Case Report

A 7-year-old girl who was otherwise healthy was referred by pediatric gastroenterology for evaluation of cutaneous Crohn disease (CD). The patient had a 4-year history of persistent lip swelling and a 3-year history of asymmetric erythematous labial swelling and perianal erythema with skin tags. She had been applying the calcineurin inhibitor tacrolimus ointment 0.03% 1 or 2 times daily to her lesions with minimal improvement. She did not have a medical history of recurrent or unusual infectious diseases. There was no family history of autoimmune disease.

The patient and her guardian reported intermittent perianal pain but denied constipation, diarrhea, abdominal pain, and blood in the stool. She denied throat and tongue swelling, dysphagia, dyspnea, drooling, facial paralysis, and eyelid edema. She was a well-nourished child whose height and weight percentiles tracked at 30% and 25%, respectively. Physical examination revealed confluent symmetric lip swelling with mild angular cheilitis. Multiple 1- to 2-mm white pustules with pinpoint erosions covered the upper and lower labial mucosa and extended onto the buccal mucosa (Figure 1). She had symmetric erythema and swelling of the left labia majora extending to and involving the left perianal mucosa. Three perianal erythematous skin tags and a perianal fissure were identified.

The patient had been assessed 2 years earlier by pediatric dermatology and gastroenterology with an extensive evaluation that favored a diagnosis of cutaneous CD because the combination of orofacial granulomatosis (OFG), vulvar edema, and perianal skin tags is strongly associated.^1-3 Contact dermatitis affecting the mouth was considered; however, allergen testing did not demonstrate a trigger.

A trial of a benzoate- and cinnamon-free diet, which has been reported to improve OFG,⁴ did not provide symptomatic improvement. Topical corticosteroids and tacrolimus reduced the perioral erythema, but the swelling persisted. An infectious cause was considered; however, topical mupirocin had no effect, and amoxicillin resulted in oral candidiasis.

A perianal biopsy revealed a granulomatous dermatitis. Fungal and bacterial cultures were negative. Upper and lower gastrointestinal (GI) endoscopy and a fecal calprotectin assay were not suggestive of inflammatory bowel disease (IBD). A complete blood cell count and QuantiFERON-TB Gold test measuring the immune response to tuberculosis antigens were normal. Chronic granulomatous disease, RAG1/RAG2 deficiency, common variable immunodeficiency, and NOD2 defects were ruled out with normal tests of dihydrorhodamine, quantitative immunoglobulins, and toll-like receptors.

Because of the discomfort associated with the patient’s lesions, she was offered treatment with tumor necrosis factor α inhibitors, including infliximab and adalimumab. These agents had been offered since the onset of symptoms; however, her parents declined systemic medication unless she developed GI involvement. Instead, the tacrolimus concentration was increased to 0.1% applied to the lips, labia, and perianal area, and fluocinonide gel 0.05% applied nightly to the oral pustules was added.

Two months later the patient had notably fewer oral pustules and diminished erythema but only slightly reduced oral, vulvar, and perianal swelling. A trial of oral metronidazole, which has been reported to clear a patient with cutaneous CD,⁵ was discontinued by her parents after 6 weeks because of a lack of interval improvement.

One year later, a pre-existing perianal skin tag doubled in size and became exquisitely tender. The calprotectin level—previously within reference range at less than 16 μg/g—was now elevated at 149 μg/g (reference range, 1–120 μg/g) and increased to 336 μg/g 3 weeks later. Testing for C-reactive protein, zinc, and stool occult blood; a comprehensive metabolic panel; and a complete blood cell count were unremarkable.

Repeat upper and lower GI endoscopy did not suggest CD. A biopsy using direct immunofluorescence (DIF) was obtained to evaluate for pyostomatitis vegetans (PSV) and rule out pemphigus vegetans of Hallopeau (PVH). Biopsy of a pustule was attempted but was challenging because of the patient’s age and difficulty cooperating.

The captured biopsy did not demonstrate the intended pustule; instead, it included less-affected mucosa and was obtained during topical treatment when few pustules and erosions persisted. Pathologic analysis revealed noncaseating granulomas without an increase in microabscesses, neutrophils, or eosinophils (Figure 2). Direct immunofluorescence staining for IgG, IgA, and C3 and indirect immunofluorescence staining for desmoglein-1 and desmoglein-3 antibodies were negative. Although the biopsy did not capture the intended pustule, diagnosis of PV was made based on clinical features and the constellation of cutaneous findings associated with IBD.

Intralesional triamcinolone, which has been of benefit for pediatric patients with orofacial granulomatosis,^1,6,7 was instituted and normalized the vulva and perianal mucosa; however, lip swelling improved only minimally.

Comment

Pyostomatitis vegetans is characterized by multiple white or yellow, friable, miliary pustules that rupture, leaving behind ulcerations and erosions that cause a varying degree of oral pain.⁸ The disorder can involve any area of the oral mucosa—most often the labia-attached gingiva, soft and hard palates, buccal mucosa, vestibule, and tonsillar areas—but often spares the floor of the mouth and tongue.^8-11 The term pyostomatitis vegetans was proposed in 1949 by McCarthy¹² when he noted in a patient who presented with the characteristic appearance of the oral mucosa, though cases of vaginal, nasal, and periocular involvement have been reported.^8,13,14

Histopathology—Pyostomatitis vegetans displays pseudoepithelial hyperplasia with acanthosis, hyperkeratosis, and intraepithelial or subepithelial microabscesses (or both) with neutrophils and eosinophils.^8,9,15 There are a few possible explanations for this patient’s lack of tissue eosinophilia. It has been theorized that the presence of granulomas could mask concurrent PSV¹⁶ or that tissue in PSV contains fewer eosinophils as the disorder progresses.¹¹ The oral biopsy obtained from our patient did not capture a pustule, and the condition had noticeably improved with topical tacrolimus at the time of biopsy; therefore, neither neutrophils nor eosinophils were identified. Peripheral eosinophilia, which is present in 42% to 90% of cases of PSV,^9,17 can be a diagnostic clue.¹⁸ However, PE is associated with IBD,²⁴ which usually occurs with PSV, so the absence of peripheral eosinophilia in our patient may be explained by her lack of bowel disease.

Pathogenesis—The pathogenesis of PSV is unknown. A proposed etiology includes cross-reacting antigens in the bowel and skin secondary to IBD as well as an aberrant immune response to an unidentified factor.⁸ Pyostomatitis vegetans is considered by many to be the mucosal variant of pyodermatitis vegetans,^9,15,19 a neutrophilic dermatosis characterized by asymmetric, crusted, erythematous papulopustules that extend peripherally and coalesce to form large vegetating plaques. These lesions commonly manifest in the axillary folds, groin, and scalp and can involve the face, trunk, and distal extremities.^9,18 Infection has been suggested as a cause of PSV, though cultures for pathogenic bacteria, viruses, and fungi consistently show only normal flora.²⁰ Zinc deficiency attributed to malabsorption from CD was reported in an adult with PSV.²¹ The PSV resolved after 6 weeks of zinc supplementation.

Differential Diagnosis—The main entity in the clinical differential diagnosis for PSV is PVH, which is considered a variant of pemphigus vulgaris. Pemphigus vegetans of Hallopeau presents with pustules and progresses to hyperpigmented vegetative plaques with peripheral hypertrophic granulation tissue.²² The clinical and histological presentation of PVH can be similar to PSV; in PVH, however, DIF demonstrates intercellular IgG and C3 due to circulating IgG autoantibodies specific for desmoglein 3, a cell adhesion molecule.^22-24 In PSV, DIF typically is negative for IgG, IgA, and C3.⁸ Immunohistochemical findings of PSV may overlap with IgA pemphigus, IgG/IgA pemphigus, and IgG pemphigus, which has sparked debate if PSV is an autoimmune blistering disorder or a secondary finding of epithelial injury.^9,18,24

Pyostomatitis vegetans is most prevalent in patients aged 20 to 59 years²⁵ but can occur at any age.^8,19 Overall, extraintestinal symptoms, including mucocutaneous findings, are common in pediatric patients—in 30% to 71% of children with CD and 21% to 22% of children with ulcerative colitis²⁶—and can predate onset of GI symptoms in 6% of pediatric patients.²⁷

Oral disease is common in CD; manifestations are listed in the Table.^28,29 In a prospective study of 48 children with CD, 42% (20/48) had oral manifestations identified at diagnosis²⁸; in a similar study of 25 children, researchers noted that 48% (12/25) had disease-specific oral lesions.²⁹ None of these children recognized the oral findings prior to the onset of systemic symptoms.²⁸ Pyostomatitis vegetans was the least common oral manifestation, reported in 1 of 73 patients in the 2 studies combined.^28,29

Two recent articles that looked at PSV in pediatric and adolescent populations identified only 9 patients with PSV.^24,30 Only 2 patients (siblings) had documented onset of PSV before 12 years of age,³¹ which suggests an underlying genetic predisposition in young children.

It has been reported that active or subclinical (ie, asymptomatic with positive endoscopic findings) IBD in adults precedes onset of PSV, which may be considered a sign of relapse.^9,30 However, PSV is incredibly rare in children and adolescents and can be an early finding of IBD in children.^16,31,32

Our patient has not developed GI involvement since her initial presentation 5 years prior, though another pediatric patient developed symptomatic CD 9 years after onset of OFG.⁵ A retrospective review of pediatric OFG without CD met criteria for CD at a median of 3.1 years (range, 0.4–6.9 years).³³ Regrettably, the early presence of PSV has been associated with future progression to CD and a complicated disease course.^12,34

Management—Pyoderma stomatitis vegetans is treated with management of underlying IBD,⁸ with scarce literature available regarding pediatric patients. Oral lesions have been treated with antiseptics and topical corticosteroids, though these have limited benefit.⁸ In an adult with IBD, topical tacrolimus initially cleared PSV; however, lesions recurred until mesalamine was initiated.³⁵ Systemic steroids were effective in a 16-year-old patient with CD and PSV,¹² but recurrence is common after corticosteroids are stopped.³⁴

Some patients benefit from steroid-sparing medications, such as dapsone, azathioprine, sulfamethoxypyridazine, methotrexate, mycophenolate mofetil, and tumor necrosis factor α inhibitors such as infliximab and adalimumab.^{8,9,15,23,34,36} A 12-year-old patient with pyodermatitis–PSV without intestinal disease was treated with prednisone, dapsone, and azathioprine with improvement but not complete resolution of oral erosions after 18 weeks of treatment.³² A 15-year-old patient with CD and pyodermatitis–PSV did not show improvement on prednisone, dapsone, and azathioprine but rapidly responded to infliximab.²³ Infliximab led to complete clearance of oral lesions in an adult with severe fistulizing CD who developed PSV.¹¹ However, 2 adolescent patients with CD developed PSV while on adalimumab,^6,34 though 1 did improve after increasing adalimumab from once to twice weekly.⁶

Conclusion

The case described here—PSV in a prepubertal 7-year-old with multiple cutaneous findings suggestive of CD, including OFG, perianal and vulvar edema with biopsy-proven noncaseating granulomas, anal skin tags, and an elevated calprotectin level, noted during a cutaneous flare without clinical or endoscopically identified underlying bowel involvement—is an extremely rare presentation. Literature regarding management of PSV primarily is found in the form of case reports and focuses on treating underlying IBD. In patients with intestinal disease, treatment with biologic therapy appears most effective.^6,23

ADDENDUM

Interestingly, 3 years after the patient’s original presentation to our clinic, chromosomal sequencing analysis to assess for copy number variants and whole exome gene sequencing identified a variant of unknown significance in the heat shock protein family A member 1-like gene, HSPA1L, which has an unknown mode of inheritance, but the literature suggests that both truncating and missense variants could be associated with individuals with ulcerative colitis, CD, and IBD.^37,38 Although we cannot use this information to render a molecular diagnosis, it is highly suspicious that this is the cause of her clinical findings. Additionally, the patient currently is aged 10 years with unchanged cutaneous findings and has not developed gastrointestinal findings of IBD.

Case Report

A 7-year-old girl who was otherwise healthy was referred by pediatric gastroenterology for evaluation of cutaneous Crohn disease (CD). The patient had a 4-year history of persistent lip swelling and a 3-year history of asymmetric erythematous labial swelling and perianal erythema with skin tags. She had been applying the calcineurin inhibitor tacrolimus ointment 0.03% 1 or 2 times daily to her lesions with minimal improvement. She did not have a medical history of recurrent or unusual infectious diseases. There was no family history of autoimmune disease.

The patient and her guardian reported intermittent perianal pain but denied constipation, diarrhea, abdominal pain, and blood in the stool. She denied throat and tongue swelling, dysphagia, dyspnea, drooling, facial paralysis, and eyelid edema. She was a well-nourished child whose height and weight percentiles tracked at 30% and 25%, respectively. Physical examination revealed confluent symmetric lip swelling with mild angular cheilitis. Multiple 1- to 2-mm white pustules with pinpoint erosions covered the upper and lower labial mucosa and extended onto the buccal mucosa (Figure 1). She had symmetric erythema and swelling of the left labia majora extending to and involving the left perianal mucosa. Three perianal erythematous skin tags and a perianal fissure were identified.

The patient had been assessed 2 years earlier by pediatric dermatology and gastroenterology with an extensive evaluation that favored a diagnosis of cutaneous CD because the combination of orofacial granulomatosis (OFG), vulvar edema, and perianal skin tags is strongly associated.^1-3 Contact dermatitis affecting the mouth was considered; however, allergen testing did not demonstrate a trigger.

A trial of a benzoate- and cinnamon-free diet, which has been reported to improve OFG,⁴ did not provide symptomatic improvement. Topical corticosteroids and tacrolimus reduced the perioral erythema, but the swelling persisted. An infectious cause was considered; however, topical mupirocin had no effect, and amoxicillin resulted in oral candidiasis.

A perianal biopsy revealed a granulomatous dermatitis. Fungal and bacterial cultures were negative. Upper and lower gastrointestinal (GI) endoscopy and a fecal calprotectin assay were not suggestive of inflammatory bowel disease (IBD). A complete blood cell count and QuantiFERON-TB Gold test measuring the immune response to tuberculosis antigens were normal. Chronic granulomatous disease, RAG1/RAG2 deficiency, common variable immunodeficiency, and NOD2 defects were ruled out with normal tests of dihydrorhodamine, quantitative immunoglobulins, and toll-like receptors.

Because of the discomfort associated with the patient’s lesions, she was offered treatment with tumor necrosis factor α inhibitors, including infliximab and adalimumab. These agents had been offered since the onset of symptoms; however, her parents declined systemic medication unless she developed GI involvement. Instead, the tacrolimus concentration was increased to 0.1% applied to the lips, labia, and perianal area, and fluocinonide gel 0.05% applied nightly to the oral pustules was added.

Two months later the patient had notably fewer oral pustules and diminished erythema but only slightly reduced oral, vulvar, and perianal swelling. A trial of oral metronidazole, which has been reported to clear a patient with cutaneous CD,⁵ was discontinued by her parents after 6 weeks because of a lack of interval improvement.

One year later, a pre-existing perianal skin tag doubled in size and became exquisitely tender. The calprotectin level—previously within reference range at less than 16 μg/g—was now elevated at 149 μg/g (reference range, 1–120 μg/g) and increased to 336 μg/g 3 weeks later. Testing for C-reactive protein, zinc, and stool occult blood; a comprehensive metabolic panel; and a complete blood cell count were unremarkable.

Repeat upper and lower GI endoscopy did not suggest CD. A biopsy using direct immunofluorescence (DIF) was obtained to evaluate for pyostomatitis vegetans (PSV) and rule out pemphigus vegetans of Hallopeau (PVH). Biopsy of a pustule was attempted but was challenging because of the patient’s age and difficulty cooperating.

The captured biopsy did not demonstrate the intended pustule; instead, it included less-affected mucosa and was obtained during topical treatment when few pustules and erosions persisted. Pathologic analysis revealed noncaseating granulomas without an increase in microabscesses, neutrophils, or eosinophils (Figure 2). Direct immunofluorescence staining for IgG, IgA, and C3 and indirect immunofluorescence staining for desmoglein-1 and desmoglein-3 antibodies were negative. Although the biopsy did not capture the intended pustule, diagnosis of PV was made based on clinical features and the constellation of cutaneous findings associated with IBD.

Intralesional triamcinolone, which has been of benefit for pediatric patients with orofacial granulomatosis,^1,6,7 was instituted and normalized the vulva and perianal mucosa; however, lip swelling improved only minimally.

Comment

Pyostomatitis vegetans is characterized by multiple white or yellow, friable, miliary pustules that rupture, leaving behind ulcerations and erosions that cause a varying degree of oral pain.⁸ The disorder can involve any area of the oral mucosa—most often the labia-attached gingiva, soft and hard palates, buccal mucosa, vestibule, and tonsillar areas—but often spares the floor of the mouth and tongue.^8-11 The term pyostomatitis vegetans was proposed in 1949 by McCarthy¹² when he noted in a patient who presented with the characteristic appearance of the oral mucosa, though cases of vaginal, nasal, and periocular involvement have been reported.^8,13,14

Histopathology—Pyostomatitis vegetans displays pseudoepithelial hyperplasia with acanthosis, hyperkeratosis, and intraepithelial or subepithelial microabscesses (or both) with neutrophils and eosinophils.^8,9,15 There are a few possible explanations for this patient’s lack of tissue eosinophilia. It has been theorized that the presence of granulomas could mask concurrent PSV¹⁶ or that tissue in PSV contains fewer eosinophils as the disorder progresses.¹¹ The oral biopsy obtained from our patient did not capture a pustule, and the condition had noticeably improved with topical tacrolimus at the time of biopsy; therefore, neither neutrophils nor eosinophils were identified. Peripheral eosinophilia, which is present in 42% to 90% of cases of PSV,^9,17 can be a diagnostic clue.¹⁸ However, PE is associated with IBD,²⁴ which usually occurs with PSV, so the absence of peripheral eosinophilia in our patient may be explained by her lack of bowel disease.

Pathogenesis—The pathogenesis of PSV is unknown. A proposed etiology includes cross-reacting antigens in the bowel and skin secondary to IBD as well as an aberrant immune response to an unidentified factor.⁸ Pyostomatitis vegetans is considered by many to be the mucosal variant of pyodermatitis vegetans,^9,15,19 a neutrophilic dermatosis characterized by asymmetric, crusted, erythematous papulopustules that extend peripherally and coalesce to form large vegetating plaques. These lesions commonly manifest in the axillary folds, groin, and scalp and can involve the face, trunk, and distal extremities.^9,18 Infection has been suggested as a cause of PSV, though cultures for pathogenic bacteria, viruses, and fungi consistently show only normal flora.²⁰ Zinc deficiency attributed to malabsorption from CD was reported in an adult with PSV.²¹ The PSV resolved after 6 weeks of zinc supplementation.

Differential Diagnosis—The main entity in the clinical differential diagnosis for PSV is PVH, which is considered a variant of pemphigus vulgaris. Pemphigus vegetans of Hallopeau presents with pustules and progresses to hyperpigmented vegetative plaques with peripheral hypertrophic granulation tissue.²² The clinical and histological presentation of PVH can be similar to PSV; in PVH, however, DIF demonstrates intercellular IgG and C3 due to circulating IgG autoantibodies specific for desmoglein 3, a cell adhesion molecule.^22-24 In PSV, DIF typically is negative for IgG, IgA, and C3.⁸ Immunohistochemical findings of PSV may overlap with IgA pemphigus, IgG/IgA pemphigus, and IgG pemphigus, which has sparked debate if PSV is an autoimmune blistering disorder or a secondary finding of epithelial injury.^9,18,24

Pyostomatitis vegetans is most prevalent in patients aged 20 to 59 years²⁵ but can occur at any age.^8,19 Overall, extraintestinal symptoms, including mucocutaneous findings, are common in pediatric patients—in 30% to 71% of children with CD and 21% to 22% of children with ulcerative colitis²⁶—and can predate onset of GI symptoms in 6% of pediatric patients.²⁷

Oral disease is common in CD; manifestations are listed in the Table.^28,29 In a prospective study of 48 children with CD, 42% (20/48) had oral manifestations identified at diagnosis²⁸; in a similar study of 25 children, researchers noted that 48% (12/25) had disease-specific oral lesions.²⁹ None of these children recognized the oral findings prior to the onset of systemic symptoms.²⁸ Pyostomatitis vegetans was the least common oral manifestation, reported in 1 of 73 patients in the 2 studies combined.^28,29

Two recent articles that looked at PSV in pediatric and adolescent populations identified only 9 patients with PSV.^24,30 Only 2 patients (siblings) had documented onset of PSV before 12 years of age,³¹ which suggests an underlying genetic predisposition in young children.

It has been reported that active or subclinical (ie, asymptomatic with positive endoscopic findings) IBD in adults precedes onset of PSV, which may be considered a sign of relapse.^9,30 However, PSV is incredibly rare in children and adolescents and can be an early finding of IBD in children.^16,31,32

Our patient has not developed GI involvement since her initial presentation 5 years prior, though another pediatric patient developed symptomatic CD 9 years after onset of OFG.⁵ A retrospective review of pediatric OFG without CD met criteria for CD at a median of 3.1 years (range, 0.4–6.9 years).³³ Regrettably, the early presence of PSV has been associated with future progression to CD and a complicated disease course.^12,34

Management—Pyoderma stomatitis vegetans is treated with management of underlying IBD,⁸ with scarce literature available regarding pediatric patients. Oral lesions have been treated with antiseptics and topical corticosteroids, though these have limited benefit.⁸ In an adult with IBD, topical tacrolimus initially cleared PSV; however, lesions recurred until mesalamine was initiated.³⁵ Systemic steroids were effective in a 16-year-old patient with CD and PSV,¹² but recurrence is common after corticosteroids are stopped.³⁴

Some patients benefit from steroid-sparing medications, such as dapsone, azathioprine, sulfamethoxypyridazine, methotrexate, mycophenolate mofetil, and tumor necrosis factor α inhibitors such as infliximab and adalimumab.^{8,9,15,23,34,36} A 12-year-old patient with pyodermatitis–PSV without intestinal disease was treated with prednisone, dapsone, and azathioprine with improvement but not complete resolution of oral erosions after 18 weeks of treatment.³² A 15-year-old patient with CD and pyodermatitis–PSV did not show improvement on prednisone, dapsone, and azathioprine but rapidly responded to infliximab.²³ Infliximab led to complete clearance of oral lesions in an adult with severe fistulizing CD who developed PSV.¹¹ However, 2 adolescent patients with CD developed PSV while on adalimumab,^6,34 though 1 did improve after increasing adalimumab from once to twice weekly.⁶

Conclusion

The case described here—PSV in a prepubertal 7-year-old with multiple cutaneous findings suggestive of CD, including OFG, perianal and vulvar edema with biopsy-proven noncaseating granulomas, anal skin tags, and an elevated calprotectin level, noted during a cutaneous flare without clinical or endoscopically identified underlying bowel involvement—is an extremely rare presentation. Literature regarding management of PSV primarily is found in the form of case reports and focuses on treating underlying IBD. In patients with intestinal disease, treatment with biologic therapy appears most effective.^6,23

ADDENDUM

Interestingly, 3 years after the patient’s original presentation to our clinic, chromosomal sequencing analysis to assess for copy number variants and whole exome gene sequencing identified a variant of unknown significance in the heat shock protein family A member 1-like gene, HSPA1L, which has an unknown mode of inheritance, but the literature suggests that both truncating and missense variants could be associated with individuals with ulcerative colitis, CD, and IBD.^37,38 Although we cannot use this information to render a molecular diagnosis, it is highly suspicious that this is the cause of her clinical findings. Additionally, the patient currently is aged 10 years with unchanged cutaneous findings and has not developed gastrointestinal findings of IBD.

Case Report

A 7-year-old girl who was otherwise healthy was referred by pediatric gastroenterology for evaluation of cutaneous Crohn disease (CD). The patient had a 4-year history of persistent lip swelling and a 3-year history of asymmetric erythematous labial swelling and perianal erythema with skin tags. She had been applying the calcineurin inhibitor tacrolimus ointment 0.03% 1 or 2 times daily to her lesions with minimal improvement. She did not have a medical history of recurrent or unusual infectious diseases. There was no family history of autoimmune disease.

The patient and her guardian reported intermittent perianal pain but denied constipation, diarrhea, abdominal pain, and blood in the stool. She denied throat and tongue swelling, dysphagia, dyspnea, drooling, facial paralysis, and eyelid edema. She was a well-nourished child whose height and weight percentiles tracked at 30% and 25%, respectively. Physical examination revealed confluent symmetric lip swelling with mild angular cheilitis. Multiple 1- to 2-mm white pustules with pinpoint erosions covered the upper and lower labial mucosa and extended onto the buccal mucosa (Figure 1). She had symmetric erythema and swelling of the left labia majora extending to and involving the left perianal mucosa. Three perianal erythematous skin tags and a perianal fissure were identified.

The patient had been assessed 2 years earlier by pediatric dermatology and gastroenterology with an extensive evaluation that favored a diagnosis of cutaneous CD because the combination of orofacial granulomatosis (OFG), vulvar edema, and perianal skin tags is strongly associated.^1-3 Contact dermatitis affecting the mouth was considered; however, allergen testing did not demonstrate a trigger.

A trial of a benzoate- and cinnamon-free diet, which has been reported to improve OFG,⁴ did not provide symptomatic improvement. Topical corticosteroids and tacrolimus reduced the perioral erythema, but the swelling persisted. An infectious cause was considered; however, topical mupirocin had no effect, and amoxicillin resulted in oral candidiasis.

A perianal biopsy revealed a granulomatous dermatitis. Fungal and bacterial cultures were negative. Upper and lower gastrointestinal (GI) endoscopy and a fecal calprotectin assay were not suggestive of inflammatory bowel disease (IBD). A complete blood cell count and QuantiFERON-TB Gold test measuring the immune response to tuberculosis antigens were normal. Chronic granulomatous disease, RAG1/RAG2 deficiency, common variable immunodeficiency, and NOD2 defects were ruled out with normal tests of dihydrorhodamine, quantitative immunoglobulins, and toll-like receptors.

Because of the discomfort associated with the patient’s lesions, she was offered treatment with tumor necrosis factor α inhibitors, including infliximab and adalimumab. These agents had been offered since the onset of symptoms; however, her parents declined systemic medication unless she developed GI involvement. Instead, the tacrolimus concentration was increased to 0.1% applied to the lips, labia, and perianal area, and fluocinonide gel 0.05% applied nightly to the oral pustules was added.

Two months later the patient had notably fewer oral pustules and diminished erythema but only slightly reduced oral, vulvar, and perianal swelling. A trial of oral metronidazole, which has been reported to clear a patient with cutaneous CD,⁵ was discontinued by her parents after 6 weeks because of a lack of interval improvement.

One year later, a pre-existing perianal skin tag doubled in size and became exquisitely tender. The calprotectin level—previously within reference range at less than 16 μg/g—was now elevated at 149 μg/g (reference range, 1–120 μg/g) and increased to 336 μg/g 3 weeks later. Testing for C-reactive protein, zinc, and stool occult blood; a comprehensive metabolic panel; and a complete blood cell count were unremarkable.

Repeat upper and lower GI endoscopy did not suggest CD. A biopsy using direct immunofluorescence (DIF) was obtained to evaluate for pyostomatitis vegetans (PSV) and rule out pemphigus vegetans of Hallopeau (PVH). Biopsy of a pustule was attempted but was challenging because of the patient’s age and difficulty cooperating.

The captured biopsy did not demonstrate the intended pustule; instead, it included less-affected mucosa and was obtained during topical treatment when few pustules and erosions persisted. Pathologic analysis revealed noncaseating granulomas without an increase in microabscesses, neutrophils, or eosinophils (Figure 2). Direct immunofluorescence staining for IgG, IgA, and C3 and indirect immunofluorescence staining for desmoglein-1 and desmoglein-3 antibodies were negative. Although the biopsy did not capture the intended pustule, diagnosis of PV was made based on clinical features and the constellation of cutaneous findings associated with IBD.

Intralesional triamcinolone, which has been of benefit for pediatric patients with orofacial granulomatosis,^1,6,7 was instituted and normalized the vulva and perianal mucosa; however, lip swelling improved only minimally.

Comment

Pyostomatitis vegetans is characterized by multiple white or yellow, friable, miliary pustules that rupture, leaving behind ulcerations and erosions that cause a varying degree of oral pain.⁸ The disorder can involve any area of the oral mucosa—most often the labia-attached gingiva, soft and hard palates, buccal mucosa, vestibule, and tonsillar areas—but often spares the floor of the mouth and tongue.^8-11 The term pyostomatitis vegetans was proposed in 1949 by McCarthy¹² when he noted in a patient who presented with the characteristic appearance of the oral mucosa, though cases of vaginal, nasal, and periocular involvement have been reported.^8,13,14

Histopathology—Pyostomatitis vegetans displays pseudoepithelial hyperplasia with acanthosis, hyperkeratosis, and intraepithelial or subepithelial microabscesses (or both) with neutrophils and eosinophils.^8,9,15 There are a few possible explanations for this patient’s lack of tissue eosinophilia. It has been theorized that the presence of granulomas could mask concurrent PSV¹⁶ or that tissue in PSV contains fewer eosinophils as the disorder progresses.¹¹ The oral biopsy obtained from our patient did not capture a pustule, and the condition had noticeably improved with topical tacrolimus at the time of biopsy; therefore, neither neutrophils nor eosinophils were identified. Peripheral eosinophilia, which is present in 42% to 90% of cases of PSV,^9,17 can be a diagnostic clue.¹⁸ However, PE is associated with IBD,²⁴ which usually occurs with PSV, so the absence of peripheral eosinophilia in our patient may be explained by her lack of bowel disease.

Pathogenesis—The pathogenesis of PSV is unknown. A proposed etiology includes cross-reacting antigens in the bowel and skin secondary to IBD as well as an aberrant immune response to an unidentified factor.⁸ Pyostomatitis vegetans is considered by many to be the mucosal variant of pyodermatitis vegetans,^9,15,19 a neutrophilic dermatosis characterized by asymmetric, crusted, erythematous papulopustules that extend peripherally and coalesce to form large vegetating plaques. These lesions commonly manifest in the axillary folds, groin, and scalp and can involve the face, trunk, and distal extremities.^9,18 Infection has been suggested as a cause of PSV, though cultures for pathogenic bacteria, viruses, and fungi consistently show only normal flora.²⁰ Zinc deficiency attributed to malabsorption from CD was reported in an adult with PSV.²¹ The PSV resolved after 6 weeks of zinc supplementation.

Differential Diagnosis—The main entity in the clinical differential diagnosis for PSV is PVH, which is considered a variant of pemphigus vulgaris. Pemphigus vegetans of Hallopeau presents with pustules and progresses to hyperpigmented vegetative plaques with peripheral hypertrophic granulation tissue.²² The clinical and histological presentation of PVH can be similar to PSV; in PVH, however, DIF demonstrates intercellular IgG and C3 due to circulating IgG autoantibodies specific for desmoglein 3, a cell adhesion molecule.^22-24 In PSV, DIF typically is negative for IgG, IgA, and C3.⁸ Immunohistochemical findings of PSV may overlap with IgA pemphigus, IgG/IgA pemphigus, and IgG pemphigus, which has sparked debate if PSV is an autoimmune blistering disorder or a secondary finding of epithelial injury.^9,18,24

Pyostomatitis vegetans is most prevalent in patients aged 20 to 59 years²⁵ but can occur at any age.^8,19 Overall, extraintestinal symptoms, including mucocutaneous findings, are common in pediatric patients—in 30% to 71% of children with CD and 21% to 22% of children with ulcerative colitis²⁶—and can predate onset of GI symptoms in 6% of pediatric patients.²⁷

Oral disease is common in CD; manifestations are listed in the Table.^28,29 In a prospective study of 48 children with CD, 42% (20/48) had oral manifestations identified at diagnosis²⁸; in a similar study of 25 children, researchers noted that 48% (12/25) had disease-specific oral lesions.²⁹ None of these children recognized the oral findings prior to the onset of systemic symptoms.²⁸ Pyostomatitis vegetans was the least common oral manifestation, reported in 1 of 73 patients in the 2 studies combined.^28,29

Two recent articles that looked at PSV in pediatric and adolescent populations identified only 9 patients with PSV.^24,30 Only 2 patients (siblings) had documented onset of PSV before 12 years of age,³¹ which suggests an underlying genetic predisposition in young children.

It has been reported that active or subclinical (ie, asymptomatic with positive endoscopic findings) IBD in adults precedes onset of PSV, which may be considered a sign of relapse.^9,30 However, PSV is incredibly rare in children and adolescents and can be an early finding of IBD in children.^16,31,32

Our patient has not developed GI involvement since her initial presentation 5 years prior, though another pediatric patient developed symptomatic CD 9 years after onset of OFG.⁵ A retrospective review of pediatric OFG without CD met criteria for CD at a median of 3.1 years (range, 0.4–6.9 years).³³ Regrettably, the early presence of PSV has been associated with future progression to CD and a complicated disease course.^12,34

Management—Pyoderma stomatitis vegetans is treated with management of underlying IBD,⁸ with scarce literature available regarding pediatric patients. Oral lesions have been treated with antiseptics and topical corticosteroids, though these have limited benefit.⁸ In an adult with IBD, topical tacrolimus initially cleared PSV; however, lesions recurred until mesalamine was initiated.³⁵ Systemic steroids were effective in a 16-year-old patient with CD and PSV,¹² but recurrence is common after corticosteroids are stopped.³⁴

Some patients benefit from steroid-sparing medications, such as dapsone, azathioprine, sulfamethoxypyridazine, methotrexate, mycophenolate mofetil, and tumor necrosis factor α inhibitors such as infliximab and adalimumab.^{8,9,15,23,34,36} A 12-year-old patient with pyodermatitis–PSV without intestinal disease was treated with prednisone, dapsone, and azathioprine with improvement but not complete resolution of oral erosions after 18 weeks of treatment.³² A 15-year-old patient with CD and pyodermatitis–PSV did not show improvement on prednisone, dapsone, and azathioprine but rapidly responded to infliximab.²³ Infliximab led to complete clearance of oral lesions in an adult with severe fistulizing CD who developed PSV.¹¹ However, 2 adolescent patients with CD developed PSV while on adalimumab,^6,34 though 1 did improve after increasing adalimumab from once to twice weekly.⁶

Conclusion

The case described here—PSV in a prepubertal 7-year-old with multiple cutaneous findings suggestive of CD, including OFG, perianal and vulvar edema with biopsy-proven noncaseating granulomas, anal skin tags, and an elevated calprotectin level, noted during a cutaneous flare without clinical or endoscopically identified underlying bowel involvement—is an extremely rare presentation. Literature regarding management of PSV primarily is found in the form of case reports and focuses on treating underlying IBD. In patients with intestinal disease, treatment with biologic therapy appears most effective.^6,23

ADDENDUM

Interestingly, 3 years after the patient’s original presentation to our clinic, chromosomal sequencing analysis to assess for copy number variants and whole exome gene sequencing identified a variant of unknown significance in the heat shock protein family A member 1-like gene, HSPA1L, which has an unknown mode of inheritance, but the literature suggests that both truncating and missense variants could be associated with individuals with ulcerative colitis, CD, and IBD.^37,38 Although we cannot use this information to render a molecular diagnosis, it is highly suspicious that this is the cause of her clinical findings. Additionally, the patient currently is aged 10 years with unchanged cutaneous findings and has not developed gastrointestinal findings of IBD.

New COVID-19 cases in children jumped by 66% during the first 2 weeks of December after an 8-week steady period lasting through October and November, according to the American Academy of Pediatrics and the Children’s Hospital Association.

New cases reached close to 48,000 for the most recent reporting week, Dec. 9-15, after rising to just over 41,000 the previous week and totaling less than 29,000 for the week of Nov. 25 to Dec. 1. That increase of almost 19,000 cases is the largest over a 2-week period since late July, the AAP and CHA said in their weekly COVID report based on data collected from state and territorial health department websites.

[This publication has been following the AAP/CHA report since the summer of 2020 and continues to share the data for the sake of consistency, but it must be noted that a number of states are no longer updating their public COVID dashboards. As a result, there is now a considerable discrepancy between the AAP/CHA weekly figures and those reported by the Centers for Disease Control and Prevention, which has no such limitations on state data.]

The situation involving new cases over the last 2 weeks is quite different from the CDC’s perspective. The agency does not publish a weekly count, instead offering cumulative cases, which stood at almost 16.1 million as of Dec. 14. Calculating a 2-week total puts the new-case count for Dec. 1-14 at 113,572 among children aged 0-17 years. That is higher than the AAP/CHA count (88,629) for roughly the same period, but it is actually lower than the CDC’s figure (161,832) for the last 2 weeks of November.

The CDC data, in other words, suggest that new cases have gone down in the last 2 weeks, while the AAP and CHA, with their somewhat limited perspective, announced that new cases have gone up.

One COVID-related measure from the CDC that is not contradicted by other sources is hospitalization rates, which had climbed from 0.16 new admissions in children aged 0-17 years with confirmed COVID per 100,000 population on Oct. 22 to 0.29 per 100,000 on Dec. 9. Visits to the emergency department with diagnosed COVID, meanwhile, have been fairly steady so far through December in children, according to the CDC.

New COVID-19 cases in children jumped by 66% during the first 2 weeks of December after an 8-week steady period lasting through October and November, according to the American Academy of Pediatrics and the Children’s Hospital Association.

New cases reached close to 48,000 for the most recent reporting week, Dec. 9-15, after rising to just over 41,000 the previous week and totaling less than 29,000 for the week of Nov. 25 to Dec. 1. That increase of almost 19,000 cases is the largest over a 2-week period since late July, the AAP and CHA said in their weekly COVID report based on data collected from state and territorial health department websites.

[This publication has been following the AAP/CHA report since the summer of 2020 and continues to share the data for the sake of consistency, but it must be noted that a number of states are no longer updating their public COVID dashboards. As a result, there is now a considerable discrepancy between the AAP/CHA weekly figures and those reported by the Centers for Disease Control and Prevention, which has no such limitations on state data.]

The situation involving new cases over the last 2 weeks is quite different from the CDC’s perspective. The agency does not publish a weekly count, instead offering cumulative cases, which stood at almost 16.1 million as of Dec. 14. Calculating a 2-week total puts the new-case count for Dec. 1-14 at 113,572 among children aged 0-17 years. That is higher than the AAP/CHA count (88,629) for roughly the same period, but it is actually lower than the CDC’s figure (161,832) for the last 2 weeks of November.

The CDC data, in other words, suggest that new cases have gone down in the last 2 weeks, while the AAP and CHA, with their somewhat limited perspective, announced that new cases have gone up.

One COVID-related measure from the CDC that is not contradicted by other sources is hospitalization rates, which had climbed from 0.16 new admissions in children aged 0-17 years with confirmed COVID per 100,000 population on Oct. 22 to 0.29 per 100,000 on Dec. 9. Visits to the emergency department with diagnosed COVID, meanwhile, have been fairly steady so far through December in children, according to the CDC.

New COVID-19 cases in children jumped by 66% during the first 2 weeks of December after an 8-week steady period lasting through October and November, according to the American Academy of Pediatrics and the Children’s Hospital Association.

New cases reached close to 48,000 for the most recent reporting week, Dec. 9-15, after rising to just over 41,000 the previous week and totaling less than 29,000 for the week of Nov. 25 to Dec. 1. That increase of almost 19,000 cases is the largest over a 2-week period since late July, the AAP and CHA said in their weekly COVID report based on data collected from state and territorial health department websites.

[This publication has been following the AAP/CHA report since the summer of 2020 and continues to share the data for the sake of consistency, but it must be noted that a number of states are no longer updating their public COVID dashboards. As a result, there is now a considerable discrepancy between the AAP/CHA weekly figures and those reported by the Centers for Disease Control and Prevention, which has no such limitations on state data.]

The situation involving new cases over the last 2 weeks is quite different from the CDC’s perspective. The agency does not publish a weekly count, instead offering cumulative cases, which stood at almost 16.1 million as of Dec. 14. Calculating a 2-week total puts the new-case count for Dec. 1-14 at 113,572 among children aged 0-17 years. That is higher than the AAP/CHA count (88,629) for roughly the same period, but it is actually lower than the CDC’s figure (161,832) for the last 2 weeks of November.

The CDC data, in other words, suggest that new cases have gone down in the last 2 weeks, while the AAP and CHA, with their somewhat limited perspective, announced that new cases have gone up.

One COVID-related measure from the CDC that is not contradicted by other sources is hospitalization rates, which had climbed from 0.16 new admissions in children aged 0-17 years with confirmed COVID per 100,000 population on Oct. 22 to 0.29 per 100,000 on Dec. 9. Visits to the emergency department with diagnosed COVID, meanwhile, have been fairly steady so far through December in children, according to the CDC.

An investigational vaccine against respiratory syncytial virus (RSV) in pregnant women has been shown to help protect infants against severe disease, according to the vaccine’s manufacturer.

Pfizer recently announced that in the course of a randomized, double-blind, placebo-controlled phase 3 study, the vaccine RSVpreF had an almost 82% efficacy against severe RSV infection in infants from birth through the first 90 days of life, according to a company press release.

The vaccine also had a 69% efficacy against severe disease through the first 6 months of life. A total of 7,400 women had received a single dose of 120 mcg RSVpreF in the late second or third trimester of their pregnancy. There were no signs of safety issues for the mothers or infants.

Due to the good results, the enrollment in the study was halted on the recommendation of the study’s Data Monitoring Committee after achieving a primary endpoint. The company plans to apply for marketing authorization to the U.S. Food and Drug Administration by the end of 2022 and to other regulatory agencies in 2023.

“The directness of the strategy, to vaccinate expectant mothers during pregnancy so that their newborn is then later protected, is new and a very interesting approach,” commented Prof. Ortwin Adams, MD, head of virologic diagnostics at the Institute for Virology of the University Hospital of Düsseldorf (Germany) to the Science Media Centre (SMC).

In terms of the RSV vaccination strategy presented, “the unborn child has taken center stage from the outset.” Because the vaccination route is the placental transfer of antibodies from mother to child (“passive immunity”), “... the medical points of contact for this vaccination will be the gynecologists, not the pediatricians,” Dr. Adams said.

“This concept imitates the natural process, since the mother normally passes immune defenses she acquired through infections to the child via the umbilical cord and her breast milk before and after birth. This procedure is long-proven and practiced worldwide, especially in nonindustrialized countries, for a variety of diseases, including tetanus, whooping cough (pertussis), and viral flu (influenza),” explained Markus Rose, MD, PhD, head of Pediatric Pulmonology at the Olgahospital, Stuttgart, Germany.

The development of an RSV vaccine had ground to a halt for many decades: A tragedy in the 1960s set the whole field of research back. Using the model of the first polio vaccine, scientists had manufactured an experimental vaccine with inactivated viruses. However, tests showed that the vaccine did not protect the children vaccinated, but it actually infected them with RSV, they then fell ill, and two children died. Today, potential RSV vaccines are first tested on adults and not on children.
 

Few treatment options

RSV causes seasonal epidemics, can lead to bronchiolitis and pneumonia in infants, and is one of the main causes of hospital stays in young children. Monoclonal antibodies are currently the only preventive option, since there is still no vaccine. Usually, 60%-70% of infants and nearly all children younger than 2 years are infected with RSV, but the virus can also trigger pneumonia in adults.

“RSV infections constitute a major public health challenge: It is the most dangerous respiratory virus for young infants, it is also a threat to the chronically ill and immunocompromised of all ages, and [it] is the second most common cause of death worldwide (after malaria) in young children,” stated Dr. Rose.

Recently, pandemic-related measures (face masks, more intense disinfection) meant that the “normal” RSV infections in healthy adults, which usually progress like a mild cold, were prevented, and mothers were unable to pass on as much RSV immune defense to their children. “This was presumably responsible in part for the massive wave of RSV infections in fall and winter of 2021/22,” explained Dr. Rose.

Thomas Mertens, MD, PhD, chair of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO) and former director of the Institute for Virology at Ulm University Hospital, Germany, also noted: “It would be an important and potentially achievable goal to significantly reduce the incidence rate of hospitalizations. In this respect, RSV poses a significant problem for young children, their parents, and the burden on pediatric clinics.”
 

Final evaluation pending

“I am definitely finding the data interesting, but the original data are needed,” Dr. Mertens said. Once the data are published at a conference or published in a peer-reviewed journal, physicians will be able to better judge the data for themselves, he said.

Dr. Rose characterized the new vaccine as “novel,” including in terms of its composition. Earlier RSV vaccines used the so-called postfusion F protein as their starting point. But it has become known in the meantime that the key to immunogenicity is the continued prefusion state of the apical epitope: Prefusion F-specific memory B cells in adults naturally infected with RSV produce potent neutralizing antibodies.

The new vaccine is bivalent and protects against both RSV A and RSV B.

To date, RSV vaccination directly in young infants have had only had a weak efficacy and were sometimes poorly tolerated. The vaccine presented here is expected to be tested in young adults first, then in school children, then young children.

Through successful vaccination of the entire population, the transfer of RS viruses to young children could be prevented. “To what extent this, or any other RSV vaccine still to be developed on the same basis, will also be effective and well tolerated in young infants is still difficult to assess,” said Dr. Rose.

Dr. Mertens emphasized that all of the study data now needs to be seen as quickly as possible: “This is also a general requirement for transparency from the pharmaceutical companies, which is also rightly criticized.”

This article was originally published in Medscape’s German edition and a version appeared on Medscape.com.

An investigational vaccine against respiratory syncytial virus (RSV) in pregnant women has been shown to help protect infants against severe disease, according to the vaccine’s manufacturer.

Pfizer recently announced that in the course of a randomized, double-blind, placebo-controlled phase 3 study, the vaccine RSVpreF had an almost 82% efficacy against severe RSV infection in infants from birth through the first 90 days of life, according to a company press release.

The vaccine also had a 69% efficacy against severe disease through the first 6 months of life. A total of 7,400 women had received a single dose of 120 mcg RSVpreF in the late second or third trimester of their pregnancy. There were no signs of safety issues for the mothers or infants.

Due to the good results, the enrollment in the study was halted on the recommendation of the study’s Data Monitoring Committee after achieving a primary endpoint. The company plans to apply for marketing authorization to the U.S. Food and Drug Administration by the end of 2022 and to other regulatory agencies in 2023.

“The directness of the strategy, to vaccinate expectant mothers during pregnancy so that their newborn is then later protected, is new and a very interesting approach,” commented Prof. Ortwin Adams, MD, head of virologic diagnostics at the Institute for Virology of the University Hospital of Düsseldorf (Germany) to the Science Media Centre (SMC).

In terms of the RSV vaccination strategy presented, “the unborn child has taken center stage from the outset.” Because the vaccination route is the placental transfer of antibodies from mother to child (“passive immunity”), “... the medical points of contact for this vaccination will be the gynecologists, not the pediatricians,” Dr. Adams said.

“This concept imitates the natural process, since the mother normally passes immune defenses she acquired through infections to the child via the umbilical cord and her breast milk before and after birth. This procedure is long-proven and practiced worldwide, especially in nonindustrialized countries, for a variety of diseases, including tetanus, whooping cough (pertussis), and viral flu (influenza),” explained Markus Rose, MD, PhD, head of Pediatric Pulmonology at the Olgahospital, Stuttgart, Germany.

The development of an RSV vaccine had ground to a halt for many decades: A tragedy in the 1960s set the whole field of research back. Using the model of the first polio vaccine, scientists had manufactured an experimental vaccine with inactivated viruses. However, tests showed that the vaccine did not protect the children vaccinated, but it actually infected them with RSV, they then fell ill, and two children died. Today, potential RSV vaccines are first tested on adults and not on children.
 

Few treatment options

RSV causes seasonal epidemics, can lead to bronchiolitis and pneumonia in infants, and is one of the main causes of hospital stays in young children. Monoclonal antibodies are currently the only preventive option, since there is still no vaccine. Usually, 60%-70% of infants and nearly all children younger than 2 years are infected with RSV, but the virus can also trigger pneumonia in adults.

“RSV infections constitute a major public health challenge: It is the most dangerous respiratory virus for young infants, it is also a threat to the chronically ill and immunocompromised of all ages, and [it] is the second most common cause of death worldwide (after malaria) in young children,” stated Dr. Rose.

Recently, pandemic-related measures (face masks, more intense disinfection) meant that the “normal” RSV infections in healthy adults, which usually progress like a mild cold, were prevented, and mothers were unable to pass on as much RSV immune defense to their children. “This was presumably responsible in part for the massive wave of RSV infections in fall and winter of 2021/22,” explained Dr. Rose.

Thomas Mertens, MD, PhD, chair of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO) and former director of the Institute for Virology at Ulm University Hospital, Germany, also noted: “It would be an important and potentially achievable goal to significantly reduce the incidence rate of hospitalizations. In this respect, RSV poses a significant problem for young children, their parents, and the burden on pediatric clinics.”
 

Final evaluation pending

“I am definitely finding the data interesting, but the original data are needed,” Dr. Mertens said. Once the data are published at a conference or published in a peer-reviewed journal, physicians will be able to better judge the data for themselves, he said.

Dr. Rose characterized the new vaccine as “novel,” including in terms of its composition. Earlier RSV vaccines used the so-called postfusion F protein as their starting point. But it has become known in the meantime that the key to immunogenicity is the continued prefusion state of the apical epitope: Prefusion F-specific memory B cells in adults naturally infected with RSV produce potent neutralizing antibodies.

The new vaccine is bivalent and protects against both RSV A and RSV B.

To date, RSV vaccination directly in young infants have had only had a weak efficacy and were sometimes poorly tolerated. The vaccine presented here is expected to be tested in young adults first, then in school children, then young children.

Through successful vaccination of the entire population, the transfer of RS viruses to young children could be prevented. “To what extent this, or any other RSV vaccine still to be developed on the same basis, will also be effective and well tolerated in young infants is still difficult to assess,” said Dr. Rose.

Dr. Mertens emphasized that all of the study data now needs to be seen as quickly as possible: “This is also a general requirement for transparency from the pharmaceutical companies, which is also rightly criticized.”

This article was originally published in Medscape’s German edition and a version appeared on Medscape.com.

An investigational vaccine against respiratory syncytial virus (RSV) in pregnant women has been shown to help protect infants against severe disease, according to the vaccine’s manufacturer.

Pfizer recently announced that in the course of a randomized, double-blind, placebo-controlled phase 3 study, the vaccine RSVpreF had an almost 82% efficacy against severe RSV infection in infants from birth through the first 90 days of life, according to a company press release.

The vaccine also had a 69% efficacy against severe disease through the first 6 months of life. A total of 7,400 women had received a single dose of 120 mcg RSVpreF in the late second or third trimester of their pregnancy. There were no signs of safety issues for the mothers or infants.

Due to the good results, the enrollment in the study was halted on the recommendation of the study’s Data Monitoring Committee after achieving a primary endpoint. The company plans to apply for marketing authorization to the U.S. Food and Drug Administration by the end of 2022 and to other regulatory agencies in 2023.

“The directness of the strategy, to vaccinate expectant mothers during pregnancy so that their newborn is then later protected, is new and a very interesting approach,” commented Prof. Ortwin Adams, MD, head of virologic diagnostics at the Institute for Virology of the University Hospital of Düsseldorf (Germany) to the Science Media Centre (SMC).

In terms of the RSV vaccination strategy presented, “the unborn child has taken center stage from the outset.” Because the vaccination route is the placental transfer of antibodies from mother to child (“passive immunity”), “... the medical points of contact for this vaccination will be the gynecologists, not the pediatricians,” Dr. Adams said.

“This concept imitates the natural process, since the mother normally passes immune defenses she acquired through infections to the child via the umbilical cord and her breast milk before and after birth. This procedure is long-proven and practiced worldwide, especially in nonindustrialized countries, for a variety of diseases, including tetanus, whooping cough (pertussis), and viral flu (influenza),” explained Markus Rose, MD, PhD, head of Pediatric Pulmonology at the Olgahospital, Stuttgart, Germany.

The development of an RSV vaccine had ground to a halt for many decades: A tragedy in the 1960s set the whole field of research back. Using the model of the first polio vaccine, scientists had manufactured an experimental vaccine with inactivated viruses. However, tests showed that the vaccine did not protect the children vaccinated, but it actually infected them with RSV, they then fell ill, and two children died. Today, potential RSV vaccines are first tested on adults and not on children.
 

Few treatment options

RSV causes seasonal epidemics, can lead to bronchiolitis and pneumonia in infants, and is one of the main causes of hospital stays in young children. Monoclonal antibodies are currently the only preventive option, since there is still no vaccine. Usually, 60%-70% of infants and nearly all children younger than 2 years are infected with RSV, but the virus can also trigger pneumonia in adults.

“RSV infections constitute a major public health challenge: It is the most dangerous respiratory virus for young infants, it is also a threat to the chronically ill and immunocompromised of all ages, and [it] is the second most common cause of death worldwide (after malaria) in young children,” stated Dr. Rose.

Recently, pandemic-related measures (face masks, more intense disinfection) meant that the “normal” RSV infections in healthy adults, which usually progress like a mild cold, were prevented, and mothers were unable to pass on as much RSV immune defense to their children. “This was presumably responsible in part for the massive wave of RSV infections in fall and winter of 2021/22,” explained Dr. Rose.

Thomas Mertens, MD, PhD, chair of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO) and former director of the Institute for Virology at Ulm University Hospital, Germany, also noted: “It would be an important and potentially achievable goal to significantly reduce the incidence rate of hospitalizations. In this respect, RSV poses a significant problem for young children, their parents, and the burden on pediatric clinics.”
 

Final evaluation pending

“I am definitely finding the data interesting, but the original data are needed,” Dr. Mertens said. Once the data are published at a conference or published in a peer-reviewed journal, physicians will be able to better judge the data for themselves, he said.

Dr. Rose characterized the new vaccine as “novel,” including in terms of its composition. Earlier RSV vaccines used the so-called postfusion F protein as their starting point. But it has become known in the meantime that the key to immunogenicity is the continued prefusion state of the apical epitope: Prefusion F-specific memory B cells in adults naturally infected with RSV produce potent neutralizing antibodies.

The new vaccine is bivalent and protects against both RSV A and RSV B.

To date, RSV vaccination directly in young infants have had only had a weak efficacy and were sometimes poorly tolerated. The vaccine presented here is expected to be tested in young adults first, then in school children, then young children.

Through successful vaccination of the entire population, the transfer of RS viruses to young children could be prevented. “To what extent this, or any other RSV vaccine still to be developed on the same basis, will also be effective and well tolerated in young infants is still difficult to assess,” said Dr. Rose.

Dr. Mertens emphasized that all of the study data now needs to be seen as quickly as possible: “This is also a general requirement for transparency from the pharmaceutical companies, which is also rightly criticized.”

This article was originally published in Medscape’s German edition and a version appeared on Medscape.com.

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

A version of this article first appeared on Medscape.com.

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

A version of this article first appeared on Medscape.com.

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

A version of this article first appeared on Medscape.com.

Key clinical point: Chronic exposure to heavy metals was not associated with an increased risk for breast cancer (BC) among never smokers in the general population.

Major finding: Serum levels of cobalt were inversely associated with the risk for BC (odds ratio 0.33; P = .033), with no association being observed between the risk for BC and exposure to other heavy metals.

Study details: Findings are from a prospective cohort study including 150 women with BC and without a smoking history and 150 matched control women without BC and smoking history.

Disclosures: This study was supported by the Tuscany Region, “Bando Ricerca Salute 2018.” The authors declared no conflicts of interest.

Source: Caini S et al. Serum heavy metals and breast cancer risk: A case-control study nested in the Florence cohort of the EPIC (European Prospective Investigation into Cancer and nutrition) study. Sci Total Environ. 2022;160568 (Dec 1). Doi: 10.1016/j.scitotenv.2022.160568

Key clinical point: Chronic exposure to heavy metals was not associated with an increased risk for breast cancer (BC) among never smokers in the general population.

Major finding: Serum levels of cobalt were inversely associated with the risk for BC (odds ratio 0.33; P = .033), with no association being observed between the risk for BC and exposure to other heavy metals.

Study details: Findings are from a prospective cohort study including 150 women with BC and without a smoking history and 150 matched control women without BC and smoking history.

Disclosures: This study was supported by the Tuscany Region, “Bando Ricerca Salute 2018.” The authors declared no conflicts of interest.

Source: Caini S et al. Serum heavy metals and breast cancer risk: A case-control study nested in the Florence cohort of the EPIC (European Prospective Investigation into Cancer and nutrition) study. Sci Total Environ. 2022;160568 (Dec 1). Doi: 10.1016/j.scitotenv.2022.160568

Key clinical point: Chronic exposure to heavy metals was not associated with an increased risk for breast cancer (BC) among never smokers in the general population.

Major finding: Serum levels of cobalt were inversely associated with the risk for BC (odds ratio 0.33; P = .033), with no association being observed between the risk for BC and exposure to other heavy metals.

Study details: Findings are from a prospective cohort study including 150 women with BC and without a smoking history and 150 matched control women without BC and smoking history.

Disclosures: This study was supported by the Tuscany Region, “Bando Ricerca Salute 2018.” The authors declared no conflicts of interest.

Source: Caini S et al. Serum heavy metals and breast cancer risk: A case-control study nested in the Florence cohort of the EPIC (European Prospective Investigation into Cancer and nutrition) study. Sci Total Environ. 2022;160568 (Dec 1). Doi: 10.1016/j.scitotenv.2022.160568

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC) who had an isolated brain metastasis as their first metastatic event reported worse survival outcomes than those with concurrent progressive or stable/responding extracranial disease (ECD).

Major finding: Patients with isolated brain relapse or no evidence of ECD (28.4 months; P = .0028) reported worse overall survival from metastatic diagnosis to death than patients with concurrent progressive ECD (48.8 months) or stable/responding disease (71.5 months).

Study details: Findings are from a retrospective analysis including 126 patients with HER2+ BC, brain metastasis, and known ECD status.

Disclosures: This study was funded by the Duke University Department of Medicine and other sources. Some authors declared receiving royalties or serving as consultants at various sources.

Source: Noteware L et al. Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer. Breast Cancer Res Treat. 2022 (Nov 20). Doi: 10.1007/s10549-022-06799-7

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC) who had an isolated brain metastasis as their first metastatic event reported worse survival outcomes than those with concurrent progressive or stable/responding extracranial disease (ECD).

Major finding: Patients with isolated brain relapse or no evidence of ECD (28.4 months; P = .0028) reported worse overall survival from metastatic diagnosis to death than patients with concurrent progressive ECD (48.8 months) or stable/responding disease (71.5 months).

Study details: Findings are from a retrospective analysis including 126 patients with HER2+ BC, brain metastasis, and known ECD status.

Disclosures: This study was funded by the Duke University Department of Medicine and other sources. Some authors declared receiving royalties or serving as consultants at various sources.

Source: Noteware L et al. Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer. Breast Cancer Res Treat. 2022 (Nov 20). Doi: 10.1007/s10549-022-06799-7

Key clinical point: Patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC) who had an isolated brain metastasis as their first metastatic event reported worse survival outcomes than those with concurrent progressive or stable/responding extracranial disease (ECD).

Major finding: Patients with isolated brain relapse or no evidence of ECD (28.4 months; P = .0028) reported worse overall survival from metastatic diagnosis to death than patients with concurrent progressive ECD (48.8 months) or stable/responding disease (71.5 months).

Study details: Findings are from a retrospective analysis including 126 patients with HER2+ BC, brain metastasis, and known ECD status.

Disclosures: This study was funded by the Duke University Department of Medicine and other sources. Some authors declared receiving royalties or serving as consultants at various sources.

Source: Noteware L et al. Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer. Breast Cancer Res Treat. 2022 (Nov 20). Doi: 10.1007/s10549-022-06799-7

Key clinical point: Breast conserving surgery (BCS) plus radiotherapy (RT) demonstrated superior survival outcomes compared to mastectomy in patients with ductal carcinoma in situ with microinvasion (DCIS-MI).

Major finding: Overall survival (hazard ratio [HR] 0.676; P < .001) and breast cancer-specific survival (HR 0.565; P = .017) were significantly improved in the BCS+RT vs mastectomy group.

Study details: This study analyzed the data of 5432 patients with DCIS-MI from the Surveillance, Epidemiology, and End Results (SEER) database, of which 52.17% of patients had received BCS+RT.

Disclosures: This study did not report a source of funding. The authors declared no conflicts of interest.

Source: Xia LY et al. Survival outcomes after breast-conserving surgery plus radiotherapy compared with mastectomy in breast ductal carcinoma in situ with microinvasion. Sci Rep. 2022;12:20132 (Nov 22). Doi: 10.1038/s41598-022-24630-7

Key clinical point: Breast conserving surgery (BCS) plus radiotherapy (RT) demonstrated superior survival outcomes compared to mastectomy in patients with ductal carcinoma in situ with microinvasion (DCIS-MI).

Major finding: Overall survival (hazard ratio [HR] 0.676; P < .001) and breast cancer-specific survival (HR 0.565; P = .017) were significantly improved in the BCS+RT vs mastectomy group.

Study details: This study analyzed the data of 5432 patients with DCIS-MI from the Surveillance, Epidemiology, and End Results (SEER) database, of which 52.17% of patients had received BCS+RT.

Disclosures: This study did not report a source of funding. The authors declared no conflicts of interest.

Source: Xia LY et al. Survival outcomes after breast-conserving surgery plus radiotherapy compared with mastectomy in breast ductal carcinoma in situ with microinvasion. Sci Rep. 2022;12:20132 (Nov 22). Doi: 10.1038/s41598-022-24630-7

Key clinical point: Breast conserving surgery (BCS) plus radiotherapy (RT) demonstrated superior survival outcomes compared to mastectomy in patients with ductal carcinoma in situ with microinvasion (DCIS-MI).

Major finding: Overall survival (hazard ratio [HR] 0.676; P < .001) and breast cancer-specific survival (HR 0.565; P = .017) were significantly improved in the BCS+RT vs mastectomy group.

Study details: This study analyzed the data of 5432 patients with DCIS-MI from the Surveillance, Epidemiology, and End Results (SEER) database, of which 52.17% of patients had received BCS+RT.

Disclosures: This study did not report a source of funding. The authors declared no conflicts of interest.

Source: Xia LY et al. Survival outcomes after breast-conserving surgery plus radiotherapy compared with mastectomy in breast ductal carcinoma in situ with microinvasion. Sci Rep. 2022;12:20132 (Nov 22). Doi: 10.1038/s41598-022-24630-7

Key clinical point: Palbociclib plus endocrine therapy (ET) improved progression-free survival (PFS) across all subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (BC).

Major finding: Median PFS was longer in patients receiving palbociclib+letrozole vs placebo+letrozole (hazard ratio [HR] 0.56; 95% CI 0.46-0.69) or palbociclib+fulvestrant vs placebo+fulvestrant (HR 0.50; 95% CI 0.40-0.62), with similar outcomes observed in subgroups of patients reporting a disease-free interval of ≤12 months, visceral disease, or ET resistance.

Study details: Findings are from a post hoc analysis of two phase 3 trials including women with HR+/HER2− advanced BC who were randomly assigned to receive letrozole with palbociclib or placebo (n = 666; PALOMA-2) or fulvestrant with palbociclib or placebo (n = 521; PALOMA-3).

Disclosures: This study was funded by Pfizer Inc. Four authors declared being employees and stockholders of Pfizer, and the other authors reported ties with several sources, including Pfizer.

Source: Rugo HS et al. Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3. Breast. 2022;66:324-331 (Nov 15). Doi: 10.1016/j.breast.2022.11.005

Key clinical point: Palbociclib plus endocrine therapy (ET) improved progression-free survival (PFS) across all subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (BC).

Major finding: Median PFS was longer in patients receiving palbociclib+letrozole vs placebo+letrozole (hazard ratio [HR] 0.56; 95% CI 0.46-0.69) or palbociclib+fulvestrant vs placebo+fulvestrant (HR 0.50; 95% CI 0.40-0.62), with similar outcomes observed in subgroups of patients reporting a disease-free interval of ≤12 months, visceral disease, or ET resistance.

Study details: Findings are from a post hoc analysis of two phase 3 trials including women with HR+/HER2− advanced BC who were randomly assigned to receive letrozole with palbociclib or placebo (n = 666; PALOMA-2) or fulvestrant with palbociclib or placebo (n = 521; PALOMA-3).

Disclosures: This study was funded by Pfizer Inc. Four authors declared being employees and stockholders of Pfizer, and the other authors reported ties with several sources, including Pfizer.

Source: Rugo HS et al. Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3. Breast. 2022;66:324-331 (Nov 15). Doi: 10.1016/j.breast.2022.11.005

Key clinical point: Palbociclib plus endocrine therapy (ET) improved progression-free survival (PFS) across all subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (BC).

Major finding: Median PFS was longer in patients receiving palbociclib+letrozole vs placebo+letrozole (hazard ratio [HR] 0.56; 95% CI 0.46-0.69) or palbociclib+fulvestrant vs placebo+fulvestrant (HR 0.50; 95% CI 0.40-0.62), with similar outcomes observed in subgroups of patients reporting a disease-free interval of ≤12 months, visceral disease, or ET resistance.

Study details: Findings are from a post hoc analysis of two phase 3 trials including women with HR+/HER2− advanced BC who were randomly assigned to receive letrozole with palbociclib or placebo (n = 666; PALOMA-2) or fulvestrant with palbociclib or placebo (n = 521; PALOMA-3).

Disclosures: This study was funded by Pfizer Inc. Four authors declared being employees and stockholders of Pfizer, and the other authors reported ties with several sources, including Pfizer.

Source: Rugo HS et al. Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3. Breast. 2022;66:324-331 (Nov 15). Doi: 10.1016/j.breast.2022.11.005

Key clinical point: Q-122, a novel nonhormonal oral treatment, significantly improved vasomotor symptoms and was well-tolerated in women with breast cancer (BC) who received oral adjuvant endocrine therapy (ET).

Major finding: After 28 days, Q-122 led to a significantly higher improvement in the mean Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats than placebo (−39% vs −26%; P = .018). Q-122 was well tolerated, and most adverse events were mild-to-moderate in severity.

Study details: Findings are from a multicenter, phase 2 study including 131 women with BC who were receiving oral adjuvant ET and were randomly assigned to receive 100 mg oral Q-122 or identical placebo, twice daily for 28 days.

Disclosures: This study was funded by QUE Oncology. The authors declared delivering lectures or receiving honoraria, grant funding, or personal fees from several sources. Two authors declared being current or former employees of QUE Oncology.

Source: Vrselja A et al. Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2022;400(10364):1704-1711 (Nov 12). Doi: 10.1016/S0140-6736(22)01977-8

Key clinical point: Q-122, a novel nonhormonal oral treatment, significantly improved vasomotor symptoms and was well-tolerated in women with breast cancer (BC) who received oral adjuvant endocrine therapy (ET).

Major finding: After 28 days, Q-122 led to a significantly higher improvement in the mean Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats than placebo (−39% vs −26%; P = .018). Q-122 was well tolerated, and most adverse events were mild-to-moderate in severity.

Study details: Findings are from a multicenter, phase 2 study including 131 women with BC who were receiving oral adjuvant ET and were randomly assigned to receive 100 mg oral Q-122 or identical placebo, twice daily for 28 days.

Disclosures: This study was funded by QUE Oncology. The authors declared delivering lectures or receiving honoraria, grant funding, or personal fees from several sources. Two authors declared being current or former employees of QUE Oncology.

Source: Vrselja A et al. Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2022;400(10364):1704-1711 (Nov 12). Doi: 10.1016/S0140-6736(22)01977-8

Key clinical point: Q-122, a novel nonhormonal oral treatment, significantly improved vasomotor symptoms and was well-tolerated in women with breast cancer (BC) who received oral adjuvant endocrine therapy (ET).

Major finding: After 28 days, Q-122 led to a significantly higher improvement in the mean Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats than placebo (−39% vs −26%; P = .018). Q-122 was well tolerated, and most adverse events were mild-to-moderate in severity.

Study details: Findings are from a multicenter, phase 2 study including 131 women with BC who were receiving oral adjuvant ET and were randomly assigned to receive 100 mg oral Q-122 or identical placebo, twice daily for 28 days.

Disclosures: This study was funded by QUE Oncology. The authors declared delivering lectures or receiving honoraria, grant funding, or personal fees from several sources. Two authors declared being current or former employees of QUE Oncology.

Source: Vrselja A et al. Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2022;400(10364):1704-1711 (Nov 12). Doi: 10.1016/S0140-6736(22)01977-8