Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: A single-centre clinical study and literature review

Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: A single-centre clinical study and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: A single-centre clinical study and literature review Tiange Xie, Na Xu, He Zhao, Yingdong Han, Juan Wu, Hong Di, Min Peng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5618843/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity-sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Pulmonary complications are responsible for high morbidity and mortality rates in patients with HIES. This study examines the progression of pulmonary disease in adult patients with HIES and compares the subsequent findings with existing literature. Methods Ten adult patients with HIES diagnosed at Peking Union Medical College Hospital (PUMCH) from January 2016 to October 2023 were included in this study. Diagnosis was confirmed using the National Institutes of Health (NIH) criteria and whole-exome sequencing. Clinical data on pulmonary disease progression, microbiology, imaging and histology were collected. A systematic literature review was conducted for comparison. Results Recurrent pulmonary infections led to significant structural lung damage, with 90.0% (9/10) of patients developing bronchiectasis and pneumatocele. Early infections (0-10years) were predominantly due to Staphylococcus aureus (80.0%,8/10), while later stages (6-22years) showed a shift to more complex infections with Aspergillus /fungus (70.0%,7/10), Mycobacterium tuberculosis (50.0%, 5/10), and Pseudomonas aeruginosa (40.0%, 4/10). Imaging revealed extensive bronchiectasis and pneumatocele formation. Histological examinations demonstrated acute inflammation (40%, 2/5), granuloma formation (80%, 4/5), and eosinophilic infiltration (100%, 5/5). Comparatively, our findings are consistent with previous reports that suggest a higher incidence of pulmonary structural damage in patients with the signal transducer and activator of the transcription 3 ( STAT3 ) mutations than in those with other gene variants. However, our cohort showed a faster progression from initial infection to structural damage, highlighting the need for early intervention. Conclusion The progression of pulmonary disease in HIES patients underscores a critical three-step process: initial recurrent infections, development of structural lung damage, and subsequent reinfections that aggravate the damage. This rapid transition from infection to structural damage, especially in patients with STAT3 mutations, highlights the importance of early and aggressive intervention. Managing reinfections after structural lung damage is essential to prevent further deterioration and to improve long-term outcomes. hyper-IgE syndromes STAT3 gene primary immunodeficiency lung disease Figures Figure 1 Figure 2 Figure 3 Introduction The hyper-IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders characterized by a triad of increased infection susceptibility, eczema, and raised serum IgE. Patients with HIES presented with recurrent skin and lung infections after birth. Major causal variants are dominant-negative variants in the signal transducer and activator of the transcription 3 ( STAT3 ) gene [ 1 – 4 ]. Close approximate incidence of HIES incidence is unknown, but it is estimated to range from 1 in 500,000 to 1 in 100,000 [ 5 – 7 ]. Due to the rarity of this disease and the lack of widespread genetic testing technology in earlier years, patients often experience delayed diagnosis, sometimes not being diagnosed until adulthood. By this time, patients may already have developed severe pulmonary complications, including secondary severe infections on the basis of structural lung disease, which is their primary cause of mortality [ 8 ]. Pulmonary complications are the primary factors affecting the quality of life and long-term prognosis in HIES patients [ 9 ]. Our understanding of pulmonary disease in HIES continues to evolve. Previously, it was believed that pulmonary disease in patients with HIES could be attributed to multiple factors, with the most significant cause being parenchymal lung damage due to frequent and severe infections [ 9 ]. Other causes include autoinflammation driven by a dysregulated immune system [ 10 ]. Recent research suggests that we may have underestimated the significant pulmonary susceptibility and impaired post-injury repair caused by primary pulmonary abnormalities [ 11 , 12 ]. Overall, research on pulmonary disease in HIES is limited, and the underlying mechanisms of structural lung damage remain unclear. Early identification is essential for patients with HIES. The first case reports date back to 1966 [ 13 ], and HIES awareness has been gradually increasing, facilitating early detection of the syndromes. Most patients are diagnosed during childhood, leading to better prognosis [ 14 ]. However, in China, recognition of this disease came relatively late, with the first cases reported in 1984 [ 15 ]. Many patients are only definitively diagnosed in adulthood, and prolonged diagnosis is associated with poorer outcomes. Researches have predominantly focused on pediatric patients [ 16 , 17 ], with only one study addressing adults who received a delayed diagnosis [ 18 ]. In many developing countries, HIES are still not widely recognized, and genetic testing technology has yet to be adopted in wider ranges, resulting in a significant number of adults with delayed diagnoses that represent a critical subgroup within the HIES patient population. We aim to gain insight into the natural course of HIES and the progression of pulmonary disease through a review of the literatures and summarizing adult HIES patients in our study. This will improve our understanding of pulmonary diseases in HIES and aid in better management of these patients. Method From January 2016 to October 2023, ten patients aged 18 years or older with HIES hospitalized at Peking Union Medical College Hospital (PUMCH) were included in our study. The diagnosis of HIES is based on the diagnostic scoring system established by National Institutes of Health (NIH) in 1999, which utilizes 19 clinical and laboratory criteria[ 19 ]. A score of greater or equal to 40 confirms the diagnosis of HIES. Also, Whole-exome sequencing was performed on each patient. Patients need to conform with NIH criteria and have a defect in STAT3 gene in order to be admitted into the database. Pathogenic variants were identified through curated databases (ClinVar [ 20 ], OMIM [ 21 ], HGMD Pro [ 22 ]), with exclusion of variants showing MAF ≥ 0.0001% in control populations (ExAC/gnomAD, 1000 Genomes). Variant pathogenicity was predicted using silico predictive algorithms including SIFT[ 23 ], PolyPhen-2[ 24 ], CADD[ 25 ], and MutationTaster[ 26 ] with default thresholds. The American College of Medical Genetics and Genomics (ACMG) classification followed the 2015 guidelines[ 27 ]. The clinical data, including patient demographics, clinical presentations, laboratory results, pathological and radiological examinations, treatment protocols, and follow-ups, were collected. In our study, pulmonary structural damage refers to irreversible damage to the lung parenchyma and interstitium caused by various reasons, including bronchiectasis, pulmonary fibrosis, pneumatocele, multiple cavities, lung destruction, and among other structural changes in the lungs. This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (PUMCH) and conducted in compliance with the Declaration of Helsinki. We conducted our systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [ 28 ]. We searched Medline, Embase, and Pubmed databases for all articles about HIES and selected published articles involving humans and written in English between 1966 and 2023. The keywords used were the following ones: “Job Syndrome”[Mesh], “Hyper-IgE Syndromes,” “Hyper-IgE Syndrome,” etc. The specific search strategy is attached. Articles were then assessed for eligibility. Ultimately, we reviewed the pulmonary conditions of patients reported in all previous literature and summarized findings from cohorts focused on pulmonary disease. Results 1.1 Demographic features Our study involved 10 adult patients diagnosed with HIES, all of Chinese descent, including 4 females and 6 males, with a median age of 28.1 years old. HIES diagnosis was confirmed using the NIH scoring system, and STAT3 mutations were identified in all the patients. These individuals were presenting onset symptoms at birth and diagnosis at a median age of 23 years. The prolonged period from onset to diagnosis, averaging 23 years, underscores a widespread issue of delayed diagnosis. 1.2 Clinical Manifestations The clinical spectrum of HIES encompasses both immunological and non-immunological symptoms (Table.1). In our cohort, immunological manifestations predominantly included eczema (100%, 10/10), skin infections (100%, 10/10), and pneumonia (90.0%, 9/10). Non-immunological symptoms were varied, featuring retained primary teeth (42.9%, 3/7), scoliosis (33.3%, 3/9), fractures with minor trauma (50.0%, 4/8), midline anomaly (11.1%, 1/9), hyperextensibility (20.0%, 1/5), characteristic face (88.9%, 8/9), increased nasal width (62.5%, 5/8), and high palates (50.0%,3/6). Laboratory analyses consistently showed elevated IgE levels (100%, 10/10) and an average eosinophil count of 1.52×10 9 cells/L (± 2.65). Notably, two patients developed finger clubbing due to chronic pulmonary issues. 1.3 STAT3 Mutation Genetic analysis identified six patients with established pathogenic variants (c.1145G > A, c.1907C > T, c.1387_1389delGTG, c.2137G > T, c.1144C > T, c.1909G > A; ClinVar-confirmed, absent in ExAC/gnomAD MAF T, c.994C > A, c.2111_2112insC; ExAC/1000 Genomes MAF C; gnomAD-absent, 4/4 algorithm concordance). All variants met ACMG criteria: established variants were classified as pathogenic (PS1), while hotspot and novel variants were classified as likely pathogenic (PM1, PM2, and PP3). 2. Pulmonary features of HIES 2.1 Overview of Pulmonary involvement Among all the patients, 9 has lung tissue destruction and the incidence of pneumonia was 90.0% (9/10). Of these 9 patients, only one patient was found to have a pulmonary cyst without pneumonia and to have underwent surgical resection with no pneumonia occurring postoperatively. The other 8 patients all developed varying degrees of pulmonary disease, notably in the form of recurrent pneumonia during the course of the disease and with pulmonary structural damages including bronchiectasis and pneumatocele. These 8 patients typically experienced pulmonary infections within the first 10 years of life (6/8), with 5 cases occurring immediately after birth. In the early stages of the disease, common infections included Staphylococcus aureus / Methicillin-resistant Staphylococcus aureus (MRSA) and Haemophilus influenzae , while later stages saw infections by Aspergillus /fungus, Pseudomonas aeruginosa , and Mycobacterium tuberculosis . Of these patients, one ( #10) had mild pulmonary disease, caused by Mycobacterium tuberculosis infection. After anti-infective treatment, the condition of this patient improved without pulmonary structural damage, and the disease remained stable. 2.2 Microbiology assessment In the early stages of repeated lung infections, Staphylococcus aureus was the most common pathogen, accounting for 90.0% (9/10) of cases. As repeated lung infections led to structural lung damage, the pathogenic spectrum gradually shifted to include Aspergillus species and other fungi (70.0%, 7/10), Mycobacterium tuberculosis (50.0%, 5/10), and Pseudomonas aeruginosa (40.0%, 4/10). Other identified pathogens included Streptococcus pyogenes (10.0%, 1/10), Haemophilus influenzae (10.0%, 1/10), Escherichia coli (10.0%, 1/10), and Flavobacterium indologenes (10.0%, 1/10). Other infection-related conditions have also been summarized in Table 2 . 2.3 Radiological Imaging Assessment All 8 patients (#1, #3, #4, #5, #6, #7, #8, #9) with recurrent pneumonia showed obvious pulmonary structural damage (80.0%, 8/10). Chest X-ray (CXR) and computerized tomography (CT) assessments revealed lung parenchyma and airway destruction. Recurrent pulmonary infections led to airway remodeling with bronchial wall-thickening, bronchiectasis, mucus-plugging, mosaic perfusion, and expiratory air-trapping. Cystic parenchymal abnormalities included cysts, pneumatoceles, and cavities; these abnormalities arose during infection and often persisted. Frequent parenchymal and airway remodelling are presented in Fig. 1 . The spectrum of CT findings in pulmonary aspergillosis associated with HIES includes (1) aspergillomas (#6, #7, #8), where fungal balls are found within pre-existing lung cavities such as bronchiectasis or pneumatoceles, (2) chronic cavitary pulmonary aspergillosis (CCPA) (#4, #5, #7, #8, #9) characterized by cavity wall thickening, fungal balls, and peri-cavitary infiltrates, and (3) an allergic bronchopulmonary aspergillosis (ABPA) (#4, #8, #9) -like presentation with bronchiectasis and mucoid impactions that resemble toothpaste-shaped or finger-in-glove opacities. Additionally, mixed patterns and occurrences of invasive aspergillosis can also be observed. Additionally, one patient (#2), without any signs of infection, was incidentally found to have a pneumatocele, which was surgically removed. Seven years after the surgery, there have been no occurrences of pneumonia or further pulmonary structural damage. 2.4 Histological Features In our patients, four cases (#1, #4, #7, #8) underwent bronchoscopy to obtain histological results, one case (#2) had postoperative histology results from surgical resection of a lung bulla, and two cases (#6, #10) had histology obtained via percutaneous needle biopsy (Figure.2). No tumor cells were observed in any of the samples (100%, 7/7). Detailed descriptions were available for five cases. Some presented with acute inflammation (40%, 2/5), while others showed chronic inflammation/granuloma formation (80%, 4/5). Eosinophils were observed in all cases (100%, 5/5). Fungal hyphae were noted in one case (#6), and special staining was positive in one case (#8). 2.5 Course of Pulmonary involvement We summarized the timeline of disease development in 9 patients with pulmonary structural damage detected by imaging (Table.2). Most patients (77.8%, 7/9) had onset after birth, with the age of initial pneumonia occurring at 5 years (± 5y), age of Staphylococcus aureus infection at 10 years (± 7y), median age of pulmonary structural damage at 14 years (± 8.5y), age of combined Aspergillus /fungus, Pseudomonas aeruginosa , and Mycobacterium infections at 27 years (± 6.75y), age of definite diagnosis at 24 years (± 6y), and age of surgery at 13 years (± 7.25y). The average time from onset to definitive diagnosis of these 9 patients was 22 years, and time from initial pneumonia to the identification of pulmonary structural damage was 0 year, with time from structural damage to Aspergillus /fungus infection averaging 5 years. Thus, these patients had onset before the age of 10 years with early-stage infections mainly caused by Staphylococcus aureus and pulmonary structural damage detected almost simultaneously with the occurrence of infection. After approximately 5 years, infections by Aspergillus /fungus, Pseudomonas aeruginosa , and Mycobacterium tuberculosis gradually appeared. 2.6 Treatment of pulmonary involvement Pulmonary treatment primarily targets lung infections and structural lung diseases. During acute lung infections, broad-spectrum antibiotics are the mainstay of treatment. In patients with structural lung disease (such as bronchiectasis and pulmonary cysts), antibiotic coverage for Pseudomonas aeruginosa and Aspergillus species is necessary. For prophylactic antibiotic therapy, sulfamethoxazole is chosen for the most common pathogen, Staphylococcus aureus. In the presence of structural lung disease, itraconazole is used to prevent fungal infections. Additionally, in cases of CCPA and ABPA, the duration of antibiotic therapy needs to be extended. Among our patients, 100% (10/10) received antibiotics, with 50.0% (5/10) receiving prophylactic antibiotics. Antifungal treatment – itraconazole, voriconazole, or amphotericin B – was administered along with extended antibiotic therapy to 7 patients with Aspergillus /fungus infections. Other treatments included local drainage, surgery, interventional procedures, intravenous immunoglobulin (IVIG), vaccination, and regular pathogen monitoring. In our cohort, 60.0% (6/10) of the patients underwent drainage, 50.0% (5/10) of the patients had surgical interventions, and 10.0% (1/10) of the patients received interventional embolization treatment. IVIG use in HIES remains controversial. While some evidence suggest benefits for patients with low immunoglobulin levels or poor vaccine responses[ 29 , 30 ], overall, it shows only mild efficacy, mainly in HIES patients with eczema[ 31 ], and its high cost, potential side effects, and limited accessibility prevent it from being a standard treatment for HIES, though it may help those with severe lung disease[ 7 ]. Thus, we did not routinely use IVIG. However, during follow-up, we observed that some patients attempted treatments with limited evidence, such as IVIG. We provided chest physiotherapy (in the form of postural drainage and percussion) and airway clearance therapies to 8 patients with structural lung disease. None of our patients underwent lung transplantation. 3. Treatment of Extrapulmonary involvement The treatment of our HIES patients adhered to the following principles, focusing on both pulmonary and extrapulmonary aspects. Extrapulmonary treatment included anti-infective therapy for other deep-seated infections. Among our patients, 70.0% (7/10) had infections outside of the skin and respiratory tract, including the lumbar spine, intracranial, endocardium, mediastinum, liver and abdomen, kidneys, and esophagus. All of these patients were treated with antibiotics, and surgery and drainage were performed in 4 cases. Other treatments included skin (for eczema, staphylococcal infections, and mucocutaneous candidiasis), skeletal and connective tissue (vitamin D supplementation, scoliosis monitoring), oral and dental care (regular check-ups, extraction of delayed deciduous teeth), vascular monitoring (regular aneurysm screening), treatment of secondary lymphomas, and genetic counselling, which will not be discussed in detail here. Stem cell transplantation remains controversial, as transplantation's long-term efficacy and cost-effectiveness for HIES patients remain inadequately established in current research. We did not performed any such transplants. 4. Follow-up and Prognosis Of the 10 patients monitored, 5 have achieved a stable condition, 2 continue to necessitate recurrent interventions for persistent infections, 1 developed lymphoma and ultimately succumbed to severe pulmonary infection with septic shock during treatment, and 2 were lost to follow-up. 5. Literature review and summary 5.1 Case and cohorts of HIES A total of 1,367 articles were retrieved (Figure.S1). Among the articles were 232 cohort studies and 573 case reports. Out of all cohorts, there were 16 national-level large cohorts [ 7 , 8 , 14 , 16 , 17 , 32 – 42 ], with one cohort lacking descriptions of pulmonary disease [ 32 ]. Pulmonary complications varied across different countries and regions. The summaries of the pulmonary complications in the other 15 cohorts focused primarily on the incidence of pneumonia, pulmonary cysts, and bronchiectasis (Table S1 ). The prevalence of pulmonary structural damage is generally higher, with a range of 15.0–65.0% for bronchiectasis and a range of 16.7–68.4% for pneumatocele. Among them, the prevalence of bronchiectasis in HIES patients with STAT3 mutation is 65.0%, and pneumatocele is 52.0%. 5.2 Studies of pulmonary disease in HIES Eight out of all cohort studies focused specifically on pulmonary disease, and the summary of them included pulmonary complications, pathogens, surgical interventions, and treatments (Table S2) [ 8 , 43 – 49 ]. 5.3 Pulmonary disease of different gene variants Recently, several new causative variants have been identified, including PGM3 , ZNF341 , CARD11 , IL6ST , IL6R , TGFBR1/2 , ERBB2IP , and SPINK5 [ 40 , 50 – 55 ]. We compared the incidence of pulmonary complications among HIES patients with other genetic mutations (Table S1 ). For IL6ST mutation, prevalence of bronchiectasis and pneumatocele are 60.0% and 54.5%. For ZNF341 mutation, they are 56.3% and 35.3%. However, TGFBR mutation has been reported in only 10.0% of patients with pneumatocele, and no pulmonary structural damage has been described. Among HIES patients, those with STAT3 mutations are more likely to experience pulmonary structural damage, particularly pneumatocele formation. 5.4 Three stages of pulmonary disease in HIES Through a review of all previously published cases, the course of pulmonary disease in HIES patients can be generally divided into three stages (Figure.3). The first stage is characterized by recurrent pneumonia (0–10 years old), primarily caused by Staphylococcus aureus . The second stage involves pulmonary structural damage (6–22 years old), including abscesses, cavity formation, bronchiectasis, and pneumatoceles. The third stage enters a malignant cycle of pulmonary structural damage and infection (20–34 years old), with a predominant shift in pathogens to mixed infections of Aspergillus /fungus, Pseudomonas aeruginosa , and Mycobacterium tuberculosis . It is noteworthy that the time from the initial pneumonia to pulmonary structural damage is very short, with a median time of 0 years (± 3.5y). Additionally, the average time from pulmonary structural damage to the onset of Aspergillus /fungus infection is 5 years. Discussion HIES are a heterogeneous group of inborn errors of immunity-sharing manifestations that include increased infection susceptibility, eczema, and raised serum IgE [ 56 ]. Our research presents significant deviations from previous reports, particularly with regard to the onset and diagnosis ages of patients. Former large case series referenced in the literature report onset ages at 0 ± 1.5 years and diagnosis ages at 24 ± 8 years. Our cohort, drawn exclusively from the adult department, includes several individuals whose disease onset occurred in adulthood, with the rest experiencing a severe diagnostic delay. The average duration from disease onset to diagnosis spanned 20 years, with the longest case extending up to 36 years. Many patients exhibited symptoms shortly after birth and underwent numerous medical consultations due to recurrent infections, leading to a convoluted path to diagnosis. The delay in diagnosis, aside from HIES's low incidence rate and the lack of adequate recognition among clinicians, is also attributed to the cumulative nature of clinical presentations as they intensify with age, such as repeated infections, retention of primary teeth, and scoliosis. It is often only after the emergence of unexplainable severe infections that HIES is identified. Moreover, even within the same mutation, HIES patients exhibit significant clinical phenotype heterogeneity, which calls for further investigation into the underlying mechanisms. The selection bias in our study's inclusion criteria provided us with opportunities to observe findings not commonly reported in previous case series. Our cases often involved long disease courses, with patients presenting with recurrent severe infections, particularly in the lungs, and a considerable number developing severe pulmonary complications, indicating a relatively advanced stage of the disease. By reviewing the disease progression in these patients, we have gained insights into a more complete progression pattern of pulmonary disease in HIES. The pathogenic genes of HIES are not limited to STAT3 ; however, its main pathogenic mechanisms and gene mutations still revolve around the JAK-STAT pathway. Since all patients in our study exhibited STAT3 gene mutations, our discussion will primarily focus on STAT3-HIES. By summarizing our case series and reviewing previous case series, we have characterized the pulmonary disease trajectory of these patients in three stages. The first stage typically presents symptoms from birth to early childhood, with recurrent pulmonary infections predominantly caused by Staphylococcus aureus . The second stage usually occurs from childhood to adolescence and is characterized by pulmonary structural damage, including abscesses, cavitation, bronchiectasis, lung cysts, and the onset of mixed infections. The pathogens become increasingly diverse, including Pseudomonas aeruginosa, Aspergillus /fungus and Mycobacterium tuberculosis . The third stage typically occurs from adolescence to adulthood, entering a malignant cycle of pulmonary infection and structural damage. Pulmonary infections become difficult to control, leading to a progressive decline in lung function. Severe cases may present with massive hemoptysis, pulmonary arterial hypertension, recurrent hospitalizations, significantly reduced quality of life, and some cases may result in death. From a pathophysiological perspective, the mechanisms of recurrent infections and the aetiology in the first stage are relatively clear. STAT3 is a critical cytoplasmic protein. Its dysregulation results in defects in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, impairing T helper cell type 17 (Th17) differentiation and function [ 57 – 59 ]. This, in turn, reduces neutrophil proliferation, diminishes chemotactic activity, suppresses inflammation, and heightens vulnerability to bacterial and fungal infections [ 60 – 62 ]. Both keratinocytes and bronchial epithelial cells require combined stimulation from Th17 and classical proinflammatory cytokines to produce anti-Staphylococcal agents, elucidating the prevalence of Staphylococcal infections in the skin and respiratory tract [ 63 ]. The production of inflammatory cytokines is compromised, leading to a subtle inflammatory response, which manifests as cold abscesses in some HIES patients [ 13 , 62 ]. The turning point in the patient's disease course is the destruction of the pulmonary structure. In our study, the average time from pulmonary structural damage to the onset of Aspergillus /fungus infection is 5 ± 3years. In other words, once transitioned from the second stage to the third stage, the microbiology of pulmonary infections in patients quickly changes from a relatively simple Staphylococcus aureus infection to mixed infections, including Pseudomonas aeruginosa, Aspergillus /fungus and Mycobacterium tuberculosis . This leads to the onset of a malignant cycle of pulmonary infection and structural damage, resulting in progressive deterioration of the condition. For HIES patients, the known clear cause of pulmonary structural damage is recurrent infections. However, our observational study results have revealed phenomena that cannot be explained solely by this cause: (1) The time from initial pneumonia to the appearance of pulmonary structural damage is very short, with a median time of 0 (-16 ~ 10)year. (2) Our observations revealed that HIES patients had a higher proportion of cystic lesions compared to other immunodeficiency disorders with recurrent pulmonary infections. (3) We noted that pulmonary complications, such as pneumatocele, could occur not only during acute infections but also in non-infectious periods. (4) In patients with other genetic mutations, the occurrence of pulmonary structural damage, especially pneumatoceles, is less frequent, while in STAT3 mutation patients, it accounts for 80.0%. Collectively, these findings lead us to postulate that there are unique pathophysiological mechanisms behind pulmonary structural damage, particularly cystic lesions. Based on these findings, we hypothesize that there may be unique pathophysiological mechanisms underlying pulmonary structural damage, particularly cystic lesions, in patients with STAT3-HIES. Previous researches have suggested several potential mechanisms that may contribute to this phenomenon. The first potential mechanism underlying pulmonary structural damage in HIES patients is impaired lung tissue repair. Studies using mouse models with selective respiratory epithelial STAT3 deficiency have demonstrated that STAT3-dependent repair of bronchiolar and alveolar epithelium is critical for maintaining lung tissue integrity [ 64 ]. Hokuto et al. discovered that mice with STAT3 deficiency in respiratory epithelial cells experienced accelerated lung injury, abnormal alveolocapillary integrity, surfactant deficiency, and poor lung mechanics, leading to epithelial and vascular damage [ 65 ]. The second potential mechanism involves the impact of STAT3 mutations on airway epithelial function. Research by Zhang et al. suggested that STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells [ 12 ]. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration [ 12 ]. These findings all suggest that in addition to impaired lung tissue repair following infection-induced injury, HIES patients possess inherent mechanical and inflammatory defects in the respiratory epithelium. Moreover, an unexpected finding in our study was the incidental discovery of a pulmonary bulla in a patient with a STAT3 mutation despite the absence of pulmonary infection. In patients with HIES, due to abnormalities in the JAK-STAT pathway, the inflammatory response is suppressed, and clinical manifestations following infections are often mild, making the condition prone to being overlooked or masked. It is highly likely that this particular patient experienced a subclinical or occult pulmonary infection process that went unnoticed. During follow-up, this patient did not exhibit recurrent or severe pulmonary infections or structural lung damage, and the overall pulmonary manifestations were relatively mild. This also suggests that, prior to the onset of severe and obvious infections or structural lung damage, patients may already have occult infections and subtle structural changes in the lungs that go undetected. Therefore, monitoring the condition of HIES patients cannot rely solely on symptoms; objective assessments such as imaging are necessary. Based on our observational findings and the mechanistic research, the treatment of pulmonary disease in HIES patients may benefit from an expanded focus on targeting epithelial and immune cells. For example, therapies targeting the cystic fibrosis transmembrane conductance regulator (CFTR) modulation for cystic fibrosis, a genetic mutation disease, may offer valuable insights. CFTR modulator therapies aim to enhance the production, intracellular processing, and function of defective CFTR protein [ 66 , 67 ]. Gene therapy and stem cell-based therapy represent promising avenues for the treatment of genetic diseases. Similarly, inhalable pharmacological activation of the STAT3 signaling pathway may hold the potential for restoring normal airway epithelial cell structure, host defense function, and injury repair. Further exploration of these therapeutic strategies is warranted. Research into the mechanisms of pulmonary disease in HIES is sparse, particularly investigations beyond infectious etiologies. Given the rarity of HIES, previous studies have been observational, and early-onset pulmonary structural damage has not been addressed in case reports. We have found few related basic research studies. Therefore, in addition to correcting poorly functioning immune cells, we provide evidence that therapies targeting STAT3-dependent airway epithelial cell abnormalities may be useful in eradicating pathogens and reducing pulmonary complications. Pulmonary complications are responsible for high morbidity and mortality rates in patients with HIES. Meanwhile, pulmonary symptoms are a heavy burden for these patients. Hence, comprehending the development of pulmonary abnormalities and the mechanisms driving them is essential for the prophylaxis and control of pulmonary disease and critically important for enhancing the survival quality and prognostic outcomes of patients. By conducting a retrospective analysis of the clinical data from the 10 patients with HIES, with special emphasis on the 9 cases that developed pulmonary complications, we have attained a deeper insight into the clinical phenotype of HIES, specifically concerning the pulmonary manifestations of the disorder. Our study has several limitations. First, the retrospective nature of the study and the small sample size may introduce selection bias and limit the generalizability of our findings. Second, the lack of comprehensive pulmonary function data limits our ability to fully characterize the functional impact of lung disease in HIES patients. Future studies should address these limitations by incorporating prospective designs, larger cohorts, and systematic functional assessments. Conclusions The progression of pulmonary disease in HIES patients underscores a critical three-step process: initial recurrent infections, development of structural lung damage, and subsequent reinfections that aggravate the damage. This rapid transition from infection to structural damage, especially in patients with STAT3 mutations, highlights the importance of early and aggressive intervention. Managing reinfections after structural lung damage is essential to prevent further deterioration and to improve long-term outcomes. Abbreviations ABPA: allergic bronchopulmonary aspergillosis ACMG: the American College of Medical Genetics and Genomics CCPA: chronic cavitary pulmonary aspergillosis CFTR: cystic fibrosis transmembrane conductance regulator CT: computerized tomography CXR: chest X-ray HIES: hyper-IgE syndromes IVIG: intravenous immunoglobulin JAK-STAT: the Janus kinase-signal transducer and activator of transcription MRSA: Methicillin-resistant Staphylococcus aureus NIH: the National Institutes of Health PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses PUMCH: Peking Union Medical College Hospital STAT3 : the signal transducer and activator of the transcription 3 Th17: T helper cell type 17 Declarations Ethics approval and consent to participate: This study was approved by the Institutional Review Board of PUMCH and conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from all participants. Consent for publication: Not applicable. Availability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests: The authors declare that they have no competing interests. Funding: This work was supported by the National Natural Science Foundation of China (Grant No.82071841); 2019 Discipline Development Project of Peking Union Medical College (Grant No. 201920200106), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-044) and Beijing Key Clinical Specialty Program. Authors’ Contributions: Responsible/contributed to study design:TX, NX, YZ, XZ; Recruitment of patients, collection, and interpretation of data: NX, MP, TZ, HF, YZ; Reevaluation of imaging: MP, TZ; Data analyses: HZ, YH, JW, HD; Writing/revising of manuscript: TX, YZ. All authors read and approved the final manuscript. Acknowledgements: We are grateful to all study participants for their cooperation. We are grateful to the support of National Natural Science Foundation of China, 2019 Discipline Development Project of Peking Union Medical College, National High Level Hospital Clinical Research Funding and Beijing Key Clinical Specialty Program. References Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O et al : Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome . Nature 2007, 448 (7157):1058-1062. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML et al : STAT3 mutations in the hyper-IgE syndrome . N Engl J Med 2007, 357 (16):1608-1619. Renner ED, Rylaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, Zhu Q, Jansson AF, Barboza J, Schimke LF et al : Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome . J Allergy Clin Immunol 2008, 122 (1):181-187. Asano T, Khourieh J, Zhang P, Rapaport F, Spaan AN, Li J, Lei W-T, Pelham SJ, Hum D, Chrabieh M et al : Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance . J Exp Med 2021, 218 (8). Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker E-O, Pietrogrande MC, Cossu F, Franco JL, Matamoros N et al : Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome . J Allergy Clin Immunol 2010, 125 (2). Mogensen TH: STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties . JAKSTAT 2013, 2 (2):e23435. Chandesris M-O, Melki I, Natividad A, Puel A, Fieschi C, Yun L, Thumerelle C, Oksenhendler E, Boutboul D, Thomas C et al : Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey . Medicine (Baltimore) 2012, 91 (4). Kröner C, Neumann J, Ley-Zaporozhan J, Hagl B, Meixner I, Spielberger BD, Dückers G, Belohradsky BH, Niehues T, Borte M et al : Lung disease in STAT3 hyper-IgE syndrome requires intense therapy . Allergy 2019, 74 (9):1691-1702. Minegishi Y: Hyper-IgE syndrome, 2021 update . Allergol Int 2021, 70 (4):407-414. Freeman AF, Olivier KN: Hyper-IgE Syndromes and the Lung . Clin Chest Med 2016, 37 (3):557-567. Gilje EA, Abbott JK: The pulmonary effects of STAT3 deficiency . J Allergy Clin Immunol 2023, 152 (2):368-370. Zhang Y, Lin T, Leung HM, Zhang C, Wilson-Mifsud B, Feldman MB, Puel A, Lanternier F, Couderc L-J, Danion F et al : STAT3 mutation-associated airway epithelial defects in Job syndrome . J Allergy Clin Immunol 2023, 152 (2):538-550. Davis SD, Schaller J, Wedgwood RJ: Job's Syndrome. Recurrent, "cold", staphylococcal abscesses . Lancet 1966, 1 (7445):1013-1015. Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K et al : Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry . J Allergy Clin Immunol Pract 2018, 6 (3). Yun Li WD, Wanle Xiong: A case report of Hyperige syndrome . Shanghai Journal of Immunology 1984(05):302-303. Wu J, Chen J, Tian Z-Q, Zhang H, Gong R-L, Chen T-X, Hong L: Clinical Manifestations and Genetic Analysis of 17 Patients with Autosomal Dominant Hyper-IgE Syndrome in Mainland China: New Reports and a Literature Review . J Clin Immunol 2017, 37 (2):166-179. Lin L, Wang Y, Sun B, Liu L, Ying W, Wang W, Zhou Q, Hou J, Yao H, Hu L et al : The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations . Allergy Asthma Clin Immunol 2020, 16 :65. Na Xu HF, Jing Zhao, Peng Wang, Hongmei Song, Xuejun Zeng: Hyper-IgE Syndromes in adults: report of 5 cases and literature review . Chinese Journal of General Practitioners 2017, 16 (12):955-960. Grimbacher B, Schäffer AA, Holland SM, Davis J, Gallin JI, Malech HL, Atkinson TP, Belohradsky BH, Buckley RH, Cossu F et al : Genetic linkage of hyper-IgE syndrome to chromosome 4 . Am J Hum Genet 1999, 65 (3):735-744. ClinVar . http://www.ncbi.nlm.nih.gov/clinvar. Accessed 4 April 2025. OMIM . http://www.omim.org. Accessed 4 April 2025. Human Gene Mutation Database . http://www.hgmd.org. Accessed 4 April 2025. SIFT . http://sift.jcvi.org. Accessed 4 April 2025. Polymorphism Phenotyping v2 . http://genetics.bwh.harvard.edu/pph2. Accessed 4 April 2025. Combined Annotation Dependent Depletion . http://cadd.gs.washington.edu. Accessed 4 April 2025. MutationTaster . http://www.mutationtaster.org. Accessed 4 April 2025. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al : Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology . Genet Med 2015, 17 (5):405-424. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . PLoS Med 2009, 6 (7):e1000097. Erlewyn-Lajeunesse MD: Hyperimmunoglobulin-E syndrome with recurrent infection: a review of current opinion and treatment . Pediatr Allergy Immunol 2000, 11 (3):133-141. Kimata H: High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome . J Allergy Clin Immunol 1995, 95 (3):771-774. Bork K, Bygum A, Hardt J: Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients . Ann Allergy Asthma Immunol 2008, 100 (2):153-161. Arora M, Bagi P, Strongin A, Heimall J, Zhao X, Lawrence MG, Trivedi A, Henderson C, Hsu A, Quezado M et al : Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome . J Clin Immunol 2017, 37 (7):695-700. Farmand S, Kremer B, Häffner M, Pütsep K, Bergman P, Sundin M, Ritterbusch H, Seidl M, Follo M, Henneke P et al : Eosinophilia and reduced STAT3 signaling affect neutrophil cell death in autosomal-dominant Hyper-IgE syndrome . Eur J Immunol 2018, 48 (12):1975-1988. Alyasin S, Esmaeilzadeh H, Ebrahimi N, Nabavizadeh SH, Kashef S, Esmaeilzadeh E, Babaei M, Amin R: Phenotyping and long-term follow up of patients with hyper IgE syndrome . Allergol Immunopathol (Madr) 2019, 47 (2):152-158. Tavassoli M, Abolhassani H, Yazdani R, Ghadami M, Azizi G, Abdolrahim Poor Heravi S, Moeini Shad T, Kokabee M, Movahedi M, Abdshahzadeh H et al : The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long-term follow-up and genetic analysis . Pediatr Allergy Immunol 2019, 30 (4):469-478. Lorenzini T, Giacomelli M, Scomodon O, Cortesi M, Rivellini V, Dotta L, Soresina A, Dellepiane RM, Carrabba M, Cossu F et al : Autosomal-dominant hyper-IgE syndrome is associated with appearance of infections early in life and/or neonatal rash: Evidence from the Italian cohort of 61 patients with elevated IgE . J Allergy Clin Immunol Pract 2019, 7 (6). Khourieh J, Rao G, Habib T, Avery DT, Lefèvre-Utile A, Chandesris M-O, Belkadi A, Chrabieh M, Alwaseem H, Grandin V et al : A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance . Proc Natl Acad Sci U S A 2019, 116 (33):16463-16472. Xiang Q, Zhang L, Liu X, Wang S, Wang T, Xiao M, Zhao X, Jiang L: Autosomal dominant hyper IgE syndrome from a single centre in Chongqing, China (2009-2018) . Scand J Immunol 2020, 91 (6):e12885. Saikia B, Rawat A, Minz RW, Suri D, Pandiarajan V, Jindal A, Sahu S, Karim A, Desai M, Taur PD et al : Clinical Profile of Hyper-IgE Syndrome in India . Front Immunol 2021, 12 :626593. Frede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, Hübscher K, Gámez-Díaz L, Proietti M, Saghafi S, Chavoshzadeh Z, Soler-Palacin P et al : Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis . J Clin Immunol 2021, 41 (8):1804-1838. Shamriz O, Rubin L, Simon AJ, Lev A, Barel O, Somech R, Korem M, Matza Porges S, Freund T, Hagin D et al : Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience . Front Immunol 2022, 13 :1044933. Yaakoubi R, Mekki N, Ben-Mustapha I, Ben-Khemis L, Bouaziz A, Ben Fraj I, Ammar J, Hamzaoui A, Turki H, Boussofara L et al : Diagnostic challenge in a series of eleven patients with hyper IgE syndromes . Front Immunol 2022, 13 :1057679. 2018 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference . J Clin Immunol 2018, 38 (3):330-444. Carrabba M, Dellepiane RM, Cortesi M, Baselli LA, Soresina A, Cirillo E, Giardino G, Conti F, Dotta L, Finocchi A et al : Long term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job's syndrome . Allergy Asthma Clin Immunol 2023, 19 (1):32. Dmenska H, Heropolitanska E, Pietrucha B, Bernatowska E: Pulmonary features of autosomal dominant hyper-IgE syndrome [AD HIES] . European Respiratory Journal 2011, 38 (Suppl 55):p3600. Duréault A, Tcherakian C, Poiree S, Catherinot E, Danion F, Jouvion G, Bougnoux ME, Mahlaoui N, Givel C, Castelle M et al : Spectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency . J Allergy Clin Immunol Pract 2019, 7 (6). Freeman AF, Renner ED, Henderson C, Langenbeck A, Olivier KN, Hsu AP, Hagl B, Boos A, Davis J, Marciano BE et al : Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome . J Clin Immunol 2013, 33 (5):896-902. Mahdaviani SA, Ghadimi S, Fallahi M, Hashemi-Moghaddam SA, Chavoshzadeh Z, Puel A, Rezaei N, Rekabi M, Daneshmandi Z, Sheikhy K et al : Interventional pulmonary procedures and their outcomes in patients with STAT3 hyper IgE syndrome . BMC Surg 2023, 23 (1):289. Urban AK, Darnell D, Peterson J, Welch P, Freeman AF, Olivier KN: Characterization of Lung Disease in Autosomal Dominant Hyper IgE Syndrome . In: C35 CLINICAL STUDIES IN IMMUNODEFICIENCY. edn.: A4797-A4797. Shahin T, Aschenbrenner D, Cagdas D, Bal SK, Conde CD, Garncarz W, Medgyesi D, Schwerd T, Karaatmaca B, Cetinkaya PG et al : Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function . Haematologica 2019, 104 (3):609-621. Béziat V, Tavernier SJ, Chen Y-H, Ma CS, Materna M, Laurence A, Staal J, Aschenbrenner D, Roels L, Worley L et al : Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome . J Exp Med 2020, 217 (6). Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, Patiroglu T, Unal E, Ozdemir MA, Jouhadi Z et al : Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels . J Allergy Clin Immunol 2014, 133 (5). Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E et al : Germline hypomorphic CARD11 mutations in severe atopic disease . Nat Genet 2017, 49 (8):1192-1201. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T et al : Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity . Immunity 2006, 25 (5):745-755. Lyons JJ, Liu Y, Ma CA, Yu X, O'Connell MP, Lawrence MG, Zhang Y, Karpe K, Zhao M, Siegel AM et al : ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans . J Exp Med 2017, 214 (3):669-680. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM: Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder . N Engl J Med 1999, 340 (9):692-702. Hillmer EJ, Zhang H, Li HS, Watowich SS: STAT3 signaling in immunity . Cytokine Growth Factor Rev 2016, 31 . Darnell JE: STATs and gene regulation . Science 1997, 277 (5332):1630-1635. Minegishi Y, Karasuyama H: Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency . Int Immunol 2009, 21 (2):105-112. Hill HR, Ochs HD, Quie PG, Clark RA, Pabst HF, Klebanoff SJ, Wedgwood RJ: Defect in neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses . Lancet 1974, 2 (7881):617-619. Ochs HD, Oukka M, Torgerson TR: TH17 cells and regulatory T cells in primary immunodeficiency diseases . J Allergy Clin Immunol 2009, 123 (5). Hill HR, Quie PG: Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections . Lancet 1974, 1 (7850):183-187. Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T et al : Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome . J Exp Med 2009, 206 (6):1291-1301. Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BLM: IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells . Proc Natl Acad Sci U S A 2014, 111 (35):E3641-E3649. Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl A-KT, Hull WM, Wert SE, Whitsett JA: Stat-3 is required for pulmonary homeostasis during hyperoxia . J Clin Invest 2004, 113 (1):28-37. King NE, Suzuki S, Barillà C, Hawkins FJ, Randell SH, Reynolds SD, Stripp BR, Davis BR: Correction of Airway Stem Cells: Genome Editing Approaches for the Treatment of Cystic Fibrosis . Hum Gene Ther 2020, 31 (17-18):956-972. Suzuki S, Crane AM, Anirudhan V, Barillà C, Matthias N, Randell SH, Rab A, Sorscher EJ, Kerschner JL, Yin S et al : Highly Efficient Gene Editing of Cystic Fibrosis Patient-Derived Airway Basal Cells Results in Functional CFTR Correction . Mol Ther 2020, 28 (7):1684-1695. Table 1 and 2 Table 1 and 2 are available in the Supplementary Files section. Supplementary Files Table1and2.docx SupplementaryfilesHIES.docx Cite Share Download PDF Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Accept 21 Apr, 2025 Reviewers invited by journal 11 Apr, 2025 Editor assigned by journal 11 Apr, 2025 First submitted to journal 07 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5618843","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":441884041,"identity":"a9e8ccec-b5b2-4449-8452-143201fa918d","order_by":0,"name":"Tiange Xie","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tiange","middleName":"","lastName":"Xie","suffix":""},{"id":441884042,"identity":"9a43d368-edb0-4013-8801-a9471cd8099c","order_by":1,"name":"Na Xu","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Xu","suffix":""},{"id":441884043,"identity":"f0cd3f47-57ad-480f-8a45-e8b80f63f031","order_by":2,"name":"He Zhao","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Zhao","suffix":""},{"id":441884044,"identity":"b7d20691-6380-42ac-8c47-beb8e3a671e1","order_by":3,"name":"Yingdong Han","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingdong","middleName":"","lastName":"Han","suffix":""},{"id":441884045,"identity":"272bcc69-0adb-4090-ae9e-d8a67693c4a1","order_by":4,"name":"Juan Wu","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Wu","suffix":""},{"id":441884046,"identity":"8f5c3a52-dd3c-465a-9e85-3378d54c8e70","order_by":5,"name":"Hong Di","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Di","suffix":""},{"id":441884047,"identity":"9a98b333-8b4f-4814-91ce-843f441df37e","order_by":6,"name":"Min Peng","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Peng","suffix":""},{"id":441884048,"identity":"f6cf440e-7e6b-4a99-bcce-7e815bc557ab","order_by":7,"name":"Ting Zhang","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Zhang","suffix":""},{"id":441884049,"identity":"4d08c3a9-c9d7-49f6-825d-357db12fc7b5","order_by":8,"name":"Hongwei Fan","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongwei","middleName":"","lastName":"Fan","suffix":""},{"id":441884050,"identity":"c162a2d8-836d-4142-999e-9dc93245fffb","order_by":9,"name":"Yun Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYDACCSjNxsx84MCHChCTh0gtfOxtiQ9nnCFFixzPGWNjzjYitMjPbn728Gvb4Tw2ibQ0acZ5dxLXtp89wPBzB24tjHOOmRvLth0uZpNIPiZduO1Z4rYzeQmMvWdwa2GWSDCTlmw7nNgGsmXmtsOJ227wGDAztuHWwiaR/g2qJcdMmncOEVp4gColP4K0gLzP20CEFgmJnDJphnPpiW3gQD72zHjbmRyDg714tMjPSN8m+aPMOnF+Mygqa+7Ibjt+xvDBTzxawEHAywZnH0Ai8QDGH3/QtIyCUTAKRsEoQAYAa+1ZSaao8fwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6373-0647","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yun","middleName":"","lastName":"Zhang","suffix":""},{"id":441884051,"identity":"040fc401-0669-4a51-917d-d8cee06b90bc","order_by":10,"name":"Xuejun Zeng","email":"","orcid":"","institution":"PUMCH: Peking Union Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuejun","middleName":"","lastName":"Zeng","suffix":""}],"badges":[],"createdAt":"2024-12-10 17:57:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5618843/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5618843/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03749-6","type":"published","date":"2025-06-03T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80785450,"identity":"cc970f0f-1bf5-4aaf-ac7f-2c3eb5cbf724","added_by":"auto","created_at":"2025-04-17 05:41:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":493032,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT of characteristic lung damage of parenchyma and airways in adult patients with STAT3-HIES.\u003c/p\u003e\n\u003cp\u003eA (Patient #6): Thin-walled cysts in the left upper lobe.\u003c/p\u003e\n\u003cp\u003eB\u0026amp;C (Patient #4): Large pneumatoceles in the left upper lobe.\u003c/p\u003e\n\u003cp\u003eD (Patient #7): Ground-glass opacities and marked bronchiectasis with mucoid impactions.\u003c/p\u003e\n\u003cp\u003eE (Patient #6): Central bronchiectasis and visible dilatation of the airways.\u003c/p\u003e\n\u003cp\u003eF (Patient #5): Multiple cavitary lesions with thickened walls, marked bronchiectasis, and surrounding consolidation, indicative of CCPA.\u003c/p\u003e\n\u003cp\u003eG (Patient #4): Bronchiectasis with a finger-in-glove sign, indicating bronchial impaction with mucus and air-fluid levels, suggestive of ABPA.\u003c/p\u003e\n\u003cp\u003eH (Patient #9): Cavitary lesions with thick posterior walls and air-fluid levels.\u003c/p\u003e\n\u003cp\u003eI (Patient #8): Extensive cavitation with thick posterior walls.\u003c/p\u003e\n\u003cp\u003eJ (Patient #7): Pneumothorax with mediastinal shift, secondary to a large ruptured pneumatocele or bulla.\u003c/p\u003e\n\u003cp\u003eK (Patient #7): Giant bulla with significant compression of adjacent lung tissue; there is a centrally located aspergilloma within one of the cavities.\u003c/p\u003e\n\u003cp\u003eL (Patient #5): Multiple pneumatoceles and thick-walled cystic spaces, indicating severe structural lung damage.\u003c/p\u003e","description":"","filename":"Figure.1web.png","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/b70e1dee3e404135d8f1a305.png"},{"id":80785455,"identity":"1af5d1c2-5eb4-4501-9c25-bd2f9700ea4c","added_by":"auto","created_at":"2025-04-17 05:41:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":537450,"visible":true,"origin":"","legend":"\u003cp\u003eHistological Features of Pulmonary disease in STAT3-HIES\u003c/p\u003e\n\u003cp\u003eA (HE, 10x) : Inflammatory exudate and mild chronic inflammation of the bronchial mucosa (#8, bronchial mucosa), with scattered eosinophil infiltration.\u003c/p\u003e\n\u003cp\u003eB (HE, 20x) : Substantial infiltration of inflammatory cells in the submucosa of the bronchus (#8, anterior segment of the left upper lobe), with granuloma formation, multinucleated giant cells, and necrosis. Special staining suggests a fungal infection.\u003c/p\u003e\n\u003cp\u003eC (HE, 10x) : Extensive infiltration of inflammatory cells in the submucosa of the bronchus (#8, left main bronchus), with granuloma formation, multinucleated giant cells, and necrosis.\u003c/p\u003e\n\u003cp\u003eD (HE, 40x) : Neutrophils, eosinophils, and ciliated columnar epithelial cells in bronchial brushings (#4, bronchoscopy brushings).\u003c/p\u003e","description":"","filename":"Figure.2web.png","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/043bef61cc9de11d35aa2fea.png"},{"id":80785468,"identity":"fa1e6a9b-1db2-48a6-851b-8548f712a25e","added_by":"auto","created_at":"2025-04-17 05:41:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1111026,"visible":true,"origin":"","legend":"\u003cp\u003eThree stages of pulmonary disease in adult patients with STAT3-HIES and the potential pathogenesis.\u003c/p\u003e\n\u003cp\u003eA. Stage 1: Recurrent pulmonary infections (0-10 years old), patients with STAT3-HIES exhibit a defect in the JAK-STAT signaling pathway, leading to impaired differentiation and function of Th17. This affects neutrophil chemotaxis and proliferation. Also, it reduces the production of antimicrobial peptides, as respiratory epithelial cells and keratinocytes rely on IL-17 to produce these peptides. Ultimately, this defect increases susceptibility to \u003cem\u003eStaphylococcus aureus \u003c/em\u003einfections, primarily affecting the skin and respiratory tract. Patients in early childhood often present with recurrent respiratory infections.\u003c/p\u003e\n\u003cp\u003eB. Stage 2: Pulmonary tissue damage (6-22 years old), repeated infections cause pulmonary tissue damage due to significant pulmonary susceptibility and impaired post-injury repair resulting from primary pulmonary abnormalities. This cycle of recurrent infections progressively damages lung tissue, while impaired repair mechanisms lead to permanent structural changes. As this cycle continues, pulmonary damage worsens, making patients more prone to develop bronchiectasis and pulmonary cysts.\u003c/p\u003e\n\u003cp\u003eC. Stage 3: Severe pulmonary damage with uncontrolled and mixed infections(22-34 years old), patients enter a malignant cycle of pulmonary structural damage and infection, with a shift in pathogens towards predominantly mixed infections involving \u003cem\u003eAspergillus\u003c/em\u003e/fungus, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. Additionally, patients exhibit abnormal differentiation of airway epithelium, characterized by decreased ciliated cells and increased goblet cells and club cells, resulting in excessive mucus secretion. These changes facilitate pathogen adherence to the local airway surfaces. Furthermore, during this process, there is a reduction in proinflammatory cytokines, collectively exacerbating the risk of infection. Severe structural abnormalities of the lungs and uncontrollable infections often develop in this stage.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/b33a9c641b70982cf8c2c2f0.png"},{"id":84242490,"identity":"06e43b56-f62f-4952-bb43-0686404e090f","added_by":"auto","created_at":"2025-06-09 16:08:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5069682,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/9ab7b4b6-2d78-4134-b273-270302f5c2a8.pdf"},{"id":80785474,"identity":"40b98dd9-a7b8-4aa9-b1ec-317ab2df2bba","added_by":"auto","created_at":"2025-04-17 05:41:05","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":43505,"visible":true,"origin":"","legend":"","description":"","filename":"Table1and2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/66fe27760e9c36ba717e7a15.docx"},{"id":80785480,"identity":"b32b0a6e-4fe6-426d-9303-5ebcea82da07","added_by":"auto","created_at":"2025-04-17 05:41:07","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":154114,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfilesHIES.docx","url":"https://assets-eu.researchsquare.com/files/rs-5618843/v1/76cc587387e7b25acffda99f.docx"}],"financialInterests":"","formattedTitle":"Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: A single-centre clinical study and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe hyper-IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders characterized by a triad of increased infection susceptibility, eczema, and raised serum IgE. Patients with HIES presented with recurrent skin and lung infections after birth. Major causal variants are dominant-negative variants in the signal transducer and activator of the transcription 3 (\u003cem\u003eSTAT3\u003c/em\u003e) gene [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClose approximate incidence of HIES incidence is unknown, but it is estimated to range from 1 in 500,000 to 1 in 100,000 [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Due to the rarity of this disease and the lack of widespread genetic testing technology in earlier years, patients often experience delayed diagnosis, sometimes not being diagnosed until adulthood. By this time, patients may already have developed severe pulmonary complications, including secondary severe infections on the basis of structural lung disease, which is their primary cause of mortality [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePulmonary complications are the primary factors affecting the quality of life and long-term prognosis in HIES patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our understanding of pulmonary disease in HIES continues to evolve. Previously, it was believed that pulmonary disease in patients with HIES could be attributed to multiple factors, with the most significant cause being parenchymal lung damage due to frequent and severe infections [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Other causes include autoinflammation driven by a dysregulated immune system [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent research suggests that we may have underestimated the significant pulmonary susceptibility and impaired post-injury repair caused by primary pulmonary abnormalities [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Overall, research on pulmonary disease in HIES is limited, and the underlying mechanisms of structural lung damage remain unclear.\u003c/p\u003e \u003cp\u003eEarly identification is essential for patients with HIES. The first case reports date back to 1966 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and HIES awareness has been gradually increasing, facilitating early detection of the syndromes. Most patients are diagnosed during childhood, leading to better prognosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, in China, recognition of this disease came relatively late, with the first cases reported in 1984 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Many patients are only definitively diagnosed in adulthood, and prolonged diagnosis is associated with poorer outcomes. Researches have predominantly focused on pediatric patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with only one study addressing adults who received a delayed diagnosis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In many developing countries, HIES are still not widely recognized, and genetic testing technology has yet to be adopted in wider ranges, resulting in a significant number of adults with delayed diagnoses that represent a critical subgroup within the HIES patient population.\u003c/p\u003e \u003cp\u003eWe aim to gain insight into the natural course of HIES and the progression of pulmonary disease through a review of the literatures and summarizing adult HIES patients in our study. This will improve our understanding of pulmonary diseases in HIES and aid in better management of these patients.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eFrom January 2016 to October 2023, ten patients aged 18 years or older with HIES hospitalized at Peking Union Medical College Hospital (PUMCH) were included in our study. The diagnosis of HIES is based on the diagnostic scoring system established by National Institutes of Health (NIH) in 1999, which utilizes 19 clinical and laboratory criteria[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A score of greater or equal to 40 confirms the diagnosis of HIES. Also, Whole-exome sequencing was performed on each patient. Patients need to conform with NIH criteria and have a defect in \u003cem\u003eSTAT3\u003c/em\u003e gene in order to be admitted into the database. Pathogenic variants were identified through curated databases (ClinVar [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], OMIM [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], HGMD Pro [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]), with exclusion of variants showing MAF\u0026thinsp;\u0026ge;\u0026thinsp;0.0001% in control populations (ExAC/gnomAD, 1000 Genomes). Variant pathogenicity was predicted using silico predictive algorithms including SIFT[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], PolyPhen-2[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], CADD[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and MutationTaster[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] with default thresholds. The American College of Medical Genetics and Genomics (ACMG) classification followed the 2015 guidelines[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The clinical data, including patient demographics, clinical presentations, laboratory results, pathological and radiological examinations, treatment protocols, and follow-ups, were collected. In our study, pulmonary structural damage refers to irreversible damage to the lung parenchyma and interstitium caused by various reasons, including bronchiectasis, pulmonary fibrosis, pneumatocele, multiple cavities, lung destruction, and among other structural changes in the lungs. This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (PUMCH) and conducted in compliance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eWe conducted our systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. We searched Medline, Embase, and Pubmed databases for all articles about HIES and selected published articles involving humans and written in English between 1966 and 2023. The keywords used were the following ones: \u0026ldquo;Job Syndrome\u0026rdquo;[Mesh], \u0026ldquo;Hyper-IgE Syndromes,\u0026rdquo; \u0026ldquo;Hyper-IgE Syndrome,\u0026rdquo; etc. The specific search strategy is attached. Articles were then assessed for eligibility. Ultimately, we reviewed the pulmonary conditions of patients reported in all previous literature and summarized findings from cohorts focused on pulmonary disease.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1.1 Demographic features\u003c/p\u003e \u003cp\u003eOur study involved 10 adult patients diagnosed with HIES, all of Chinese descent, including 4 females and 6 males, with a median age of 28.1 years old. HIES diagnosis was confirmed using the NIH scoring system, and \u003cem\u003eSTAT3\u003c/em\u003e mutations were identified in all the patients. These individuals were presenting onset symptoms at birth and diagnosis at a median age of 23 years. The prolonged period from onset to diagnosis, averaging 23 years, underscores a widespread issue of delayed diagnosis.\u003c/p\u003e \u003cp\u003e1.2 Clinical Manifestations\u003c/p\u003e \u003cp\u003eThe clinical spectrum of HIES encompasses both immunological and non-immunological symptoms (Table.1). In our cohort, immunological manifestations predominantly included eczema (100%, 10/10), skin infections (100%, 10/10), and pneumonia (90.0%, 9/10). Non-immunological symptoms were varied, featuring retained primary teeth (42.9%, 3/7), scoliosis (33.3%, 3/9), fractures with minor trauma (50.0%, 4/8), midline anomaly (11.1%, 1/9), hyperextensibility (20.0%, 1/5), characteristic face (88.9%, 8/9), increased nasal width (62.5%, 5/8), and high palates (50.0%,3/6). Laboratory analyses consistently showed elevated IgE levels (100%, 10/10) and an average eosinophil count of 1.52\u0026times;10\u003csup\u003e9\u003c/sup\u003ecells/L (\u0026plusmn;\u0026thinsp;2.65). Notably, two patients developed finger clubbing due to chronic pulmonary issues.\u003c/p\u003e \u003cp\u003e1.3 \u003cem\u003eSTAT3\u003c/em\u003e Mutation\u003c/p\u003e \u003cp\u003eGenetic analysis identified six patients with established pathogenic variants (c.1145G\u0026thinsp;\u0026gt;\u0026thinsp;A, c.1907C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1387_1389delGTG, c.2137G\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1144C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1909G\u0026thinsp;\u0026gt;\u0026thinsp;A; ClinVar-confirmed, absent in ExAC/gnomAD MAF\u0026thinsp;\u0026lt;\u0026thinsp;0.0001%), three with hotspot variants (c.1850C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.994C\u0026thinsp;\u0026gt;\u0026thinsp;A, c.2111_2112insC; ExAC/1000 Genomes MAF\u0026thinsp;\u0026lt;\u0026thinsp;0.001%), and one novel variant (c.53T\u0026thinsp;\u0026gt;\u0026thinsp;C; gnomAD-absent, 4/4 algorithm concordance). All variants met ACMG criteria: established variants were classified as \u003cem\u003epathogenic\u003c/em\u003e (PS1), while hotspot and novel variants were classified as \u003cem\u003elikely pathogenic\u003c/em\u003e (PM1, PM2, and PP3).\u003c/p\u003e\u003cp\u003e2. Pulmonary features of HIES\u003c/p\u003e\n\u003cp\u003e2.1 Overview of Pulmonary involvement\u003c/p\u003e\n\u003cp\u003eAmong all the patients, 9 has lung tissue destruction and the incidence of pneumonia was 90.0% (9/10). Of these 9 patients, only one patient was found to have a pulmonary cyst without pneumonia and to have underwent surgical resection with no pneumonia occurring postoperatively. The other 8 patients all developed varying degrees of pulmonary disease, notably in the form of recurrent pneumonia during the course of the disease and with pulmonary structural damages including bronchiectasis and pneumatocele. These 8 patients typically experienced pulmonary infections within the first 10 years of life (6/8), with 5 cases occurring immediately after birth. In the early stages of the disease, common infections included \u003cem\u003eStaphylococcus aureus\u003c/em\u003e/ Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MRSA) and \u003cem\u003eHaemophilus influenzae\u003c/em\u003e, while later stages saw infections by \u003cem\u003eAspergillus\u003c/em\u003e/fungus, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. Of these patients, one ( #10) had mild pulmonary disease, caused by \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e infection. After anti-infective treatment, the condition of this patient improved without pulmonary structural damage, and the disease remained stable.\u003c/p\u003e\n\u003cp\u003e2.2 Microbiology assessment\u003c/p\u003e\n\u003cp\u003eIn the early stages of repeated lung infections, \u003cem\u003eStaphylococcus aureus\u003c/em\u003e was the most common pathogen, accounting for 90.0% (9/10) of cases. As repeated lung infections led to structural lung damage, the pathogenic spectrum gradually shifted to include \u003cem\u003eAspergillus\u003c/em\u003e species and other fungi (70.0%, 7/10), \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (50.0%, 5/10), and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (40.0%, 4/10). Other identified pathogens included \u003cem\u003eStreptococcus pyogenes\u003c/em\u003e (10.0%, 1/10), \u003cem\u003eHaemophilus influenzae\u003c/em\u003e (10.0%, 1/10), \u003cem\u003eEscherichia coli\u003c/em\u003e (10.0%, 1/10), and \u003cem\u003eFlavobacterium indologenes\u003c/em\u003e (10.0%, 1/10). Other infection-related conditions have also been summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e2.3 Radiological Imaging Assessment\u003c/p\u003e\n\u003cp\u003eAll 8 patients (#1, #3, #4, #5, #6, #7, #8, #9) with recurrent pneumonia showed obvious pulmonary structural damage (80.0%, 8/10). Chest X-ray (CXR) and computerized tomography (CT) assessments revealed lung parenchyma and airway destruction. Recurrent pulmonary infections led to airway remodeling with bronchial wall-thickening, bronchiectasis, mucus-plugging, mosaic perfusion, and expiratory air-trapping. Cystic parenchymal abnormalities included cysts, pneumatoceles, and cavities; these abnormalities arose during infection and often persisted. Frequent parenchymal and airway remodelling are presented in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThe spectrum of CT findings in pulmonary aspergillosis associated with HIES includes (1) aspergillomas (#6, #7, #8), where fungal balls are found within pre-existing lung cavities such as bronchiectasis or pneumatoceles, (2) chronic cavitary pulmonary aspergillosis (CCPA) (#4, #5, #7, #8, #9) characterized by cavity wall thickening, fungal balls, and peri-cavitary infiltrates, and (3) an allergic bronchopulmonary aspergillosis (ABPA) (#4, #8, #9) -like presentation with bronchiectasis and mucoid impactions that resemble toothpaste-shaped or finger-in-glove opacities. Additionally, mixed patterns and occurrences of invasive aspergillosis can also be observed.\u003c/p\u003e\n\u003cp\u003eAdditionally, one patient (#2), without any signs of infection, was incidentally found to have a pneumatocele, which was surgically removed. Seven years after the surgery, there have been no occurrences of pneumonia or further pulmonary structural damage.\u003c/p\u003e\n\u003cp\u003e2.4 Histological Features\u003c/p\u003e\n\u003cp\u003eIn our patients, four cases (#1, #4, #7, #8) underwent bronchoscopy to obtain histological results, one case (#2) had postoperative histology results from surgical resection of a lung bulla, and two cases (#6, #10) had histology obtained via percutaneous needle biopsy (Figure.2). No tumor cells were observed in any of the samples (100%, 7/7). Detailed descriptions were available for five cases. Some presented with acute inflammation (40%, 2/5), while others showed chronic inflammation/granuloma formation (80%, 4/5). Eosinophils were observed in all cases (100%, 5/5). Fungal hyphae were noted in one case (#6), and special staining was positive in one case (#8).\u003c/p\u003e\n\u003cp\u003e2.5 Course of Pulmonary involvement\u003c/p\u003e\n\u003cp\u003eWe summarized the timeline of disease development in 9 patients with pulmonary structural damage detected by imaging (Table.2). Most patients (77.8%, 7/9) had onset after birth, with the age of initial pneumonia occurring at 5 years (\u0026plusmn;\u0026thinsp;5y), age of \u003cem\u003eStaphylococcus aureus\u003c/em\u003e infection at 10 years (\u0026plusmn;\u0026thinsp;7y), median age of pulmonary structural damage at 14 years (\u0026plusmn;\u0026thinsp;8.5y), age of combined \u003cem\u003eAspergillus\u003c/em\u003e/fungus, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eMycobacterium\u003c/em\u003e infections at 27 years (\u0026plusmn;\u0026thinsp;6.75y), age of definite diagnosis at 24 years (\u0026plusmn;\u0026thinsp;6y), and age of surgery at 13 years (\u0026plusmn;\u0026thinsp;7.25y). The average time from onset to definitive diagnosis of these 9 patients was 22 years, and time from initial pneumonia to the identification of pulmonary structural damage was 0 year, with time from structural damage to \u003cem\u003eAspergillus\u003c/em\u003e/fungus infection averaging 5 years. Thus, these patients had onset before the age of 10 years with early-stage infections mainly caused by \u003cem\u003eStaphylococcus aureus\u003c/em\u003e and pulmonary structural damage detected almost simultaneously with the occurrence of infection. After approximately 5 years, infections by \u003cem\u003eAspergillus\u003c/em\u003e/fungus, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e gradually appeared.\u003c/p\u003e\n\u003cp\u003e2.6 Treatment of pulmonary involvement\u003c/p\u003e\n\u003cp\u003ePulmonary treatment primarily targets lung infections and structural lung diseases. During acute lung infections, broad-spectrum antibiotics are the mainstay of treatment. In patients with structural lung disease (such as bronchiectasis and pulmonary cysts), antibiotic coverage for \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e and \u003cem\u003eAspergillus\u003c/em\u003e species is necessary. For prophylactic antibiotic therapy, sulfamethoxazole is chosen for the most common pathogen, \u003cem\u003eStaphylococcus aureus.\u003c/em\u003e In the presence of structural lung disease, itraconazole is used to prevent fungal infections.\u003c/p\u003e\n\u003cp\u003eAdditionally, in cases of CCPA and ABPA, the duration of antibiotic therapy needs to be extended. Among our patients, 100% (10/10) received antibiotics, with 50.0% (5/10) receiving prophylactic antibiotics. Antifungal treatment \u0026ndash; itraconazole, voriconazole, or amphotericin B \u0026ndash; was administered along with extended antibiotic therapy to 7 patients with \u003cem\u003eAspergillus\u003c/em\u003e/fungus infections. Other treatments included local drainage, surgery, interventional procedures, intravenous immunoglobulin (IVIG), vaccination, and regular pathogen monitoring. In our cohort, 60.0% (6/10) of the patients underwent drainage, 50.0% (5/10) of the patients had surgical interventions, and 10.0% (1/10) of the patients received interventional embolization treatment. IVIG use in HIES remains controversial. While some evidence suggest benefits for patients with low immunoglobulin levels or poor vaccine responses[\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e], overall, it shows only mild efficacy, mainly in HIES patients with eczema[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e], and its high cost, potential side effects, and limited accessibility prevent it from being a standard treatment for HIES, though it may help those with severe lung disease[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, we did not routinely use IVIG. However, during follow-up, we observed that some patients attempted treatments with limited evidence, such as IVIG. We provided chest physiotherapy (in the form of postural drainage and percussion) and airway clearance therapies to 8 patients with structural lung disease. None of our patients underwent lung transplantation.\u003c/p\u003e\n\u003cp\u003e3. Treatment of Extrapulmonary involvement\u003c/p\u003e\n\u003cp\u003eThe treatment of our HIES patients adhered to the following principles, focusing on both pulmonary and extrapulmonary aspects. Extrapulmonary treatment included anti-infective therapy for other deep-seated infections. Among our patients, 70.0% (7/10) had infections outside of the skin and respiratory tract, including the lumbar spine, intracranial, endocardium, mediastinum, liver and abdomen, kidneys, and esophagus. All of these patients were treated with antibiotics, and surgery and drainage were performed in 4 cases. Other treatments included skin (for eczema, staphylococcal infections, and mucocutaneous candidiasis), skeletal and connective tissue (vitamin D supplementation, scoliosis monitoring), oral and dental care (regular check-ups, extraction of delayed deciduous teeth), vascular monitoring (regular aneurysm screening), treatment of secondary lymphomas, and genetic counselling, which will not be discussed in detail here. Stem cell transplantation remains controversial, as transplantation\u0026apos;s long-term efficacy and cost-effectiveness for HIES patients remain inadequately established in current research. We did not performed any such transplants.\u003c/p\u003e\n\u003cp\u003e4. Follow-up and Prognosis\u003c/p\u003e\n\u003cp\u003eOf the 10 patients monitored, 5 have achieved a stable condition, 2 continue to necessitate recurrent interventions for persistent infections, 1 developed lymphoma and ultimately succumbed to severe pulmonary infection with septic shock during treatment, and 2 were lost to follow-up.\u003c/p\u003e\n\u003cp\u003e5. Literature review and summary\u003c/p\u003e\n\u003cp\u003e5.1 Case and cohorts of HIES\u003c/p\u003e\n\u003cp\u003eA total of 1,367 articles were retrieved (Figure.S1). Among the articles were 232 cohort studies and 573 case reports. Out of all cohorts, there were 16 national-level large cohorts [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e], with one cohort lacking descriptions of pulmonary disease [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]. Pulmonary complications varied across different countries and regions. The summaries of the pulmonary complications in the other 15 cohorts focused primarily on the incidence of pneumonia, pulmonary cysts, and bronchiectasis (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e). The prevalence of pulmonary structural damage is generally higher, with a range of 15.0\u0026ndash;65.0% for bronchiectasis and a range of 16.7\u0026ndash;68.4% for pneumatocele. Among them, the prevalence of bronchiectasis in HIES patients with \u003cem\u003eSTAT3\u003c/em\u003e mutation is 65.0%, and pneumatocele is 52.0%.\u003c/p\u003e\n\u003cp\u003e5.2 Studies of pulmonary disease in HIES\u003c/p\u003e\n\u003cp\u003eEight out of all cohort studies focused specifically on pulmonary disease, and the summary of them included pulmonary complications, pathogens, surgical interventions, and treatments (Table S2) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e5.3 Pulmonary disease of different gene variants\u003c/p\u003e\n\u003cp\u003eRecently, several new causative variants have been identified, including \u003cem\u003ePGM3\u003c/em\u003e, \u003cem\u003eZNF341\u003c/em\u003e, \u003cem\u003eCARD11\u003c/em\u003e, \u003cem\u003eIL6ST\u003c/em\u003e, \u003cem\u003eIL6R\u003c/em\u003e, \u003cem\u003eTGFBR1/2\u003c/em\u003e, \u003cem\u003eERBB2IP\u003c/em\u003e, and \u003cem\u003eSPINK5\u003c/em\u003e [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e]. We compared the incidence of pulmonary complications among HIES patients with other genetic mutations (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e). For IL6ST mutation, prevalence of bronchiectasis and pneumatocele are 60.0% and 54.5%. For \u003cem\u003eZNF341\u003c/em\u003e mutation, they are 56.3% and 35.3%. However, \u003cem\u003eTGFBR\u003c/em\u003e mutation has been reported in only 10.0% of patients with pneumatocele, and no pulmonary structural damage has been described. Among HIES patients, those with \u003cem\u003eSTAT3\u003c/em\u003e mutations are more likely to experience pulmonary structural damage, particularly pneumatocele formation.\u003c/p\u003e\n\u003cp\u003e5.4 Three stages of pulmonary disease in HIES\u003c/p\u003e\n\u003cp\u003eThrough a review of all previously published cases, the course of pulmonary disease in HIES patients can be generally divided into three stages (Figure.3). The first stage is characterized by recurrent pneumonia (0\u0026ndash;10 years old), primarily caused by \u003cem\u003eStaphylococcus aureus\u003c/em\u003e. The second stage involves pulmonary structural damage (6\u0026ndash;22 years old), including abscesses, cavity formation, bronchiectasis, and pneumatoceles. The third stage enters a malignant cycle of pulmonary structural damage and infection (20\u0026ndash;34 years old), with a predominant shift in pathogens to mixed infections of \u003cem\u003eAspergillus\u003c/em\u003e/fungus, \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. It is noteworthy that the time from the initial pneumonia to pulmonary structural damage is very short, with a median time of 0 years (\u0026plusmn;\u0026thinsp;3.5y). Additionally, the average time from pulmonary structural damage to the onset of \u003cem\u003eAspergillus\u003c/em\u003e/fungus infection is 5 years.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHIES are a heterogeneous group of inborn errors of immunity-sharing manifestations that include increased infection susceptibility, eczema, and raised serum IgE [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Our research presents significant deviations from previous reports, particularly with regard to the onset and diagnosis ages of patients. Former large case series referenced in the literature report onset ages at 0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 years and diagnosis ages at 24\u0026thinsp;\u0026plusmn;\u0026thinsp;8 years. Our cohort, drawn exclusively from the adult department, includes several individuals whose disease onset occurred in adulthood, with the rest experiencing a severe diagnostic delay. The average duration from disease onset to diagnosis spanned 20 years, with the longest case extending up to 36 years. Many patients exhibited symptoms shortly after birth and underwent numerous medical consultations due to recurrent infections, leading to a convoluted path to diagnosis. The delay in diagnosis, aside from HIES's low incidence rate and the lack of adequate recognition among clinicians, is also attributed to the cumulative nature of clinical presentations as they intensify with age, such as repeated infections, retention of primary teeth, and scoliosis. It is often only after the emergence of unexplainable severe infections that HIES is identified. Moreover, even within the same mutation, HIES patients exhibit significant clinical phenotype heterogeneity, which calls for further investigation into the underlying mechanisms.\u003c/p\u003e \u003cp\u003e The selection bias in our study's inclusion criteria provided us with opportunities to observe findings not commonly reported in previous case series. Our cases often involved long disease courses, with patients presenting with recurrent severe infections, particularly in the lungs, and a considerable number developing severe pulmonary complications, indicating a relatively advanced stage of the disease. By reviewing the disease progression in these patients, we have gained insights into a more complete progression pattern of pulmonary disease in HIES. The pathogenic genes of HIES are not limited to \u003cem\u003eSTAT3\u003c/em\u003e; however, its main pathogenic mechanisms and gene mutations still revolve around the JAK-STAT pathway. Since all patients in our study exhibited \u003cem\u003eSTAT3\u003c/em\u003e gene mutations, our discussion will primarily focus on STAT3-HIES.\u003c/p\u003e \u003cp\u003eBy summarizing our case series and reviewing previous case series, we have characterized the pulmonary disease trajectory of these patients in three stages. The first stage typically presents symptoms from birth to early childhood, with recurrent pulmonary infections predominantly caused by \u003cem\u003eStaphylococcus aureus\u003c/em\u003e. The second stage usually occurs from childhood to adolescence and is characterized by pulmonary structural damage, including abscesses, cavitation, bronchiectasis, lung cysts, and the onset of mixed infections. The pathogens become increasingly diverse, including \u003cem\u003ePseudomonas aeruginosa, Aspergillus\u003c/em\u003e/fungus and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. The third stage typically occurs from adolescence to adulthood, entering a malignant cycle of pulmonary infection and structural damage. Pulmonary infections become difficult to control, leading to a progressive decline in lung function. Severe cases may present with massive hemoptysis, pulmonary arterial hypertension, recurrent hospitalizations, significantly reduced quality of life, and some cases may result in death.\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, the mechanisms of recurrent infections and the aetiology in the first stage are relatively clear. STAT3 is a critical cytoplasmic protein. Its dysregulation results in defects in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, impairing T helper cell type 17 (Th17) differentiation and function [\u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. This, in turn, reduces neutrophil proliferation, diminishes chemotactic activity, suppresses inflammation, and heightens vulnerability to bacterial and fungal infections [\u003cspan additionalcitationids=\"CR61\" citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Both keratinocytes and bronchial epithelial cells require combined stimulation from Th17 and classical proinflammatory cytokines to produce anti-Staphylococcal agents, elucidating the prevalence of Staphylococcal infections in the skin and respiratory tract [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. The production of inflammatory cytokines is compromised, leading to a subtle inflammatory response, which manifests as cold abscesses in some HIES patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe turning point in the patient's disease course is the destruction of the pulmonary structure. In our study, the average time from pulmonary structural damage to the onset of \u003cem\u003eAspergillus\u003c/em\u003e/fungus infection is 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3years. In other words, once transitioned from the second stage to the third stage, the microbiology of pulmonary infections in patients quickly changes from a relatively simple \u003cem\u003eStaphylococcus aureus\u003c/em\u003e infection to mixed infections, including \u003cem\u003ePseudomonas aeruginosa, Aspergillus\u003c/em\u003e/fungus and \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e. This leads to the onset of a malignant cycle of pulmonary infection and structural damage, resulting in progressive deterioration of the condition.\u003c/p\u003e \u003cp\u003eFor HIES patients, the known clear cause of pulmonary structural damage is recurrent infections. However, our observational study results have revealed phenomena that cannot be explained solely by this cause: (1) The time from initial pneumonia to the appearance of pulmonary structural damage is very short, with a median time of 0 (-16\u0026thinsp;~\u0026thinsp;10)year. (2) Our observations revealed that HIES patients had a higher proportion of cystic lesions compared to other immunodeficiency disorders with recurrent pulmonary infections. (3) We noted that pulmonary complications, such as pneumatocele, could occur not only during acute infections but also in non-infectious periods. (4) In patients with other genetic mutations, the occurrence of pulmonary structural damage, especially pneumatoceles, is less frequent, while in \u003cem\u003eSTAT3\u003c/em\u003e mutation patients, it accounts for 80.0%. Collectively, these findings lead us to postulate that there are unique pathophysiological mechanisms behind pulmonary structural damage, particularly cystic lesions. Based on these findings, we hypothesize that there may be unique pathophysiological mechanisms underlying pulmonary structural damage, particularly cystic lesions, in patients with STAT3-HIES. Previous researches have suggested several potential mechanisms that may contribute to this phenomenon.\u003c/p\u003e \u003cp\u003eThe first potential mechanism underlying pulmonary structural damage in HIES patients is impaired lung tissue repair. Studies using mouse models with selective respiratory epithelial STAT3 deficiency have demonstrated that STAT3-dependent repair of bronchiolar and alveolar epithelium is critical for maintaining lung tissue integrity [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Hokuto et al. discovered that mice with STAT3 deficiency in respiratory epithelial cells experienced accelerated lung injury, abnormal alveolocapillary integrity, surfactant deficiency, and poor lung mechanics, leading to epithelial and vascular damage [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. The second potential mechanism involves the impact of \u003cem\u003eSTAT3\u003c/em\u003e mutations on airway epithelial function. Research by Zhang et al. suggested that \u003cem\u003eSTAT3\u003c/em\u003e mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These findings all suggest that in addition to impaired lung tissue repair following infection-induced injury, HIES patients possess inherent mechanical and inflammatory defects in the respiratory epithelium.\u003c/p\u003e \u003cp\u003eMoreover, an unexpected finding in our study was the incidental discovery of a pulmonary bulla in a patient with a \u003cem\u003eSTAT3\u003c/em\u003e mutation despite the absence of pulmonary infection. In patients with HIES, due to abnormalities in the JAK-STAT pathway, the inflammatory response is suppressed, and clinical manifestations following infections are often mild, making the condition prone to being overlooked or masked. It is highly likely that this particular patient experienced a subclinical or occult pulmonary infection process that went unnoticed. During follow-up, this patient did not exhibit recurrent or severe pulmonary infections or structural lung damage, and the overall pulmonary manifestations were relatively mild. This also suggests that, prior to the onset of severe and obvious infections or structural lung damage, patients may already have occult infections and subtle structural changes in the lungs that go undetected. Therefore, monitoring the condition of HIES patients cannot rely solely on symptoms; objective assessments such as imaging are necessary.\u003c/p\u003e \u003cp\u003eBased on our observational findings and the mechanistic research, the treatment of pulmonary disease in HIES patients may benefit from an expanded focus on targeting epithelial and immune cells. For example, therapies targeting the cystic fibrosis transmembrane conductance regulator (CFTR) modulation for cystic fibrosis, a genetic mutation disease, may offer valuable insights. CFTR modulator therapies aim to enhance the production, intracellular processing, and function of defective CFTR protein [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Gene therapy and stem cell-based therapy represent promising avenues for the treatment of genetic diseases. Similarly, inhalable pharmacological activation of the STAT3 signaling pathway may hold the potential for restoring normal airway epithelial cell structure, host defense function, and injury repair.\u003c/p\u003e \u003cp\u003eFurther exploration of these therapeutic strategies is warranted. Research into the mechanisms of pulmonary disease in HIES is sparse, particularly investigations beyond infectious etiologies. Given the rarity of HIES, previous studies have been observational, and early-onset pulmonary structural damage has not been addressed in case reports. We have found few related basic research studies.\u003c/p\u003e \u003cp\u003eTherefore, in addition to correcting poorly functioning immune cells, we provide evidence that therapies targeting STAT3-dependent airway epithelial cell abnormalities may be useful in eradicating pathogens and reducing pulmonary complications.\u003c/p\u003e \u003cp\u003ePulmonary complications are responsible for high morbidity and mortality rates in patients with HIES. Meanwhile, pulmonary symptoms are a heavy burden for these patients. Hence, comprehending the development of pulmonary abnormalities and the mechanisms driving them is essential for the prophylaxis and control of pulmonary disease and critically important for enhancing the survival quality and prognostic outcomes of patients.\u003c/p\u003e \u003cp\u003eBy conducting a retrospective analysis of the clinical data from the 10 patients with HIES, with special emphasis on the 9 cases that developed pulmonary complications, we have attained a deeper insight into the clinical phenotype of HIES, specifically concerning the pulmonary manifestations of the disorder.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, the retrospective nature of the study and the small sample size may introduce selection bias and limit the generalizability of our findings. Second, the lack of comprehensive pulmonary function data limits our ability to fully characterize the functional impact of lung disease in HIES patients. Future studies should address these limitations by incorporating prospective designs, larger cohorts, and systematic functional assessments.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe progression of pulmonary disease in HIES patients underscores a critical three-step process: initial recurrent infections, development of structural lung damage, and subsequent reinfections that aggravate the damage. This rapid transition from infection to structural damage, especially in patients with \u003cem\u003eSTAT3\u003c/em\u003e mutations, highlights the importance of early and aggressive intervention. Managing reinfections after structural lung damage is essential to prevent further deterioration and to improve long-term outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eABPA: allergic bronchopulmonary aspergillosis\u003c/p\u003e\n\u003cp\u003eACMG: the American College of Medical Genetics and Genomics\u003c/p\u003e\n\u003cp\u003eCCPA: chronic cavitary pulmonary aspergillosis\u003c/p\u003e\n\u003cp\u003eCFTR: cystic fibrosis transmembrane conductance regulator\u003c/p\u003e\n\u003cp\u003eCT: computerized tomography\u003c/p\u003e\n\u003cp\u003eCXR: chest X-ray\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHIES: hyper-IgE syndromes\u003c/p\u003e\n\u003cp\u003eIVIG: intravenous immunoglobulin\u003c/p\u003e\n\u003cp\u003eJAK-STAT: the Janus kinase-signal transducer and activator of transcription\u003c/p\u003e\n\u003cp\u003eMRSA: Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNIH: the National Institutes of Health\u003c/p\u003e\n\u003cp\u003ePRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e\n\u003cp\u003ePUMCH: Peking Union Medical College Hospital\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSTAT3\u003c/em\u003e: the signal transducer and activator of the transcription 3\u003c/p\u003e\n\u003cp\u003eTh17: T helper cell type 17\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study was approved by the Institutional Review Board of PUMCH and conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the National Natural Science Foundation of China (Grant No.82071841); 2019 Discipline Development Project of Peking Union Medical College (Grant No. 201920200106), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-044) and Beijing Key Clinical Specialty Program.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions:\u003c/strong\u003e Responsible/contributed to study design:TX, NX, YZ, XZ; Recruitment of patients, collection, and interpretation of data: NX, MP, TZ, HF, YZ; Reevaluation of imaging: MP, TZ; Data analyses: HZ, YH, JW, HD; Writing/revising of manuscript: TX, YZ. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe are grateful to all study participants for their cooperation. We are grateful to the support of National Natural Science Foundation of China, 2019 Discipline Development Project of Peking Union Medical College, National High Level Hospital Clinical Research Funding and Beijing Key Clinical Specialty Program.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMinegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eNature \u003c/em\u003e2007, \u003cstrong\u003e448\u003c/strong\u003e(7157):1058-1062.\u003c/li\u003e\n\u003cli\u003eHolland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSTAT3 mutations in the hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2007, \u003cstrong\u003e357\u003c/strong\u003e(16):1608-1619.\u003c/li\u003e\n\u003cli\u003eRenner ED, Rylaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, Zhu Q, Jansson AF, Barboza J, Schimke LF\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNovel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2008, \u003cstrong\u003e122\u003c/strong\u003e(1):181-187.\u003c/li\u003e\n\u003cli\u003eAsano T, Khourieh J, Zhang P, Rapaport F, Spaan AN, Li J, Lei W-T, Pelham SJ, Hum D, Chrabieh M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHuman STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance\u003c/strong\u003e. \u003cem\u003eJ Exp Med \u003c/em\u003e2021, \u003cstrong\u003e218\u003c/strong\u003e(8).\u003c/li\u003e\n\u003cli\u003eWoellner C, Gertz EM, Sch\u0026auml;ffer AA, Lagos M, Perro M, Glocker E-O, Pietrogrande MC, Cossu F, Franco JL, Matamoros N\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2010, \u003cstrong\u003e125\u003c/strong\u003e(2).\u003c/li\u003e\n\u003cli\u003eMogensen TH: \u003cstrong\u003eSTAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties\u003c/strong\u003e. \u003cem\u003eJAKSTAT \u003c/em\u003e2013, \u003cstrong\u003e2\u003c/strong\u003e(2):e23435.\u003c/li\u003e\n\u003cli\u003eChandesris M-O, Melki I, Natividad A, Puel A, Fieschi C, Yun L, Thumerelle C, Oksenhendler E, Boutboul D, Thomas C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAutosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey\u003c/strong\u003e. \u003cem\u003eMedicine (Baltimore) \u003c/em\u003e2012, \u003cstrong\u003e91\u003c/strong\u003e(4).\u003c/li\u003e\n\u003cli\u003eKr\u0026ouml;ner C, Neumann J, Ley-Zaporozhan J, Hagl B, Meixner I, Spielberger BD, D\u0026uuml;ckers G, Belohradsky BH, Niehues T, Borte M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLung disease in STAT3 hyper-IgE syndrome requires intense therapy\u003c/strong\u003e. \u003cem\u003eAllergy \u003c/em\u003e2019, \u003cstrong\u003e74\u003c/strong\u003e(9):1691-1702.\u003c/li\u003e\n\u003cli\u003eMinegishi Y: \u003cstrong\u003eHyper-IgE syndrome, 2021 update\u003c/strong\u003e. \u003cem\u003eAllergol Int \u003c/em\u003e2021, \u003cstrong\u003e70\u003c/strong\u003e(4):407-414.\u003c/li\u003e\n\u003cli\u003eFreeman AF, Olivier KN: \u003cstrong\u003eHyper-IgE Syndromes and the Lung\u003c/strong\u003e. \u003cem\u003eClin Chest Med \u003c/em\u003e2016, \u003cstrong\u003e37\u003c/strong\u003e(3):557-567.\u003c/li\u003e\n\u003cli\u003eGilje EA, Abbott JK: \u003cstrong\u003eThe pulmonary effects of STAT3 deficiency\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2023, \u003cstrong\u003e152\u003c/strong\u003e(2):368-370.\u003c/li\u003e\n\u003cli\u003eZhang Y, Lin T, Leung HM, Zhang C, Wilson-Mifsud B, Feldman MB, Puel A, Lanternier F, Couderc L-J, Danion F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSTAT3 mutation-associated airway epithelial defects in Job syndrome\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2023, \u003cstrong\u003e152\u003c/strong\u003e(2):538-550.\u003c/li\u003e\n\u003cli\u003eDavis SD, Schaller J, Wedgwood RJ: \u003cstrong\u003eJob\u0026apos;s Syndrome. Recurrent, \u0026quot;cold\u0026quot;, staphylococcal abscesses\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e1966, \u003cstrong\u003e1\u003c/strong\u003e(7445):1013-1015.\u003c/li\u003e\n\u003cli\u003eGernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAutosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol Pract \u003c/em\u003e2018, \u003cstrong\u003e6\u003c/strong\u003e(3).\u003c/li\u003e\n\u003cli\u003eYun Li WD, Wanle Xiong: \u003cstrong\u003eA case report of Hyperige syndrome\u003c/strong\u003e. \u003cem\u003eShanghai Journal of Immunology \u003c/em\u003e1984(05):302-303.\u003c/li\u003e\n\u003cli\u003eWu J, Chen J, Tian Z-Q, Zhang H, Gong R-L, Chen T-X, Hong L: \u003cstrong\u003eClinical Manifestations and Genetic Analysis of 17 Patients with Autosomal Dominant Hyper-IgE Syndrome in Mainland China: New Reports and a Literature Review\u003c/strong\u003e. \u003cem\u003eJ Clin Immunol \u003c/em\u003e2017, \u003cstrong\u003e37\u003c/strong\u003e(2):166-179.\u003c/li\u003e\n\u003cli\u003eLin L, Wang Y, Sun B, Liu L, Ying W, Wang W, Zhou Q, Hou J, Yao H, Hu L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations\u003c/strong\u003e. \u003cem\u003eAllergy Asthma Clin Immunol \u003c/em\u003e2020, \u003cstrong\u003e16\u003c/strong\u003e:65.\u003c/li\u003e\n\u003cli\u003eNa Xu HF, Jing Zhao, Peng Wang, Hongmei Song, Xuejun Zeng: \u003cstrong\u003eHyper-IgE Syndromes in adults: report of 5 cases and literature review\u003c/strong\u003e. \u003cem\u003eChinese Journal of General Practitioners \u003c/em\u003e2017, \u003cstrong\u003e16\u003c/strong\u003e(12):955-960.\u003c/li\u003e\n\u003cli\u003eGrimbacher B, Sch\u0026auml;ffer AA, Holland SM, Davis J, Gallin JI, Malech HL, Atkinson TP, Belohradsky BH, Buckley RH, Cossu F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenetic linkage of hyper-IgE syndrome to chromosome 4\u003c/strong\u003e. \u003cem\u003eAm J Hum Genet \u003c/em\u003e1999, \u003cstrong\u003e65\u003c/strong\u003e(3):735-744.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eClinVar\u003c/strong\u003e. http://www.ncbi.nlm.nih.gov/clinvar. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eOMIM\u003c/strong\u003e. http://www.omim.org. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eHuman Gene Mutation Database\u003c/strong\u003e. http://www.hgmd.org. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSIFT\u003c/strong\u003e. http://sift.jcvi.org. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePolymorphism Phenotyping v2\u003c/strong\u003e. http://genetics.bwh.harvard.edu/pph2. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eCombined Annotation Dependent Depletion\u003c/strong\u003e. http://cadd.gs.washington.edu. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eMutationTaster\u003c/strong\u003e. http://www.mutationtaster.org. Accessed 4 April 2025.\u003c/li\u003e\n\u003cli\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology\u003c/strong\u003e. \u003cem\u003eGenet Med \u003c/em\u003e2015, \u003cstrong\u003e17\u003c/strong\u003e(5):405-424.\u003c/li\u003e\n\u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG: \u003cstrong\u003ePreferred reporting items for systematic reviews and meta-analyses: the PRISMA statement\u003c/strong\u003e. \u003cem\u003ePLoS Med \u003c/em\u003e2009, \u003cstrong\u003e6\u003c/strong\u003e(7):e1000097.\u003c/li\u003e\n\u003cli\u003eErlewyn-Lajeunesse MD: \u003cstrong\u003eHyperimmunoglobulin-E syndrome with recurrent infection: a review of current opinion and treatment\u003c/strong\u003e. \u003cem\u003ePediatr Allergy Immunol \u003c/em\u003e2000, \u003cstrong\u003e11\u003c/strong\u003e(3):133-141.\u003c/li\u003e\n\u003cli\u003eKimata H: \u003cstrong\u003eHigh-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e1995, \u003cstrong\u003e95\u003c/strong\u003e(3):771-774.\u003c/li\u003e\n\u003cli\u003eBork K, Bygum A, Hardt J: \u003cstrong\u003eBenefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients\u003c/strong\u003e. \u003cem\u003eAnn Allergy Asthma Immunol \u003c/em\u003e2008, \u003cstrong\u003e100\u003c/strong\u003e(2):153-161.\u003c/li\u003e\n\u003cli\u003eArora M, Bagi P, Strongin A, Heimall J, Zhao X, Lawrence MG, Trivedi A, Henderson C, Hsu A, Quezado M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome\u003c/strong\u003e. \u003cem\u003eJ Clin Immunol \u003c/em\u003e2017, \u003cstrong\u003e37\u003c/strong\u003e(7):695-700.\u003c/li\u003e\n\u003cli\u003eFarmand S, Kremer B, H\u0026auml;ffner M, P\u0026uuml;tsep K, Bergman P, Sundin M, Ritterbusch H, Seidl M, Follo M, Henneke P\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEosinophilia and reduced STAT3 signaling affect neutrophil cell death in autosomal-dominant Hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eEur J Immunol \u003c/em\u003e2018, \u003cstrong\u003e48\u003c/strong\u003e(12):1975-1988.\u003c/li\u003e\n\u003cli\u003eAlyasin S, Esmaeilzadeh H, Ebrahimi N, Nabavizadeh SH, Kashef S, Esmaeilzadeh E, Babaei M, Amin R: \u003cstrong\u003ePhenotyping and long-term follow up of patients with hyper IgE syndrome\u003c/strong\u003e. \u003cem\u003eAllergol Immunopathol (Madr) \u003c/em\u003e2019, \u003cstrong\u003e47\u003c/strong\u003e(2):152-158.\u003c/li\u003e\n\u003cli\u003eTavassoli M, Abolhassani H, Yazdani R, Ghadami M, Azizi G, Abdolrahim Poor Heravi S, Moeini Shad T, Kokabee M, Movahedi M, Abdshahzadeh H\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long-term follow-up and genetic analysis\u003c/strong\u003e. \u003cem\u003ePediatr Allergy Immunol \u003c/em\u003e2019, \u003cstrong\u003e30\u003c/strong\u003e(4):469-478.\u003c/li\u003e\n\u003cli\u003eLorenzini T, Giacomelli M, Scomodon O, Cortesi M, Rivellini V, Dotta L, Soresina A, Dellepiane RM, Carrabba M, Cossu F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAutosomal-dominant hyper-IgE syndrome is associated with appearance of infections early in life and/or neonatal rash: Evidence from the Italian cohort of 61 patients with elevated IgE\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol Pract \u003c/em\u003e2019, \u003cstrong\u003e7\u003c/strong\u003e(6).\u003c/li\u003e\n\u003cli\u003eKhourieh J, Rao G, Habib T, Avery DT, Lef\u0026egrave;vre-Utile A, Chandesris M-O, Belkadi A, Chrabieh M, Alwaseem H, Grandin V\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance\u003c/strong\u003e. \u003cem\u003eProc Natl Acad Sci U S A \u003c/em\u003e2019, \u003cstrong\u003e116\u003c/strong\u003e(33):16463-16472.\u003c/li\u003e\n\u003cli\u003eXiang Q, Zhang L, Liu X, Wang S, Wang T, Xiao M, Zhao X, Jiang L: \u003cstrong\u003eAutosomal dominant hyper IgE syndrome from a single centre in Chongqing, China (2009-2018)\u003c/strong\u003e. \u003cem\u003eScand J Immunol \u003c/em\u003e2020, \u003cstrong\u003e91\u003c/strong\u003e(6):e12885.\u003c/li\u003e\n\u003cli\u003eSaikia B, Rawat A, Minz RW, Suri D, Pandiarajan V, Jindal A, Sahu S, Karim A, Desai M, Taur PD\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eClinical Profile of Hyper-IgE Syndrome in India\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2021, \u003cstrong\u003e12\u003c/strong\u003e:626593.\u003c/li\u003e\n\u003cli\u003eFrede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, H\u0026uuml;bscher K, G\u0026aacute;mez-D\u0026iacute;az L, Proietti M, Saghafi S, Chavoshzadeh Z, Soler-Palacin P\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis\u003c/strong\u003e. \u003cem\u003eJ Clin Immunol \u003c/em\u003e2021, \u003cstrong\u003e41\u003c/strong\u003e(8):1804-1838.\u003c/li\u003e\n\u003cli\u003eShamriz O, Rubin L, Simon AJ, Lev A, Barel O, Somech R, Korem M, Matza Porges S, Freund T, Hagin D\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2022, \u003cstrong\u003e13\u003c/strong\u003e:1044933.\u003c/li\u003e\n\u003cli\u003eYaakoubi R, Mekki N, Ben-Mustapha I, Ben-Khemis L, Bouaziz A, Ben Fraj I, Ammar J, Hamzaoui A, Turki H, Boussofara L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDiagnostic challenge in a series of eleven patients with hyper IgE syndromes\u003c/strong\u003e. \u003cem\u003eFront Immunol \u003c/em\u003e2022, \u003cstrong\u003e13\u003c/strong\u003e:1057679.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003e2018 CIS Annual Meeting: Immune Deficiency \u0026amp; Dysregulation North American Conference\u003c/strong\u003e. \u003cem\u003eJ Clin Immunol \u003c/em\u003e2018, \u003cstrong\u003e38\u003c/strong\u003e(3):330-444.\u003c/li\u003e\n\u003cli\u003eCarrabba M, Dellepiane RM, Cortesi M, Baselli LA, Soresina A, Cirillo E, Giardino G, Conti F, Dotta L, Finocchi A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLong term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job\u0026apos;s syndrome\u003c/strong\u003e. \u003cem\u003eAllergy Asthma Clin Immunol \u003c/em\u003e2023, \u003cstrong\u003e19\u003c/strong\u003e(1):32.\u003c/li\u003e\n\u003cli\u003eDmenska H, Heropolitanska E, Pietrucha B, Bernatowska E: \u003cstrong\u003ePulmonary features of autosomal dominant hyper-IgE syndrome [AD HIES]\u003c/strong\u003e. \u003cem\u003eEuropean Respiratory Journal \u003c/em\u003e2011, \u003cstrong\u003e38\u003c/strong\u003e(Suppl 55):p3600.\u003c/li\u003e\n\u003cli\u003eDur\u0026eacute;ault A, Tcherakian C, Poiree S, Catherinot E, Danion F, Jouvion G, Bougnoux ME, Mahlaoui N, Givel C, Castelle M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSpectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol Pract \u003c/em\u003e2019, \u003cstrong\u003e7\u003c/strong\u003e(6).\u003c/li\u003e\n\u003cli\u003eFreeman AF, Renner ED, Henderson C, Langenbeck A, Olivier KN, Hsu AP, Hagl B, Boos A, Davis J, Marciano BE\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLung parenchyma surgery in autosomal dominant hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eJ Clin Immunol \u003c/em\u003e2013, \u003cstrong\u003e33\u003c/strong\u003e(5):896-902.\u003c/li\u003e\n\u003cli\u003eMahdaviani SA, Ghadimi S, Fallahi M, Hashemi-Moghaddam SA, Chavoshzadeh Z, Puel A, Rezaei N, Rekabi M, Daneshmandi Z, Sheikhy K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eInterventional pulmonary procedures and their outcomes in patients with STAT3 hyper IgE syndrome\u003c/strong\u003e. \u003cem\u003eBMC Surg \u003c/em\u003e2023, \u003cstrong\u003e23\u003c/strong\u003e(1):289.\u003c/li\u003e\n\u003cli\u003eUrban AK, Darnell D, Peterson J, Welch P, Freeman AF, Olivier KN: \u003cstrong\u003eCharacterization of Lung Disease in Autosomal Dominant Hyper IgE Syndrome\u003c/strong\u003e. In: \u003cem\u003eC35 CLINICAL STUDIES IN IMMUNODEFICIENCY.\u003c/em\u003e edn.: A4797-A4797.\u003c/li\u003e\n\u003cli\u003eShahin T, Aschenbrenner D, Cagdas D, Bal SK, Conde CD, Garncarz W, Medgyesi D, Schwerd T, Karaatmaca B, Cetinkaya PG\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSelective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function\u003c/strong\u003e. \u003cem\u003eHaematologica \u003c/em\u003e2019, \u003cstrong\u003e104\u003c/strong\u003e(3):609-621.\u003c/li\u003e\n\u003cli\u003eB\u0026eacute;ziat V, Tavernier SJ, Chen Y-H, Ma CS, Materna M, Laurence A, Staal J, Aschenbrenner D, Roels L, Worley L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDominant-negative mutations in human IL6ST underlie hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eJ Exp Med \u003c/em\u003e2020, \u003cstrong\u003e217\u003c/strong\u003e(6).\u003c/li\u003e\n\u003cli\u003eSassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, Patiroglu T, Unal E, Ozdemir MA, Jouhadi Z\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2014, \u003cstrong\u003e133\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003eMa CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGermline hypomorphic CARD11 mutations in severe atopic disease\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2017, \u003cstrong\u003e49\u003c/strong\u003e(8):1192-1201.\u003c/li\u003e\n\u003cli\u003eMinegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHuman tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity\u003c/strong\u003e. \u003cem\u003eImmunity \u003c/em\u003e2006, \u003cstrong\u003e25\u003c/strong\u003e(5):745-755.\u003c/li\u003e\n\u003cli\u003eLyons JJ, Liu Y, Ma CA, Yu X, O\u0026apos;Connell MP, Lawrence MG, Zhang Y, Karpe K, Zhao M, Siegel AM\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eERBIN deficiency links STAT3 and TGF-\u0026beta; pathway defects with atopy in humans\u003c/strong\u003e. \u003cem\u003eJ Exp Med \u003c/em\u003e2017, \u003cstrong\u003e214\u003c/strong\u003e(3):669-680.\u003c/li\u003e\n\u003cli\u003eGrimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O\u0026apos;Connell AC, Puck JM: \u003cstrong\u003eHyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e1999, \u003cstrong\u003e340\u003c/strong\u003e(9):692-702.\u003c/li\u003e\n\u003cli\u003eHillmer EJ, Zhang H, Li HS, Watowich SS: \u003cstrong\u003eSTAT3 signaling in immunity\u003c/strong\u003e. \u003cem\u003eCytokine Growth Factor Rev \u003c/em\u003e2016, \u003cstrong\u003e31\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eDarnell JE: \u003cstrong\u003eSTATs and gene regulation\u003c/strong\u003e. \u003cem\u003eScience \u003c/em\u003e1997, \u003cstrong\u003e277\u003c/strong\u003e(5332):1630-1635.\u003c/li\u003e\n\u003cli\u003eMinegishi Y, Karasuyama H: \u003cstrong\u003eDefects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency\u003c/strong\u003e. \u003cem\u003eInt Immunol \u003c/em\u003e2009, \u003cstrong\u003e21\u003c/strong\u003e(2):105-112.\u003c/li\u003e\n\u003cli\u003eHill HR, Ochs HD, Quie PG, Clark RA, Pabst HF, Klebanoff SJ, Wedgwood RJ: \u003cstrong\u003eDefect in neutrophil granulocyte chemotaxis in Job\u0026apos;s syndrome of recurrent \u0026quot;cold\u0026quot; staphylococcal abscesses\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e1974, \u003cstrong\u003e2\u003c/strong\u003e(7881):617-619.\u003c/li\u003e\n\u003cli\u003eOchs HD, Oukka M, Torgerson TR: \u003cstrong\u003eTH17 cells and regulatory T cells in primary immunodeficiency diseases\u003c/strong\u003e. \u003cem\u003eJ Allergy Clin Immunol \u003c/em\u003e2009, \u003cstrong\u003e123\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003eHill HR, Quie PG: \u003cstrong\u003eRaised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e1974, \u003cstrong\u003e1\u003c/strong\u003e(7850):183-187.\u003c/li\u003e\n\u003cli\u003eMinegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMolecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome\u003c/strong\u003e. \u003cem\u003eJ Exp Med \u003c/em\u003e2009, \u003cstrong\u003e206\u003c/strong\u003e(6):1291-1301.\u003c/li\u003e\n\u003cli\u003eTadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BLM: \u003cstrong\u003eIL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells\u003c/strong\u003e. \u003cem\u003eProc Natl Acad Sci U S A \u003c/em\u003e2014, \u003cstrong\u003e111\u003c/strong\u003e(35):E3641-E3649.\u003c/li\u003e\n\u003cli\u003eHokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl A-KT, Hull WM, Wert SE, Whitsett JA: \u003cstrong\u003eStat-3 is required for pulmonary homeostasis during hyperoxia\u003c/strong\u003e. \u003cem\u003eJ Clin Invest \u003c/em\u003e2004, \u003cstrong\u003e113\u003c/strong\u003e(1):28-37.\u003c/li\u003e\n\u003cli\u003eKing NE, Suzuki S, Barill\u0026agrave; C, Hawkins FJ, Randell SH, Reynolds SD, Stripp BR, Davis BR: \u003cstrong\u003eCorrection of Airway Stem Cells: Genome Editing Approaches for the Treatment of Cystic Fibrosis\u003c/strong\u003e. \u003cem\u003eHum Gene Ther \u003c/em\u003e2020, \u003cstrong\u003e31\u003c/strong\u003e(17-18):956-972.\u003c/li\u003e\n\u003cli\u003eSuzuki S, Crane AM, Anirudhan V, Barill\u0026agrave; C, Matthias N, Randell SH, Rab A, Sorscher EJ, Kerschner JL, Yin S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHighly Efficient Gene Editing of Cystic Fibrosis Patient-Derived Airway Basal Cells Results in Functional CFTR Correction\u003c/strong\u003e. \u003cem\u003eMol Ther \u003c/em\u003e2020, \u003cstrong\u003e28\u003c/strong\u003e(7):1684-1695.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1 and 2","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"hyper-IgE syndromes, STAT3 gene, primary immunodeficiency, lung disease","lastPublishedDoi":"10.21203/rs.3.rs-5618843/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5618843/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity-sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Pulmonary complications are responsible for high morbidity and mortality rates in patients with HIES. This study examines the progression of pulmonary disease in adult patients with HIES and compares the subsequent findings with existing literature.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTen adult patients with HIES diagnosed at Peking Union Medical College Hospital (PUMCH) from January 2016 to October 2023 were included in this study. Diagnosis was confirmed using the National Institutes of Health (NIH) criteria and whole-exome sequencing. Clinical data on pulmonary disease progression, microbiology, imaging and histology were collected. A systematic literature review was conducted for comparison.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eRecurrent pulmonary infections led to significant structural lung damage, with 90.0% (9/10) of patients developing bronchiectasis and pneumatocele. Early infections (0-10years) were predominantly due to \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (80.0%,8/10), while later stages (6-22years) showed a shift to more complex infections with \u003cem\u003eAspergillus\u003c/em\u003e/fungus (70.0%,7/10), \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (50.0%, 5/10), and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (40.0%, 4/10). Imaging revealed extensive bronchiectasis and pneumatocele formation. Histological examinations demonstrated acute inflammation (40%, 2/5), granuloma formation (80%, 4/5), and eosinophilic infiltration (100%, 5/5). Comparatively, our findings are consistent with previous reports that suggest a higher incidence of pulmonary structural damage in patients with the signal transducer and activator of the transcription 3 (\u003cem\u003eSTAT3\u003c/em\u003e) mutations than in those with other gene variants. However, our cohort showed a faster progression from initial infection to structural damage, highlighting the need for early intervention.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe progression of pulmonary disease in HIES patients underscores a critical three-step process: initial recurrent infections, development of structural lung damage, and subsequent reinfections that aggravate the damage. This rapid transition from infection to structural damage, especially in patients with \u003cem\u003eSTAT3\u003c/em\u003e mutations, highlights the importance of early and aggressive intervention. Managing reinfections after structural lung damage is essential to prevent further deterioration and to improve long-term outcomes.\u003c/p\u003e","manuscriptTitle":"Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: A single-centre clinical study and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 05:40:57","doi":"10.21203/rs.3.rs-5618843/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2025-04-21T07:37:46+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-12T00:10:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-11T11:38:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-04-07T07:41:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6878a9fc-a75a-4050-8e7d-8cf68424eb67","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T15:59:40+00:00","versionOfRecord":{"articleIdentity":"rs-5618843","link":"https://doi.org/10.1186/s13023-025-03749-6","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-06-03 15:57:04","publishedOnDateReadable":"June 3rd, 2025"},"versionCreatedAt":"2025-04-17 05:40:57","video":"","vorDoi":"10.1186/s13023-025-03749-6","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03749-6","workflowStages":[]},"version":"v1","identity":"rs-5618843","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5618843","identity":"rs-5618843","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}