generation cephalosporin, or metronidazole for anaerobic coverage if there is concern about intracranial involvement. Surgical intervention is often reserved for patients with inadequate response to antibiotic therapy, necessitating biopsy for pathogen identification, as well as drainage of large abscesses refractory to antibiotics.

Erysipelas

Erysipelas, a related yet distinct form of cellulitis, is a bacterial infection of the superficial dermis and hypodermis and is commonly caused by group A streptococcus.^5,9 Other less common organisms include S aureus, P aeruginosa, and enterobacteria. Erysipelas predominantly affects the lower extremities unilaterally (~90%); the arms and the face are the next most common locations. In addition to the rapid onset of well-demarcated erythema, pain, and swelling, patients may have fever and regional lymphadenopathy. Risk factors include portal of entry (eg, tinea pedis, ulceration), lymphedema, and diabetes. Complications of erysipelas include bullae from edema, abscess formation, and, rarely, bacteremia.

When clinical exam alone is inconclusive when evaluating skin and softtissue infections in children and adolescents, consider using ultrasound to improve diagnostic accuracy.

Antibiotic treatment regimens include penicillin G, macrolides (reserved for those with penicillin allergies), fluoroquinolones, and cephalosporins, with duration of treatment ranging from 10 to 14 days depending on infection severity. Fever, pain, and erythema generally improve within 48 to 72 hours of antibiotic therapy. If there is no improvement, consider alternative diagnoses, such as necrotizing fasciitis. Recurrence rates following the initial episode of erysipelas are estimated at 10% of patients at 6 months and 30% at 3 years.¹⁰

Folliculitis

Inflammation of hair follicles is characterized by superficial inflammation with the development of perifollicular papules or pustules on an erythematous base.^11,12 Folliculitis most commonly affects the face, scalp, thighs, buttocks, axillae, and inguinal areas.¹³ It may be caused by infection, an inflammatory reaction, or physical injury. Diagnosis is typically based on the patient’s history and physical examination.

Bacteria are the most common cause of infection, although fungi, viruses, and other entities can cause folliculitis. S aureus (methicillin sensitive or methicillin resistant) is the most common pathogen; in the past, superficial pustular folliculitis attributed to S aureus was referred to as Bockhart impetigo. Folliculitis secondary to P aeruginosa, often seen after exposure to contaminated water or hot tubs, is frequently referred to as “hot tub folliculitis.” Malassezia, a reported cause of fungal folliculitis, tends to occur in adolescents of either sex and men with high sebum production, is common in tropical climates, and can be associated with HIV or immunosuppression.^11,12,14

Continue to: Differential diagnosis...

Differential diagnosis of folliculitis includes pseudofolliculitis barbae, eosinophilic folliculitis, keratosis pilaris, acne vulgaris, candidiasis, contact dermatitis, impetigo, and miliaria.¹³ Pseudofolliculitis barbae is an inflammatory reaction to shaving, more commonly seen in darkly pigmented skin. Pseudofolliculitis develops when the hair shaft penetrates the wall of the follicle or directly enters the epidermis.

Initial treatment for mild disease includes the elimination of predisposing factors such as occlusion, moisture, and abrasion. The area should be kept clean and dry, avoiding friction. For localized disease, prescribe topical clindamycin, mupirocin ointment, or benzoyl peroxide. If symptoms fail to respond, prescribe a 7-day course of antibiotic that targets methicillin-sensitive S aureus—eg, cephalexin or dicloxacillin. Also consider doxycycline, which has anti-inflammatory effects and is effective against MRSA. For refractory lesions, ­trimethoprim-sulfamethoxazole, clindamycin, or minocycline may be useful. If you suspect pseudomonas, consider giving ciprofloxacin for 10 to 14 days for persistent lesions or if the patient is immunocompromised.^13,15 Consider obtaining bacterial, fungal, or viral cultures for lesions that fail to respond to initial treatment.

Do not routinely order cultures or prescribe antibiotics for uncomplicated abscesses.

Furuncles/carbuncles/abscesses

A furuncle, commonly referred to as a boil, is an infected hair follicle that becomes enclosed, creating a collection of pus. A carbuncle is a collection of furuncles that converge and drain through a single opening. An abscess is a localized collection of pus arising from within the dermis that can extend within deeper tissues.⁵ Furuncles, carbuncles, and abscesses are managed similarly with drainage and consideration for MRSA risk factors.

S aureus is the most common cause of these infections; 59% of skin abscesses are due to community-acquired MRSA.¹⁶ Anaerobes may contribute to the polymicrobial flora of skin abscesses.¹⁷ Risk factors for MRSA infection include a history of previous MRSA infection, diabetes, dialysis or renal failure, placement of an indwelling catheter or medical device, injection drug use, incarceration, close contact with a person with known MRSA infection or colonization, long-term care residence, hospitalization or surgery within the past 12 months, and high prevalence of MRSA in the community.⁵

Ultrasound improves diagnostic accuracy. One study showed that when a clinical exam alone was inconclusive in evaluating skin and soft-tissue infections in children and adolescents, an ultrasound-assisted examination improved diagnostic accuracy.¹⁸ Sensitivity of the clinical examination was 43.7%, compared with 77.6% for the clinical examination plus ultrasound.¹⁸

Continue to: Incision and drainage first

Incision and drainage first. Ultrasound-guided needle aspiration, however, has not improved treatment efficacy compared with incision and drainage,¹⁹ the mainstay approach for abscesses.¹⁷ The procedure to drain a furuncle, carbuncle, or abscess should include the expression of all purulent material and the removal of all loculations if possible. Wound culture is recommended during incision and drainage per current guidelines.⁵ Simple dry dressings are convenient and effective, although some wounds may require packing. Tap water (that is potable) is suitable for wound cleansing. However, there is no strong evidence that irrigating wounds increases healing or reduces infection.²⁰

Routine use of antibiotics is not recommended for simple cutaneous abscesses.^5,17,21 Evidence has been conflicting regarding empiric antibiotic coverage of MRSA following incision and drainage.^22-25 Guidelines recommend considering the initiation of antibiotics if there are multiple abscesses, gangrene, surrounding cellulitis, or systemic signs of infection, or if the host is immunocompromised.⁵

If MRSA is suspected, recommended antibiotic coverage includes trimethoprim-­sulfamethoxazole, clindamycin, doxycycline, or minocycline.⁵ If MRSA is identified, treatment options include dicloxacillin or cephalexin. For severe infections persisting after incision and drainage, in addition to oral antibiotic therapy, consider intravenous antibiotic options for MRSA: cefazolin, clindamycin, linezolid, nafcillin, telavancin, or vancomycin.⁵

Necrotizing fasciitis

Necrotizing fasciitis is a rare but potentially deadly infection of the skin and soft tissue. It progresses rapidly and spreads along fascial planes, leading to the necrosis of the superficial fascia. The infection often is more extensive than is indicated by superficial signs. Prompt diagnosis is imperative as necrotizing fasciitis is a surgical emergency.^5,26 In the United States, 500 to 1500 cases of necrotizing fasciitis occur each year.²⁷ Risk factors for necrotizing fasciitis include diabetes, peripheral vascular disease, malignancy, obesity, cirrhosis, renal failure, injection drug use, chronic corticosteroid therapy, alcohol abuse, malnutrition, and iatrogenic immunosuppression.^26,28

Monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.

Necrotizing fasciitis may be polymicrobial or monomicrobial. Polymicrobial infection, also referred to as type I, is often due to multiple bacteria that originate from the bowel flora, typically including a mix of anaerobic and aerobic organisms. On average, there can be 5 infecting organisms identified per wound, although in some cases up to 15 organisms have been identified in a single wound.⁵ Type I infection is often associated with tissue injury, abscess, or abdominal surgery. The majority of cases of necrotizing fasciitis are polymicrobial.^27,28

Continue to: Monomicrobial infection...

Monomicrobial infection, also referred to as type II, is often due to group A streptococcus, S aureus, vibrio spp, Aeromonas hyrophilio, or an anaerobic streptococci like peptostreptococcus spp. Typically monomicrobial infections, which account for 20% to 30% of cases of necrotizing fasciitis, are community acquired.^5,26,29,30

Clinical presentation. In the early stages of disease, patients commonly complain of flu-like symptoms and extreme pain that is out of proportion to findings on the exam. Additional warning signs include fevers and other symptoms of toxicity such as tachycardia, hypotension, nausea, vomiting, and diarrhea. Later in the course, symptoms may localize to the affected area and include erythema, tense swelling, development of blisters or bullae, blackish blue discoloration of the skin, severe pain, and loss of sensation. In some cases involving gas-forming bacteria, tissue crepitus may be noted on exam.^5,27-31

Rely on clinical judgment to hasten surgical intervention. Laboratory or imaging findings may augment clinical judgment. But if you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery. Blood tests that may aid in the diagnosis of necrotizing fasciitis include a complete blood count with differential; coagulation studies; a comprehensive metabolic panel; assays of lactate, C-reactive protein (CRP), and creatinine kinase; and blood cultures. Most often, patients with necrotizing fasciitis will have leukocytosis or leukopenia, evidence of hemolysis, thrombocytopenia, acute renal failure, and significantly elevated CRP.

If you suspect necrotizing fasciitis, obtaining blood tests and imaging should not delay surgery.

On any imaging modality, indications of necrotizing fasciitis are inflammatory infiltration of the deep fascia on the affected side that is absent on the contralateral side, and the presence of subcutaneous air (which is a specific but rare finding). Imaging modalities may include CT or magnetic resonance imaging. A definitive diagnosis can only be made with surgical exploration of the involved area. Definitive microbiologic diagnosis will require culture of organisms from affected tissue or blood.^5,26,30,31

First address any hemodynamic instability (hypotension is frequently encountered), followed by urgent surgical exploration, debridement of the wound, and antimicrobial therapy. Antibiotic treatment should align with probable pathogens and treatment should be continued until repeated surgical debridement is no longer necessary, clinical improvement is evident, and 48 to 72 hours have passed since defervescence. A reasonable initial empiric regimen in adults would include an agent that is effective against group A streptococcus, gram-negative pathogens, and anaerobes, such as a carbapenem or a beta-lactam-­beta-lactamase inhibitor such as piperacillin-­tazobactam. Additionally, include an agent that targets MRSA, such as vancomycin, linezolid, or clindamycin.⁵

CORRESPONDENCE
Karl T. Clebak, MD, Department of Family and Community Medicine Residency Program, Penn State Health M.S. Hershey Medical Center, 500 University Drive, H154/C1613, Hershey, PA 17033; [email protected]

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; [email protected]

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; [email protected]

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; [email protected]

Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.

Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.

A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.

“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.

The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.

In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.

A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.

For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.

When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.

For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.

Gout similarly associated with proinflammatory diet

The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.

When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
 

Impact of weight on risk for gout

The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.

copyright joloei/Thinkstock

The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.

All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.

Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.

Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.

Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.

Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.

Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.

A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.

“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.

The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.

In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.

A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.

For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.

When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.

For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.

Gout similarly associated with proinflammatory diet

The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.

When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
 

Impact of weight on risk for gout

The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.

copyright joloei/Thinkstock

The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.

All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.

Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.

Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.

Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.

Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.

Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.

A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.

“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.

The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.

In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.

A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.

For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.

When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.

For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.

Gout similarly associated with proinflammatory diet

The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.

When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
 

Impact of weight on risk for gout

The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.

copyright joloei/Thinkstock

The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.

All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.

Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.

Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.

Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.

In early June the Food and Drug Administration – amid a storm of controversy – approved aducanumab, a monoclonal antibody developed to treat Alzheimer’s disease. The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.

But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.

The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.

Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.

This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
 

Fielding broad interest

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.

“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.

For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.

“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”

The challenge of delivery

Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.

Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.

“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.

“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”

Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.

“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.

Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.

Uncertainty over costs

Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”

Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”

Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.

The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”

Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.

Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.

The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.

Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
 

Geriatricians wary

On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.

Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.

A fractured research community

Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.

Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.

“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”

Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.

Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.

Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.

Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.

“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.

“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”

Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.

In early June the Food and Drug Administration – amid a storm of controversy – approved aducanumab, a monoclonal antibody developed to treat Alzheimer’s disease. The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.

But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.

The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.

Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.

This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
 

Fielding broad interest

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.

“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.

For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.

“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”

The challenge of delivery

Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.

Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.

“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.

“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”

Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.

“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.

Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.

Uncertainty over costs

Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”

Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”

Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.

The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”

Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.

Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.

The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.

Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
 

Geriatricians wary

On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.

Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.

A fractured research community

Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.

Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.

“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”

Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.

Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.

Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.

Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.

“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.

“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”

Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.

In early June the Food and Drug Administration – amid a storm of controversy – approved aducanumab, a monoclonal antibody developed to treat Alzheimer’s disease. The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.

But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.

The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.

Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.

This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
 

Fielding broad interest

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.

“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.

For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.

“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”

The challenge of delivery

Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.

Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.

“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.

“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”

Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.

“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.

Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.

Uncertainty over costs

Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”

Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”

Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.

The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”

Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.

Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.

The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.

Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
 

Geriatricians wary

On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.

Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.

A fractured research community

Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.

Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.

“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”

Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.

Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.

Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.

Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.

“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.

“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”

Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.