Improvement in Atopic Dermatitis and Recurrent Infection With Dupilumab in Children With Distinct Genetic Types of Hyper‐IgE Syndrome: A Case Series and Literature Review

ABSTRACT

Hyperimmunoglobulin E syndrome (HIES) is a group of rare genetic disorders characterized by severe atopic dermatitis and recurrent skin and pulmonary infections. The efficacy of dupilumab in pediatric patients with HIES‐associated severe atopic dermatitis is relatively understudied. Here, we present a series of three children with HIES, two with AD‐HIES caused by STAT3 mutations, and one with AR‐HIES caused by biallelic mutations in ZNF341. In all cases, dupilumab treatment led to sustained clearance of severe atopic dermatitis over multiple years, as well as improvements in systemic symptoms of HIES.

1. Introduction

Hyper‐IgE syndrome (HIES) is a group of genetic disorders characterized by elevated IgE levels, severe atopic dermatitis, recurrent skin and sinopulmonary infections, and in certain distinct HIES variants, connective tissue, and bony abnormalities as well. The clinical manifestations and inheritance pattern of HIES is dependent on genotype. HIES is divided into autosomal dominant HIES (AD‐HIES) and autosomal recessive HIES (AR‐HIES) according to different gene inheritance patterns [1]. AD‐HIES is caused by autosomal dominant‐negative variants of STAT3 [2, 3, 4, 5, 6], IL6ST [7, 8], and heterozygous mutations in CARD11 [9, 10], while AR‐HIES is causes by mutations in PGM3 [11], DOCK8 [12, 13, 14, 15], TKY2 [16], and ZNF341 [17]. The specific clinical manifestations and inheritance pattern of HIES vary depending on genotype, though one commonality is that the dermatologic manifestations typically present in the first few weeks of life. Specifically, patients present with infantile‐onset severe atopic dermatitis with a predilection for the face and scalp. Dupilumab is a human monoclonal IgG4 antibody directed against the interleukin‐4 alpha receptors, which inhibits both IL‐4 and IL‐13. Dupilumab is approved to treat severe atopic dermatitis in patients 6 months of age and older [4, 18, 19, 20, 21, 22]. Few cases have described the role of dupilumab in the context of AD‐ and AR‐HIES. To our knowledge, none have reported on the use of dupilumab in a child with AR‐HIES due to ZNF341 mutations. Furthermore, none have followed HIES patients that have been treated with dupilumab over multiple years. In this case series, we describe the successful use of dupilumab to treat atopic dermatitis and other non‐cutaneous symptoms in pediatric patients with HIES.

2. Case Reports

2.1. Patient 1

An 8‐year‐old male with AD‐HIES due to a STAT3 mutation presented for evaluation of his dermatitis. He had a history of chronic eczematous eruptions, lip fissuring, recurrent bacterial skin infections, pneumonia, and asthma. At the time of presentation, he had moderate eczematous plaques covering > 50% body surface area (BSA) and an investigator's global assessment (IGA) score of 3 [23]. Dupilumab was initiated at a 400 mg loading dose followed by 200 mg every 2 weeks. After 2 months, his skin improved with the atopic dermatitis covering 30% BSA and IGA score of 2. After 3 years of dupilumab treatment, he has had a durable response with no adverse effects and no additional cutaneous infections. At his most recent appointment, his BSA was < 2% and IGA score was 1. Additionally, he has had neither asthma exacerbations nor cutaneous or pulmonary infections since starting dupilumab.

2.2. Patient 2

An 8‐year‐old female with AD‐HIES due to a STAT3 mutation presented with severe erythematous xerotic and pruritic plaques covering > 50% BSA and an IGA score of 3. She had been diagnosed with HIES at age 1 year after suffering from chronic eczematous eruptions and secondary chronic otitis externa; she had no sinopulmonary infections. She was started on dupilumab at age 9 years with a loading dose of 400 mg and then dosed at 200 mg every 2 weeks based on weight. After 9 months of treatment with dupilumab, the atopic dermatitis covered < 2% BSA, she has an IGA score of 1, and her skin infections completely resolved. After 3 years of dupilumab treatment, she has had a durable response with no adverse effects. Additionally, her otitis externa infections decreased from 2 to 3 infections/year to none over the past 3 years on dupilumab.

2.3. Patient 3

A 2‐year‐old female presented to dermatology clinic for treatment of her severe atopic dermatitis. Her history was significant for dermatitis since 2 months of age and several hospitalizations for cutaneous infections including staphylococcal scalded skin syndrome and recurrent eczema herpeticum (Figure 1). When she presented to dermatology clinic, she had severe hyperpigmented plaques along her upper and lower extremities and back covering > 70% BSA, an IGA score of 4, and diffuse pruritus which made it difficult to sleep. Of note, natural killer (NK) cells were low in this patient, with her absolute NK cells at 98 μL/mL. She was prescribed dupilumab 300 mg every 4 weeks and concurrently diagnosed with AR‐HIES due to biallelic mutations in ZNF341 mutation. Due to the extensive nature of the disease, after 3 months her dupilumab dose was increased to 200 mg every 2 weeks. After 6 months, her severe atopic dermatitis drastically improved to mild atopic dermatitis with an IGA score of 1, covering < 10% BSA and the pruritus was completely resolved (Figure 2). The patient then took a 4‐month hiatus from dupilumab therapy due to extended international travel during which time her atopic dermatitis flared. When she returned, she presented with worsened eczematous dermatitis with possible bacterial superinfection on the left thigh. She was restarted on dupilumab at 300 mg every 4 weeks given the mild severity of the atopic dermatitis, which was the initial dose she was started. Over the past year, she has remained clinically stable with atopic dermatitis limited to 1%–2% BSA and no additional cutaneous infections.

FIGURE 1.

Patient 3 prior to dupilumab treatment.

FIGURE 2.

Patient 3 after 6 months of dupilumab treatment.

3. Discussion

Herein we present three children with various genetic forms of HIES for whom treatment with dupilumab led to marked and sustained improvement in cutaneous and systemic symptoms. Immunologically, multiple forms of HIES, including those due to mutations in STAT3, are characterized by a deficiency in Th17 lymphocytes and a skewing of the immune response toward type 2 inflammation and the T‐helper 2 (Th2) pathway, including elevated levels of type 2 cytokines including IL‐13 and IL‐4. The increased proportion of Th2 cells likely underlies the high serum levels of IgE, eczema, and other allergic manifestations seen in HIES patients [24]. The deficiency of Th17 lymphocytes is thought to be related to the predominancy of staphylococcal skin infections [2]. Dupilumab is a monoclonal antibody directed against the IL‐4 receptor alpha, leading to disruption of the IL‐4 and IL‐13 signaling pathways, preferentially downregulating the Th2 pathway implicated in atopic dermatitis [18]. We speculate that IL‐4/IL‐13 blockade by dupilumab prevents skin and sinopulmonary infections in HIES through downregulating the Th2 pathway and prompting Th1 responses which are known to play a role in control Staphylococcal infections and promoting Th17 differentiation. IL‐4 also impairs wound healing, so we predict that by blocking IL‐4, this promotes faster wound healing which subsequently minimized skin infection [25]. Another possible mechanism is that the improvement in skin and sinopulmonary infections could be downstream to the improvements in the patients' atopic dermatitis and asthma.

Although many reports have described the role of dupilumab in treating severe atopic dermatitis (Table 1), few cases have described the sustained use of dupilumab over years in children. These cases add to the existing literature in demonstrating sustained clearance of atopic dermatitis and cutaneous infections in the context of HIES in children over a long period of time (1–4 years). Additionally, this case series is the first to report on a child with AR‐HIES caused by a mutation in ZNF341 to be treated with dupilumab. This case series supports the finding that dupilumab works beyond the skin and leads to improvements in other associated complications of HIES, with associated decreases in cutaneous infections, otitis externa, and pulmonary infections. Further clinical trials are warranted to assess long term outcomes with respect to dupilumab therapy for children with all types of HIES.

TABLE 1.

Literature review of previous case reports and the three cases in this report of children with HIES and those that were treated with dupilumab.

Diagnosis	Study	Age (years)	Sex	Clinical manifestations	Severity index	Pre‐treatment lab	Dupilumab dose	Response	Post‐treatment lab
AD‐HIES
CARD11 (c.518_535 del; pLeu173_Glue178 del)	Diaz‐Cabrera 2021 [10]	11	F	Atopic dermatitis, recurrent infection, asthma	SCORAD 84	IgE 1670 IU/mL, Eos 1470/μL	200 mg Q2W	SCORAD 40 (4 m)	N/A
CARD11 (c.193A > g; p.Met65Val)	Diaz‐Cabrera 2021	12	F	Atopic dermatitis, recurrent infection, asthma	N/A	IgE 4080 IU/mL, Eos 1200/μL	400 mg loading, 200 mg Q2W	N/A	N/A
CARD11 (c.169G > A; pGlu57Lys)	Gualdi 2023 [8]	12	M	Pruritic eczematous dermatitis and alopecia areata	N/A	IgE 2376 kU/L	400 mg loading, 200 mg Q2W	Disappearance of prurigo nodules, eczema, and alopecia (2 m)	N/A
IL6ST (encoding GP130 p.N4040Y)	Schwerd 2017 [7]	2	F	Eczema, recurrent infections, craniosynostosis	N/A	IgE > 5000 IU/mL	N/A—duplilumab not used in this case	N/A	N/A
STAT3	This manuscript	8	M	Chronic eczematous eruptions, lip fissuring, recurrent bacterial skin infections, asthma, pneumonia, pulmonary infections	IGA score 3, 90% TBSA	IgE 7663 IU/mL	400 mg loading dose. 200 mg Q2W	After 2 months: 30% TBSA and IGA score of 2 3 years: < 5% TBSA, IGA score 0	After 3 years: IgE 900 IU/mL
STAT3 (c.475G > A; p.Glu159Lys)	This manuscript	8	F	Erythematous xerotic and pruritic plaques, recurrent bacterial skin infections, otitis externa	> 50% TBSA, IGA score 3	IgE 15,0890 IU/mL	400 mg loading dose. 200 mg Q2W	After 9 months: < 2% TBSA	After 9 months: IgE 787 IU/mL
STAT3 (c.1294 G > A; p.Val432Met)	Dixit 2021	14	M	Pruritic eczematous dermatitis with recurrent infection, EoE	SCORAD 60	IgE 8587 IU/mL, Eos 800/μL	600 mg loading, 300 mg Q2W	SCORAD 10 (2 m)	N/A
STAT3	Moraczewski 2021 [10]	13	F	Suppurative scalp infection, sinusitis	N/A	IgE 14,000 IU/mL	600 mg loading, 300 mg Q2W	Clearing of scalp lesion and decrease in lymphadenitis (3w)	N/A
STAT3 (c.21323C > G)	Staudacher 2021 [3]	9	M	Pruritic skin rash since 1 year old, recurrent infection	SCORAD 58	IgE 1800 IU/mL	300 mg Q2W, then 300 mg Q4W	SCORAD 5 (4 m)	IgE 1100 IU/mL
STAT3 (V343L)	Staudacher 2021	11	M	Severe pruritic skin rash, recurrent infection	SCORAD 78	IgE 28,800 IU/mL	300 mg Q2W, then 300 mg Q4W	SCORAD 15 (4 m)	IgE 11,000 IU/mL
STAT3 (R32Q)	Staudacher 2021	11	M	Pruritic skin rash, recurrent infection	SCORAD 72	IgE 40,000 IU/mL	300 mg Q2W, then 300 mg Q4W	SCORAD 7 (4 m)	IgE 25,000 IU/mL
STAT3 (c.1144C > T; p.Arg382Trp)	Nihal 2022 [4]	1.5	F	Atopic dermatitis, recurrent skin and pulmonary infections, eosinophilic folliculitis	n.d.	65 IU/mL	600 mg loading, 300 mg Q4W	Complete resolution of itch and pian (6 m)	N/A
STAT3 (c.1150T > C; p.F384L)	Matucci‐Cerinic 2022 [5]	17	M	Severe pruritis skin rash, recurrent skin infections	SCORAD 45	IgE > 5000 IU/mL	600 mg loading, 300 mg Q2W	SCORAD 28 (12 m)	N/A
AR‐HIES
DOCK8	Ollech 2021 [14]	11	F	Severe dermatitis, recurrent infection	Pruritus NRS 10, IGA score 4	IgE 7650 IU/m	400 mg loading, 200 mg Q2W	Pruritus NRS 3, IGA score 1 (2w), decreased infection	N/A
DOCK8	Ollech 2021 [14]	10	F	Severe dermatitis, frequent skin and lung infection	Pruritus NRS 10, IGA score 4	IgE 16,500 IU/m	600 mg loading, 300 mg Q2W	Pruritus NRS 2, IGA score 2 (1 m), reduced skin infection	IgE 4510 IU/mL (1 M)
DOCK8	Johar 2023 [12]	6	F	Pruritic eczematous dermatitis, recurrent skin infections	N/A	N/A	200 mg Q4W	Resolution of pustular scalp lesions, absence of active skin lesion (6 m)	N/A
DOCK8	Joshi, 2021 [15]	12	M	Pruritic eczematous dermatitis, asthma, recurrent skin infection	SCORAD 91.7	IgE > 50,000 IU/mL	200 mg Q2W	SCORAD 23.95 (NA), decreased skin infection, improved asthma (3 m)	IgE 5820 IU/mL (NA)
PGM3 (c.337C > G; p.Pro113Ala)	Kao 2023 [11]	2 months	F	Eczematous dermatitis with recurrent infection, asthma	N/A	IgE 1521 IU/mL	120 mg loading, 60 mg Q4W	Improved pruritis, reduced skin infection (2 m)	N/A
TYK2 (c.2395G > A; p.G799R)	Wu 2020 [16]	2	M	Eczema, disseminated mycobacterial and viral infections	N/A	IgE 27.4 IU/mL	N/A—duplilumab not used in this case	N/A	N/A
ZNF341 (c.538C > G; p.Pro180Ala)	This manuscript	2	F	Hyperpigmented plaques, diffuse xerosis and pruritis, cutaneous infections including eczema herpeticum	IGA score of 4, > 70% TBSA	IgE > 40,000 IU/mL	600 mg loading dose, 200 mg Q2W	After: 6 months: IGA score of 1, < 10% TBSA	After 6 months: IgE 6935 IU/mL

Ethics Statement

Exempt per University of Minnesota IRB protocol STUDY00021577.

Consent

A wavier of consent was accepted based the IRB process. Patients who opted out of research at the University of Minnesota were excluded from the data set.

Conflicts of Interest

Sheilagh M. Maguiness is a co‐founder of Stryke Club, personal care for teenage boys and has participated on an advisory board for Regeneron Pharmaceuticals.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.