Interventional pulmonary procedures and their outcomes in patients with STAT3 hyper IgE syndrome

Background STAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures. Method Four patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed. Result Recurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications. Conclusion Patients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies.


Introduction
Hyper immunoglobulin E (IgE) syndrome (HIES) is an inborn error of immunity with an annual incidence of 1 in 100,000 people, which was initially described in 1966 [1,2].A high level of serum IgE is immunologic characteristic of several autosomal recessive IEIs, namely interleukin 6 (IL-6) receptor deficiency, IL-6 signal transducer deficiency, ZNF431 deficiency, DOCK8 deficiency, PGM3 deficiency, CARD11 deficiency, CARD14 deficiency, and Comel-Netherton syndrome [3,4].However, Job's syndrome, the prototype of HIES (AD-HIES), arises from a dominant negative mutation of the STAT3 gene (signal transducer and activator of transcription 3) [5][6][7].STAT3 is a member of the JAK-STAT pathway, which is involved in the differentiation and function of TH17.Abnormal Th17 function results in susceptibility to fungal and bacterial infections, particularly in the skin and respiratory system [8,9].Most patients present with the triad of eczema, frequent opportunistic infections, and elevated serum IgE levels.Moreover, non-immunological findings include facial characteristics, skeletal and dental abnormalities, vasculopathy, and malignancy [7][8][9].Cutaneous involvement may present as skin abscesses and eczematous rashes.Abscesses commonly affect the face, neck, and scalp in the early years of life; they may not develop the typical signs and symptoms of infection and manifest as "cold "abscesses.The most prevalent pathogens are Staphylococcus aureus and Candida albicans.Papulopustular and eczematoid rashes first appear on the face and scalp in early infancy and progress to the upper trunk [10][11][12][13].Sinopulmonary infections mostly caused by Staphylococcus aureus, Streptococcus, and Haemophilus species are prevalent and potentially fatal.Bronchitis and pneumatoceles are common complications of abnormal healing after lung infection which can be complicated due to secondary infection with Pseudomonas aeruginosa and Aspergillus fumigatus [1-5, 8, 14-16].High levels of serum IgE (> 2,000 IU/uL) and eosinophilia are frequently observed in patients, however, increased serum IgE and eosinophilia do not predict the severity of the disease [1].The IgE level tends to decrease or even reaches a normal level as age progresses.Low proportions of memory B and T cells associated with reduced IL-17A-producing T cells are also found in patients [1,10].
General management goals in patients with STAT3-HIES include prophylaxis with antimicrobials, aggressive treatment of infection, and management of eczematoid dermatitis [17].As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures such as abscesses drainage, lobectomy, or segmental lung resection because of the persistent pneumatoceles.Herein, we investigate the application of interventional pulmonary procedures and their outcomes in patients with hyper IgE syndrome.

Method
The study was performed at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Tehran, Iran, which is the national referral center for patients with inborn errors of immunity and pulmonary complications.The medical records of all patients with a clinical diagnosis of hyper IgE syndrome based on the European Society for Immunodeficiencies (ESID) diagnostic criteria and molecular diagnosis of dominant-negative STAT3 mutations were investigated for a history of interventional pulmonary procedures.Follow-up of alive patients was performed via telephone interviews with patients.
The immunologic profiles of patients were determined by the measurement of complete blood count (CBC), lymphocyte subsets, serum immunoglobulin levels (IgG, IgA, IgM, and IgE), human immunodeficiency virus (HIV) serology, and lymphocyte transformation test (LTT).
Based on the clinical and laboratory findings, an NIH score was determined for each patient according to the National Institutes of Health (NIH) HIES rating system [18].
The DNA samples were sent to the Laboratory of Human Genetics of Infectious Diseases, France, and Research Center for Immunodeficiencies, Iran, and genetic studies by whole-exome sequencing (WES) were performed to identify underlying genetic defects.
A questionnaire was prepared and filled with patients' data including demographics, molecular and clinical features.All statistical analyses were performed using SPSS software (v.26.0, Chicago, IL).
Written informed consent for participation in this study was obtained from patients or their parents.This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (Approval Code: IR.SBMU.NRITLD.REC.1400.049).
Reference lists of all full-text articles and major reviews were manually searched for additional studies.

Summary of findings in study population
Four Iranian patients (3 males and 1 female) from four different families were enrolled, all of whom had a clinical and molecular diagnosis of dominant-negative STAT3 mutation and a history of interventional pulmonary surgery (Table 1).The NIH scores of all patients at the time of diagnosis exceeded 40.All patients except P4 had consanguineous parents and none of them had a family history of STAT3-HIES.The disease first manifested at a median (IQR) age of 0.1 (0.1-0.5) years, while the clinical diagnosis of HIES was confirmed at a median (IQR) age of 12.0 (8.0-17.0)years after a median (IQR) delay of 11.9 (16.5-7.9)years.
Malignancy, chronic Epstein-Barr virus (EBV) infection and major bleeding or thrombotic vascular event were not found in any of the patients during the median (IQR) 4.75 (6.15-3.8)years of follow-up.
Immunological workup was performed in all 4 patients.The most prominent finding was the elevated serum IgE level and eosinophil count (4/4).White blood cell (WBC) count and lymphocyte subpopulations were normal in all patients except P3 who had increased CD19 + B cell count.High levels of IgG and IgM were detected in 3 patients (P1, P3, P4), while all had normal levels of IgA.The most prevalent findings on high-resolution computed tomography (HRCT) at the earliest recording were bronchiectasis (4/4), lung abscess (4/4), pneumatocele, and cavitary lesion (2/4).All patients underwent pulmonary surgery and P1 (bronchopleural fistula) and P3 (wound infection) experienced complications.Four patients received antibacterial and antifungal prophylaxis along with intravenous immunoglobulin (IVIG) (except P3).Two patients (P2 and P4) died due to pulmonary arrest and massive hemoptysis.

Detailed description of patients Case 1
The patient was a 10-year-old male born to consanguineous parents with a history of eczematous dermatitis from the age of 10 days, which had extended to the face and diaper area.He had a productive cough and fever at the age of 3 years, which led to the diagnosis of pulmonary abscess and he underwent drainage and lower right lung lobectomy.He developed a cough and fever when he was 4 years old.Physical examination revealed hyperextensible joints.Laboratory findings at the age of 4 showed normal WBC count, increased eosinophil count (15%), IgE (532 (IU/ml)) and IgG level (2160 (IU/ml)).Lymphocyte subpopulations (CD3 + , CD4 + , CD8 + T cells, CD19 + B cell, natural killer (NK) cell) were normal.Bronchoalveolar lavage (BAL) culture was positive for Aspergillus terreus and Acinetobacter.Moreover, chest X-ray (CXR) demonstrated lung cavity formation in right lower lobe, pneumothorax, pleural effusion on the right side, and necrotizing pneumonia with empyema.According to the National Institutes of Health (NIH) HIES rating system [18], he scored 49 and the diagnosis of HIES was made.At the age of 5 years, he was presented with a fever and cough.The Chest sonography was suggesting for infectious lesion (abscess or empyema) and he underwent drainage and medical treatment.He was referred to the hospital again with cough and fever at the age of 7 years due to pulmonary empyema with Acinetobacter species.A thoracostomy window was opened for the patient from the back of the chest (Eloesser flapped surgery).Bronchopleural fistula occurred as a complication of surgery.He has received monthly IVIG and antimicrobial prophylaxis with tavanex, cephalexin and voriconazole.He responded well and the frequency of infections has reduced.

Case 2
The patient was a 26-year-old boy born to consanguineous parents.His family history was unremarkable.His medical history was notable for newborn rush, recurrent skin abscess, eczematous dermatitis, FTT, bronchiectasis and scoliosis.The HIES was suspected based on laboratory findings and clinical features.Laboratory findings at the age of 22 years revealed increased eosinophil count (610 × 10 3 (cells /µL)) and IgE level (> 1250 (IU/ml)).However, WBC count, lymphocyte subpopulations (CD3 + , CD4 + , CD8 + T cell, CD19 + B cell and NK cell) and serum level of immunoglobulins   He received antimicrobial prophylaxis with vancomycin, imipenem, cotrimoxazole, and itraconazole and responded well.

Case 4
The patient was a 15-year-old girl born to non-consanguineous parents.Her family history was unremarkable.She had a history of newborn rash, eczematous dermatitis, skin abscess since she was 45 days old, scoliosis and FTT.In addition, multiple hospitalizations due to recurrent lung infections and lung abscesses were reported.At the age of 12, she was hospitalized due to pneumonia.Laboratory findings revealed increased eosinophil count (800 × 10 3 (cells /µL)), IgG (1805 mg/dl), IgM (199 mg/ dl) and IgE level (4848 IU/ml).BAL culture was positive for Pseudomonas aeruginosa.Moreover, HRCT findings were suggestive of extensive cystic bronchiectasis, abscess and pneumatocele.CXR demonstrated multiple cavities.According to the NIH HIES rating system, she scored 55 and the diagnosis of HIES was confirmed based on clinical features, laboratory findings and identification of missense STAT3 mutation.She underwent a thoracotomy due to a lung abscess when she was 12 years old.She received pulmonary physiotherapy, IVIG and antimicrobial prophylaxis with colistin, vancomycin, meropenem, cotrimoxazole, fluconazole and amphotericin B, but unfortunately, she died due to massive hemoptysis at the age of 15 years.

Discussion
In this study, we presented four patients with STAT3-HIES receiving various types of interventional pulmonary procedures and searched the literature for similar patients.Recurrent pulmonary infections are frequently observed in STAT3-HIES patients since childhood.Surgical procedures are utilized to manage lung infections and complications such as the formation of pneumatoceles which are prone to secondary infection, abscess and empyema.The number of large cohorts evaluating the impact of interventional lung procedures in STAT3-HIES patients is limited, three of which is discussed in more details.
Post-operative sequels are often reported due to underlying dominant-negative STAT3 mutations and wound-healing abnormalities [15].In the present study, bronchopleural fistula and wound infection occurred in two patients after surgery.In a retrospective study by Freeman et al. on 32 STAT3-HIES patients receiving 36 pulmonary surgeries, surgical complications were observed in more than half of all procedures.The most frequent complication, occurring in 47% of surgeries, was bronchopleural fistula which frequently led to empyema.Among complicated surgeries, 47% required further surgery due to long-standing bronchopleural fistula and empyema.It was suggested to prioritize medical treatment and only select surgical options in cases with ineffective medical treatment and significant symptoms [33].
In the same manner, in another study on nine patients with STAT3-HIES, Kroner et al. observed high rates of post-surgical complications, declined functional lung tissue, and negative impact on the long-term outcome.They recommended strict monitoring of pulmonary function and regular inhalation therapy with hypertonic saline, chest physiotherapy, airway clearance techniques, workout programs, and using intensive therapy for controlling infections (i.e., continuous use of oral antibiotics against S. aureus, regular antibiotic therapy in patients with high rates of pulmonary exacerbations, intense IV antibiotic therapy of exacerbations using fluoroquinolones) [15].
In the review of the literature, almost one-third of patients (27.3%) required more than one episode of lung surgery.The pre-surgery condition is an important determinant of surgical outcome.In accordance with previous studies, a history of infection with specific organisms was associated with a worse prognosis.Two out of four patients described in the current study suffered from Aspergillus infection and one of them required two other episodes of lung surgery.In a retrospective French study on STAT3-HIES patients with pulmonary Aspergillosis, six patients underwent seven episodes of surgery.The authors concluded that while many patients with HIES may develop aspergillosis infections, surgery can provide a permanent cure for pulmonary aspergillosis, but a recurrence might be inevitable [28].
None of the patients in the present study underwent hematopoietic stem cell transplantation (HSCT), although all patients received antimicrobial prophylaxis and IVIG and two of them responded well.Recently Harrison et al. in a cohort of patients with STAT3-HIES receiving HSCT suggested allogeneic HSCT as a curative measurement even in patients with prior severe lung disease.In their cohort, three patients had undergone lung surgeries before HSCT, but considerable improvement in lung disorders was only achieved after HSCT.None of them required lung surgery post-HSCT and no peritransplant pulmonary inflammatory complications were observed [19].
This study faced several limitations including small number of participants and its retrospective nature.In addition, in the literature review some patients might have been included in more than one study, affecting the calculation of percentages.However, this study highlights the consequences of lung surgery in STAT3-HIES patients and the therapeutic dilemma for clinicians, which will be hopefully solved with future reports of more patients.

Conclusion
Patients with STAT3-HIES are prone to frequent pulmonary infection and other infection-related complications which lead to lung tissue destruction and significant mortality or morbidity; therefore, prompt diagnosis and prophylaxis initiation are critical.Furthermore, thoracic surgeries in these patients carry a considerable risk of complications, thus surgical procedures are only recommended when medical treatment has failed or there are severe symptoms.

Table 1
Summary of studies reported STAT3-HIES patients with lung surgical interventions

Table 1
(continued) CPAP Continuous positive airway pressure, F Female, HSCT Hematopoietic stem cell transplantation, HTN Hypertension, IQR Interquartile range, M Male, NA Not available, RTI Respiratory tract infection, Spp.Several species, y/o year (s) old(IgG, IgA, IgM) were normal.Non-immunological findings included clubbing, chronic diarrhea, and anemia.According to the NIH HIES rating system, he scored 46.