Sarah N. Rimmer, MD, Nicholas Culotta, MD, and India Hill, MD take readers through a case highlighting need what they see as a need to understand dupilumab’s dose-dependent modulation of pediatric immune systems.
Introduction
Atopic dermatitis (AD), one of the most common pediatric skin disorders, is a chronic, predominantly T-helper-2 mediated inflammatory disorder.1,2 Dupilumab is a monoclonal antibody that blocks the shared receptor subunit of IL-4 and IL-13; these interleukins are key components of Th-2 mediated inflammatory disorders such as AD. Targeted systemic therapy with dupilumab has been shown to be a safe and effective treatment for moderate to severe AD in children.3,4
Studies of dupilumab use in children > 6 years of age report injection site reactions and conjunctivitis as the most frequent AEs, and children treated with optimal doses of dupilumab report a decrease in skin (bacterial, viral, fungal) and herpesvirus infections versus placebo.3 Three dosing regimens have been approved in the United States (US) for use in children > 6 years of age: 600 mg once followed by 300 mg every 4 weeks (q4w) if 15 kilograms (kg) to <30 kg, 400 mg once followed by 200 mg every other week (q2w) if 30 kg to <60 kg, and 600 mg once followed by 300 mg q2w if >60 kg, as these are the optimal doses for efficacy and safety demonstrated in clinical trials.3 We present a case of a 6-year-old, appropriately vaccinated male weighing 22 kg who was overdosed by his weight on dupilumab for 4 months. He subsequently developed disseminated infection with both varicella zoster virus (VZV) and herpes zoster virus (HZV).
Case Report
A 6-year-old male weighing 22 kg with a past medical history of severe AD presented to the hospital with two days of right periorbital erythema and a diffuse vesicular eruption. Dermatology was consulted for further evaluation. It was discovered that the patient initiated dupilumab four months prior with a loading dose of 400 mg followed by 200 mg q2w. The patient had been vaccinated against VZV at 1 and 4 years and had no history of prior VZV infection.
Examination revealed right periorbital edema and erythema with superimposed yellow and hemorrhagic crusting. Vesicles on an erythematous base were noted on the bilateral ear helices, right palmar and dorsal hand over the first MCP joint, and left antecubital fossa. Punched out erosions with hemorrhagic crusting were noted to the right and left ear lobules (Images 1-7). Vesicular fluid collected from the left antecubital area was positive for VZV via direct fluorescent antibody (DFA) staining and HSV via polymerase chain reaction (PCR).
Due to concern for periorbital cellulitis after an ophthalmology consultation, intravenous (IV) vancomycin was started. After a four-day course of IV acyclovir and vancomycin, the vesicles had evolved into crusted, erythematous papules in various stages of progression. The patient was discharged on 5 days of oral acyclovir and instructed to resume dupilumab at 300 mg every 29 days after resolution of skin lesions.
Discussion
Targeted systemic therapy with dupilumab has been shown to be a safe and effective treatment for moderate to severe AD in children.3,4 AEs are rarely reported and include conjunctivitis, injection site reactions, viral upper respiratory infections, facial eruptions (facial dermatitis, facial eczematous rash) and herpesvirus infections.3,5,6 In a study of children 6 to 11 years old with severe AD treated with dupilumab and topical corticosteroids, all herpesvirus infections were reported in 2% of children receiving 300mg of dupilumab q4w, 3% in those receiving dupilumab 100/200 mg q2w, and 5% in the placebo group.3 While dupilumab use is associated with herpesvirus infections, this does not appear to be a significant increase when compared to placebo.
Our patient was receiving higher than the recommended dupilumab dose for his weight of 22 kg. Dupilumab dosing in children >6 years of age if 15 kg to <30 kg if 600 mg once followed by 300 mg q4w.3 However, our patient received an initial loading dose of 400 mg followed by 200 mg q2w for a total of four months. In clinical trials using dupilumab in children >6 years of age, 200 mg q2w maintained consistently higher trough blood levels than did the 300 mg q4w, concurrent with increasing drug effect. However, this regimen was only tested using individuals >30 kg.3 The dosing regimen that our patient received has not been studied in clinical trials for patients of his age and body weight.
HZV infection is a result of the reactivation of VZV after the virus has become latent in sensory ganglia. Although HZV infection in children is rare and has declined since the advent of VZV vaccination in the US, the incidence rate of HZV in vaccinated children is reported to be 38 per 100,000 person years.7 HZV from wild-type or vaccine-strain VZV can occur in children after VZV vaccination; as our patient was vaccinated for VZV at 1 and 4 years old, we suspect that the HZV was caused by subclinical infection or vaccine strain VZV.7 No confirmatory laboratory examination to identify the strain of VZV was performed, which is a limitation of this report. The cause of HZV in vaccinated children is controversial, but may be related to previous vaccine-associated rash or breakthrough VZV, underlying immunodeficiency, reduced immunogenicity of the VZV strain used in the vaccine, and genetic mutations.7,8 Concurrent infection with VZV and HSV in an immunocompetent, pediatric patient is rare. This has, however, been reported in the literature, likely due to infection with a herpesvirus modulating cell-mediated immunity such that infection with another herpesvirus is more likely.9,10
Our healthy patient’s inappropriate dosing regimen of dupilumab likely contributed concurrent, disseminated VZV and HZV infection, despite the patient’s vaccination status and lack of VZV infection history. Diagnoses were confirmed based on clinical appearance, positive DFA testing for VZV (96-100% specificity), and positive PCR testing for HZV (high sensitivity and specificity).11,12 This case elucidates the need to further understand dupilumab’s dose-dependent modulation of pediatric immune systems, specifically TH2 immunity and its role in combatting viral infection (including herpes viruses).
Image 1 (above). Right periorbital edema and erythema with superimposed yellow and heme crust. Yellow and heme to the right inferonasal and upper lip regions.
Image 2 (above). Vesicles on an erythematous base on the right ear helix. Punched out erosions with hemorrhagic crusting on the right ear lobule.
Image 3 (above). Vesicles on an erythematous base on the left ear helix. Punched out erosions with hemorrhagic crusting on the left ear lobule.
Image 4 (above). Vesicles on an erythematous base on the left ear helix.
Image 5 (above). Vesicles on an erythematous base on the right first MCP joint.
Image 6 (above). Vesicles on an erythematous base on the right palmar hand.
Image 7 (above). Vesicles on an erythematous base on the left antecubital fossa.
Disclosures: The authors report no relevant financial disclosures.
Sarah N. Rimmer, MD, and Nicholas Culotta, MD, are dermatology residents at the Louisiana State University School of Medicine in New Orleans. India Hill, MD, is a dermatologist at Children’s Hospital in New Orleans.
1. Mortz CG, Andersen KE, Dellgren C, Barington T, Bindslev-Jensen C. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 2015;70(7):836-845. doi:10.1111/all.12619
2. Hay RJ, Johns NE, Williams HC, et al. The Global Burden of Skin Disease in 2010: An Analysis of the Prevalence and Impact of Skin Conditions. J Invest Dermatol. 2014;134(6):1527-1534. doi:10.1038/jid.2013.446
3. Paller AS, Siegfried EC, Thaçi D, et al. Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial. J Am Acad Dermatol. 2020;83(5):1282-1293. doi:10.1016/j.jaad.2020.06.054
4. Igelman S, Kurta AO, Sheikh U, et al. Off-label use of dupilumab for pediatric patients with atopic dermatitis: A multicenter retrospective review. J Am Acad Dermatol. 2020;82(2):407-411. doi:10.1016/j.jaad.2019.10.010
5. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/NEJMoa1610020
6. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and Safety of Dupilumab in Adolescents With Uncontrolled Moderate to Severe Atopic Dermatitis: A Phase 3 Randomized Clinical Trial. JAMA Dermatol. 2020;156(1):44. doi:10.1001/jamadermatol.2019.3336
7. Weinmann S, Naleway AL, Koppolu P, et al. Incidence of Herpes Zoster Among Children: 2003–2014. Pediatrics. 2019;144(1):e20182917. doi:10.1542/peds.2018-2917
8. Gershon AA. The current status of live attenuated varicella vaccine. In: Gershon AA, Arvin AM, Calisher CH, eds. Immunity to and Prevention of Herpes Zoster. Springer Vienna; 2001:1-6. doi:10.1007/978-3-7091-6259-0_1
9. Giehl K, Müller-Sander E, Rottenkolber M, Degitz K, Volkenandt M, Berking C. Identification and characterization of 20 immunocompetent patients with simultaneous varicella zoster and herpes simplex virus infection. J Eur Acad Dermatol Venereol. 2008;22(6):722-728. doi:10.1111/j.1468-3083.2008.02587.x
10. Park HH, Lee MH. Concurrent Reactivation of Varicella Zoster Virus and Herpes Simplex Virus in an Immunocompetent Child. J Korean Med Sci. 2004;19(4):598-600. doi:10.3346/jkms.2004.19.4.598
11. Binkhamis K, Al-Siyabi T, Heinstein C, Hatchette TF, LeBlanc JJ. Molecular detection of varicella zoster virus while keeping an eye on the budget. J Virol Methods. 2014;202:24-27. doi:10.1016/j.jviromet.2014.02.009
12. Leung J, Harpaz R, Baughman AL, et al. Evaluation of Laboratory Methods for Diagnosis of Varicella. Clin Infect Dis. 2010;51(1):23-32. doi:10.1086/653113
Sarah N. Rimmer, MD, Nicholas Culotta, MD, and India Hill, MD take readers through a case highlighting need what they see as a need to understand dupilumab’s dose-dependent modulation of pediatric immune systems.