Adverse Effects Under Th2 Biologics (Dupilumab and Tezepelumab) in a Patient with Severe Asthma and Atopic Dermatitis

Introduction: This is the first report of a patient with severe asthma and atopic dermatitis that developed local perioral skin infection which onset coincided with the patient’s treatment with dupilumab (candida albicans) and later with tezepelumab (microscopic detection of yeast). Case Presentation: Besides moderate headache, macular exanthema was found after administration of tezepelumab, which was subsequently accompanied by a worsening of symptoms upon reexposure to the treatment. Both sensations needed multidisciplinary treatment and both antibody therapies were stopped.


Introduction
In recent years, antibody treatments have emerged as an effective treatment for severe asthma.In the EU/ Germany, the two most recently approved biologics are dupilumab, 2019, and tezepelumab 2022.Both biologics have been shown to lower bronchial inflammation, improve asthma control and lung function [1].While serious adverse events were rare [2], conjunctivitis is a frequently reported side effect in atopic dermatitis patients [3].With regards to tezepelumab, pharyngitis, local injection side reaction, headache, and bronchitis were reported [4].In the phase 3 study, one anaphylactic shock was reported under highest dose of tezepelumab but no skin or subcutaneous tissue disorders [4], perioral changes were not observed.

Case Report
We report on a 25-year-old female patient who has been receiving treatment for severe asthma at Hannover Medical School's outpatient clinic for several years.The patient has given written informed consent to publish the case (including publication of images).The patient has a history of severe allergic asthma since early childhood which resulted in frequent hospitalizations during her early years.Since 2020, the patient had been increasingly uncontrolled despite high-dose inhaled steroid therapy and oral corticosteroids required for years.Comorbidities were allergic rhinitis with nasal polyps and atopic dermatitis.Latter was a problem in early childhood and decreased in severity with age.Since years, only topical anti-inflammatory treatment by means of topical corticosteroids and calcineurin inhibitors was used reactively.The patient works as an educator and has never smoked.Sensitizations to grasses, various trees, and dust mites were present, and the patient received an allergen-specific immunotherapy during adolescence.Due to many years of steroid use, adrenal insufficiency was diagnosed, and hydrocortisone therapy was initiated (daily 25 mg).In late 2020, a therapy with omalizumab was initiated (600 mg every 4 weeks s.c.), which resulted in a decrease of exacerbations (from >4 in the year before to 0 in the following year) and an increase in asthma control (asthma control test [ACT] increased from 5 to 10 points).The patient showed an FEV1 of 68% predicted and an exhaled NO of 15 ppm at the start of antibody therapy.However, in October 2021, the patient's asthma control was still inadequate (ACT 10 points) and the patient continued to experience episodes of dyspnea.Therefore, the therapy was switched to dupilumab.The further asthma controller therapy with indacaterol/mometason fuorat, tiotropium, montelukast was continued.After the first dose of dupilumab (600 mg s.c.), the patient exhibited perioral lesions first (Fig. 1a) as well as a worsened nasal breathing, so that the patient opted to discontinue the therapy with dupilumab.Microbiological smears showed cultural evidence of Candida albicans and Serratia marcescens, virological examinations were negative for HSV and VZV.The patient was treated with ciclopirox-olamine 1% cream and zinc paste for the perioral skin changes.In addition, amphotericin B lozenges were administered.Subsequently, therapy with omalizumab was reinitiated and subsequently bronchial thermoplasty was performed, resulting in a decrease in asthmatic symptoms and an ACT of 13.No acute perioral lesions occurred under omalizumab therapy before.In November 2022, the decision was made to switch from omalizumab to tezepelumab.The first dose of tezepelumab was administered on December 20, 2022, 4 weeks after the last dose of omalizumab.Three days later, the patient developed perioral redness and swelling.Yeast infection was diagnosed in microscopy of skin scrapings from those lesions.Topical therapy with ciclopirox-olamine 1% cream twice daily was initiated immediately.Furthermore, the patient reported mild shortness of breath, moderate cough, and short-lived headache with migraine-like character.Additionally, a skin rash affecting most prominently the extremities and was accompanied by pain Side Effects of Th2 Modulation in Severe Asthma (Fig. 1b).Topical therapy with mometasone furoat 1% cream led to a resolution of symptoms in 14 days, and it was decided to readminister tezepelumab in consultation with the patient.After the second injection, there was an extremity accentuated rash with significantly more pain and itching developed within only 2 h.The patient was instructed to use ebastel up to three times per day in addition to applying mometasone furoat cream and ciclopirox cream.Headache did not occur but subjectively the feeling of chills and fever (38.8°C in the self-measurement), which lasted for 5 days.The shortness of breath and cough did not deteriorate/ impair, while the ACT increased to 16 points.Laboratory chemistry and lung function showed no change with tezepelumab (Table 1).Therapy with tezepelumab was discontinued due to the side effects.A switch back to omalizumab was made in consultation with the patient.

Discussion
This case report describes perioral fungal infections in temporal connection with different biologics (dupilumab and tezepelumab) and a systemic skin reaction after tezepelumab.Generally, patients with atopic dermatitis have increased risk and incidence of skin infections, such as viral and fungal infection [5].However, no increased rates of viral or bacterial infections have been found with dupilumab therapy in a pooled study [6].Moreover, no increases of fungal infections have been described in clinical studies with dupilumab.Metaanalysis from clinical studies provided evidence for even reduced frequencies of severe herpes infections and bacterial cutaneous infections in atopic dermatitis patients treated with dupilumab [7].This is conclusive as IL4/13 blockade does not affect antimicrobial immune responses.Quite in contrary, a type 2 suppression could result in pronounced type 1 immune response, as reported in psoriasis-like skin eruption and arthritis [8,9].Besides conjunctivitis, there are increasing reports of the occurrence of facial dermatitis, named dupilumab facial redness [10,11].Different hypotheses are discussed such as a type 3 induced inflammation by malassezia yeast, a localized treatment failure, aeroallergen-induced dermatitis, contact dermatitis or an increased Demodex mite colonization.
Potential differential diagnoses were explored in the patient, which involved investigating for cellular or humoral immunodeficiency, including HIV testing and zinc deficiency.However, no explanation or mechanism for the observed infections was identified [12].Although not found in the patient, sensitizations to the yeast malassezia sympodiales were found in some patients with facial redness induced by dupilumab and beneficial effects of anti-mycotic treatment were described [13].Coincidental occurrence of perioral candida infection in connection with the therapy with dupilumab would also be conceivable in the case of inhalative and oral hydrocortisone therapy, which also causes or promotes fungal infections.Moreover, the use of the face mask by the patient would also be a favorable factor for the spread of an oral candida infection to the perioral skin [14].
The presentation of a generalized skin eruption characterized by erythema, pain, and itching after tezepelumab injection may suggest different hypotheses: It is possible that the patient experienced an acute exacerbation of her atopic dermatitis, although epidermal involvement in the form of scaling or excoriation was absent, as seen in Figure 1b.Alternatively, an allergic mechanism may have played a role in the observed skin reaction.Furthermore, a parainfectious event could be considered as a potential cause for the observed skin rash and associated symptoms.Further investigation may be necessary to fully understand the underlying cause.Possible risk factors for perioral yeast infection were the same as discussed with dupilumab before.Even mental stress might promote the discussed perioral lesions.Meanwhile, it was observed that the dermal symptoms worsened following second tezepelumab injections with no negative effect on respiratory performance; it remains unclear if there might be a link between the two Th2 suppressing biologics in regard to perioral problems.However, the adverse events reported here were non-life threatening and self-limiting.

Statement of Ethics
Ethical approval was not required for this study in accordance with local guidelines.Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Fig. 1 .
Fig. 1. a Perioral infection (cultural Candida albicans and Serratia marsc.)after one administration of 600 mg dupilumab.b Shows the left leg of the patient after 210 mg Tezepelumab administration.a Redness and eczema are visible (permission to use the picture was given by the patient).

Table 1 .
Course of laboratory and functional parameters at different time points shown