Efficacy of omalizumab in the treatment of STAT3 loss-of-function mutations associated with autosomal dominant hyperimmunoglobulin E syndrome—a case report

Introduction

Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by elevated serum immunoglobulin E (IgE), eczema, and recurrent skin and respiratory infections. HIES can be inherited through both autosomal dominant and recessive patterns (1). Common autosomal dominant pathogenic genes include signal transducer and activator of transcription 3 (STAT3), ERBIN, and CARD11, while autosomal recessive gene mutations include IL6R, PGM3, ZNF341, and SPINK5. Mutations in IL6ST exhibit different patterns of inheritance (2). STAT3 loss-of-function (LOF) mutations cause HIES (3), which is characterized by recurrent skin and lung infections (including cold abscesses and lung cysts), systemic inflammation, connective tissue disorders, and bone abnormalities (4). Prophylactic anti-infective therapy is the primary treatment for HIES, supplemented by other therapies such as anti-allergic treatments, including the use of inhaled corticosteroids for asthma-like symptoms. The established treatment protocols and pathogenesis for autosomal dominant HIES (AD-HIES) remain largely unknown, significantly affecting patients’ quality of life (5). Recently, monoclonal antibodies have demonstrated efficacy in managing allergic and eosinophilic inflammation in HIES and related conditions, such as mepolizumab, omalizumab, reslizumab, and benralizumab (6). Significant improvement in STAT3-HIES-associated dermatitis has been reported in three children treated with dupilumab (7). However, pulmonary benefits have not yet been described extensively (8). Omalizumab, a monoclonal anti-human IgE antibody, is approved for the treatment of asthma and chronic spontaneous urticaria (9,10), but is rarely used in HIES. Relevant studies on the application of omalizumab in HIES patients primarily focus on alleviating skin issues, with significant improvements reported in most cases (4,5,11,12). In some of these reports, lung lesions also showed improvement following the use of omalizumab (12,13). In this paper, we present two cases of STAT3-LOF related AD-HIES with pulmonary complications. Both patients exhibited varying degrees of improvement after treatment with omalizumab and conventional therapy. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-379/rc).

Case presentation

Whole-exome sequencing was performed by Beijing Genomics Institution from blood samples of patients and their parents.

From birth to age 8, patient 1 exhibited recurrent pustular rashes and frequent respiratory infections (approximately twice monthly), requiring repeated oral antibiotic courses (Table 1). Additional manifestations included annual facial abscesses over three years, treatment-refractory severe eczema, suppurative folliculitis, lymphadenitis, and characteristic facial features (Figure 1). Cultures from sputum and blood were positive for Staphylococcus aureus, and fungal elements were detected on skin microscopy. The patient received prolonged oral linezolid and itraconazole for infection prophylaxis after a 3-week course of intravenous antibacterial and antifungal therapy during hospitalization. Due to low-normal immunoglobulin G (IgG) levels, intravenous immunoglobulin was administered.

Figure 1 Clinical characteristics of patient 1. (A) Stunted growth; (B,C,E) distinctive clinical features including severe eczema, flattened nasal bridge, and saddle-shaped cranium; (D) severe dental caries. This image is published with the consent of the patient’s parents.

Despite aggressive antimicrobial treatment, skin and pulmonary symptoms persisted. Genetic testing at age 6 identified a de novo heterozygous pathogenic STAT3 variant (c.1144C>T, NM_139276.2), consistent with AD-HIES (Figure 2). Prior to omalizumab initiation, his National Institutes of Health (NIH) HIES score was 62 and serum IgE was 35,271 kU/L (reference: <114 kU/L).

Figure 2 A heterozygous variant of the STAT3 gene was identified in both patients and the parents of patient 2.

An initial omalizumab dose of 450 mg (15 mg/kg) was administered, followed by maintenance doses of 300 mg (10 mg/kg). After 2 months of biweekly injections, skin lesions improved markedly with resolution of rash and smoothing of skin texture, allowing the interval to be extended to monthly. A chest computed tomography (CT) at 6 months demonstrated radiographic improvement. Although one skin abscess occurred within this period, no respiratory infections were noted, and recovery was faster than previous episodes. The dosing interval was subsequently extended to every 2 months, which remains the current regimen. Serum IgE peaked at 3 months and gradually declined thereafter. Omalizumab treatment also significantly reduced T lymphocyte counts and interleukin-18 (IL-8) levels (Table 2). Throughout the 9-month follow-up, lung infections remained well-controlled (Figure 3), with substantial alleviation of eczema and pruritus.

Figure 3 Comparison of pre- and post-treatment chest CT scans in patient 1. Prior to omalizumab administration, the patient’s chest CT revealed varying degrees of cystic and cylindrical dilation of the bronchial lumina in the lateral segment of the right middle lobe and in each lobe and segment of the right lower lobe, accompanied by bronchial wall thickening and small fluid levels in some lesions. Following the administration of omalizumab and concurrent anti-infection treatment, there was a noticeable improvement in the previously observed cystic and cylindrical dilation of the bronchial lumina in each lobe and segment of the right lower lobe, with reduced bronchial wall thickening. Notably, the large cavity present in the original right lower lobe lesion had resolved. The arrow points to the affected area. CT, computed tomography.

Patient 2 was a 17-year-old female with a history of recurrent respiratory infections and multiple lung cysts since birth, requiring pulmonary cystectomies and long-term anti-infective therapy. Bronchoalveolar lavage fluid cultures identified Mycoplasma pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, parainfluenza virus, and Aspergillus fumigatus. Sinus calcifications suggested chronic fungal involvement. During hospitalizations, she received intravenous amikacin, meropenem, and voriconazole; her outpatient regimen included nebulized amikacin and oral voriconazole.

Her phenotype included characteristic facial features (Figure 4), refractory eczema, subcutaneous abscesses, suppurative lymphadenitis, and liver abscesses. Pre-treatment chest CT revealed severe bronchiectasis with active infection, pulmonary bullae, and pulmonary hypertension (Figure 5). Respiratory function was severely impaired, precluding pulmonary function testing. She scored 79 on the NIH HIES scale, and genetic testing identified a de novo heterozygous STAT3 mutation (c.1144C>T, NM_139276.2), absent in both parents (Figure 2). Additional complications included pulmonary hypertension and previous cardiac insufficiency. She was maintained on oral and inhaled anti-infectives, pulmonary antihypertensive agents, and anti-asthmatic drugs. Omalizumab was initiated at 600 mg (12 mg/kg) subcutaneously every 2 weeks for 2 months, alongside continued background therapies. Skin lesions improved markedly, and the frequency of acute infections declined. No hospitalizations for infection occurred during the 9-month follow-up. Pulmonary arterial systolic pressure decreased from 35 to 29 mmHg, although follow-up CT showed only modest improvement (Figure 5). The omalizumab interval was subsequently extended to 4–8 weeks. Serum IgE levels peaked at 1 month and then declined. T lymphocyte counts increased (Table 2), and cytokine profiling showed reductions in interleukin-12 (IL-12), interferon-α (IFN-α), and interleukin-17A (IL-17A), with an increase in interleukin-16 (IL-6) (Table 3). Throughout follow-up, both cutaneous and respiratory symptoms improved substantially without recurrence of cardiac insufficiency, though radiological changes remained minimal.

Figure 4 Clinical characters of patient 2. (A) Stunted growth; (B-D) the patient presented with distinctive clinical features, including severe eczema, broadening of the nasal bridge, and a highly arched palate; (E) the patient had acropachia as a result of her pulmonary insufficiency; (F) the patient exhibited a bone age that fell below the 90th percentile of her peers. This image is published with the consent of the patient’s parents. BMD, bone mineral density; H, high temperature; L, low temperature.

Figure 5 Comparison of pre- and post-treatment chest CT in patient 2. The chest CT findings revealed extensive destruction of the left lung parenchyma, left-sided thoracic cage collapse, multiple congenital pulmonary adenomatoid malformations or bronchiectasis with superimposed infection in the left lung, and scattered areas of bronchiectasis with infection in the right lung. CT scan showed only slight improvement following omalizumab administration. The arrow points to the affected area. CT, computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (No. ES-2024-K003-02). Written informed consent was obtained from the patients’ parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

AD-HIES, characterized by elevated serum IgE, eczema, and recurrent respiratory infections, is classified as a primary immunodeficiency disorder. The most common genetic abnormalities associated with AD-HIES are mutations in the STAT3 gene (3). STAT3 is one of the STAT proteins, which play a crucial role in several signaling pathways; many cytokines transmit signals through the Janus kinase (JAK)/STAT pathway (14). STAT3 simultaneously mediates the expression of both pro-inflammatory and anti-inflammatory factors. When STAT3 is inactivated, the body may exhibit both an inhibition of the inflammatory response and an excessive inflammatory response. For instance, interleukin-21 (IL-21) inhibits IgE production in B lymphocytes via the STAT3 signaling pathway. When the STAT3 pathway is compromised, IL-21 is unable to exert its negative regulatory effect on IgE synthesis in B lymphocytes (15).

The two patients were not related. Both had the same STAT3 mutation and received omalizumab injections, anti-infective therapy, and regular gamma globulin injections. Staphylococcus aureus was detected in the blood and alveolar lavage fluid of patient 1. Mycoplasma pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, parainfluenza virus, and Aspergillus fumigatus were identified in the alveolar lavage fluid of patient 2. Staphylococcus aureus is the most common pathogen in HIES; however, Haemophilus influenzae and enteric Gram-negative bacteria are occasionally isolated from patients. Fungal infections are also very common (16). Patient 1 showed improvement on chest CT scans, while patient 2 exhibited less improvement on follow-up scans, possibly due to a longer duration of the disease. Specifically, patient 1 presented with acute lung inflammation and a shorter illness duration. In contrast, patient 2 developed pulmonary fibrosis and remodeling as a result of frequent pulmonary infections over a decade, despite having lower serum IgE levels compared to patient 1 prior to omalizumab treatment. According to reported cases, the serum IgE level initially increases before declining (12,13). Omalizumab demonstrated better outcomes in treating eczema among patients with controlled serum IgE levels (12), which aligns with the benefits observed in the two STAT3-related AD-HIES patients discussed here. Patient 1, who had elevated serum IgE levels and pulmonary infections before receiving omalizumab treatment, achieved control of their condition. Conversely, patient 2, who had lower serum IgE levels prior to omalizumab treatment, showed minimal improvement on follow-up CT scans. These findings are consistent with previous reports indicating that patients with higher baseline IgE levels tend to respond more favorably to omalizumab therapy (12).

Omalizumab binds to circulating free IgE, thereby inhibiting its interaction with FcɛRI receptor on the surface of mast cells and basophils. This action prevents the activation and degranulation of these cells, leading to a reduction in Th2 lymphocyte-mediated cytokine production and lymphocytopenia, thus exerting an immunomodulatory effect (17). The efficacy of omalizumab has been demonstrated in refractory asthma and autoimmune skin diseases associated with IgE (9,10,18); however, its effectiveness in HIES remains uncertain. Currently, the use of omalizumab in children is limited. It is approved only for allergic asthma in children over 6 years old, chronic urticaria in children over 12 years old, and food allergies in children over 1 year old. The dosage is determined based on IgE levels and body weight (19). Theoretically, omalizumab is expected to alleviate symptoms associated with elevated IgE levels in AD-HIES, such as eczema and asthma-like manifestations. However, our observations indicate that while the eczema symptoms in the two pediatric patients were significantly alleviated, there was also a notable improvement in pulmonary symptoms. The frequency of acute infections decreased, and when infections did occur, their duration was shorter compared to previous episodes. Some studies have suggested that elevated IgE antibodies may increase susceptibility to Staphylococcus aureus and Candida albicans infections (20). We hypothesize that omalizumab binds to IgE, preventing IgE antibodies in the blood from binding to their receptors. This reduces the levels of free IgE antibodies, lowers susceptibility to Staphylococcus aureus infection, facilitates pathogen clearance, and thereby improves lung function. However, the precise mechanisms underlying this association remain to be elucidated. In patient 1, treatment with omalizumab resulted in a significant decrease in T lymphocyte numbers and IL-8 levels (Table 2). Elevated IL-8 levels were observed in a 10-year-old girl with HIES and severe necrotizing pulmonary infection, but decreased after treatment (21). T lymphocyte numbers increased in patient 2. Patient 2 also exhibited abnormal IL-17A production due to a STAT3 mutation, which led to an impaired T helper 17 cell (TH17) response (22). Omalizumab treatment reduced the production of IL-6, IL-12, and IFN-α in patient 2, promoting Th2 polarization (Table 2) and improving pulmonary damage (4). Although the two have the same mutation site, their clinical manifestations differ, the pathogens they are infected with vary, and the disease progression is also distinct. The differences in elevated cytokines may be related to these factors, further suggesting that there is no direct correlation between gene loci and phenotypes.

In our study, omalizumab was administered for a duration of up to 9 months, during which the two patients did not experience any negative effects. Previous reports on the use of omalizumab in patients with hyper-IgE syndrome did not document any adverse reactions. These findings suggest that the administration of omalizumab in hyper-IgE syndrome appears to be relatively safe and beneficial for patients. When traditional treatments prove ineffective, numerous biological agents are now available and these agents may help improve patients’ symptoms. However, further studies and long-term follow-up are still required to provide sufficient evidence.

Conclusions

Although the precise role of IgE in the pathogenesis of HIES remains unclear, omalizumab has demonstrated clinical efficacy in both domestic and international studies involving HIES patients. Further prospective investigations and long-term follow-up studies may help elucidate its mechanism of action.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-379/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-379/prf

Funding: This work was supported by the Basic and Applied Basic Research Foundation of Guangdong Province Enterprise Mutual Funds on the Project (No. 2021A1515220043); Guangzhou Science and Technology Bureau, Special Project of Basic Research Program Jointly Funded by Municipal Universities and Enterprises (No. 2024A04J3538); and Guangzhou Science and Technology Bureau, Joint Funding Project of Municipal Universities (research institutes) and Enterprises (No. 2024A03J1203).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-379/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (No. ES-2024-K003-02). Written informed consent was obtained from the patients’ parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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