Pulmonary Infections and Surgical Complications in a Young Girl with Signal Transducer and Activator of Transcription 3 Loss-of-Function Mutation Hyperimmunoglobulin E Syndrome: A Case Report

Abstract

Introduction:

Hyperimmunoglobulin E syndromes (HIESs) are characterized by a high serum immunoglobulin E (IgE) level, eczematoid rashes, recurrent staphylococcal skin abscesses, and recurrent pneumonia and pneumatocele formation. Autosomal dominant HIES is the most common form of HIES and mainly occurs due to loss-of-function mutations in the Signal Transducer and Activator of Transcription 3 (STAT3) gene (STAT3 LOF).

Case Presentation:

We report the case of an 11-year-old Peruvian girl diagnosed with STAT3 LOF caused by p.R382W mutation. She presented with recurrent staphylococcal pneumonia and empyema caused by the rarely reported Achromobacter xylosoxidans, which led to severe destruction of the lung parenchyma, multiple lung surgeries, and the development of bronchopleural fistulas. A laparotomy was also performed, which showed evidence of sigmoid colon perforation. The patient received immunoglobulin replacement therapy (IRT) and antibiotic prophylaxis, and the frequency of her infections has decreased over the past 3 years.

Conclusion:

This is the first case of STAT3 LOF diagnosed by genomic sequencing in Peru. Patients with this mutation have recurrent pulmonary infections, and require multiple surgical procedures with frequent complications. A. xylosoxidans infection could be related to the prolonged stay in intensive care leading to high mortality; therefore, additional care must be taken when treating patients with this infection. In addition, colonic perforation is a rare complication in STAT3 LOF patients. IRT and antibiotic prophylaxis appear to decrease the frequency of infections and hospitalizations.

Introduction

Hyperimmunoglobulin E syndromes (HIESs) are classically described as high serum immunoglobulin E (IgE), eczematoid rashes, recurrent staphylococcal skin abscesses, and recurrent pneumonia and pneumatocele formation.^1,2 The most common form of HIES is autosomal dominant HIES (AD-HIES).

AD-HIES is a rare primary immunodeficiency disease (PIDD) that is mainly caused by sporadic or familial missense (dominant-negative) mutations in the Src homology 2 (SH2), DNA-binding domain, or transactivation domains of the Signal Transducer and Activator of Transcription 3 (STAT3) gene.² AD-HIES that results from missense or short in-frame mutations is usually referred to as STAT3 loss-of-function mutation HIES (STAT3 LOF) or Job syndrome.^2,3 These patients often have musculoskeletal (scoliosis, osteopenia, minimal trauma fractures, or hyperextensibility), craniofacial (coarse facies, craniosynostosis, delayed teeth shedding, or a high-arched palate), and vascular (aneurysms) abnormalities.^1,2

Pulmonary manifestations include recurrent pyogenic pneumonia that typically begins in the first years of life and responds well to antibiotics; however, complications are common, and include empyema and parenchymal abnormalities (eg, pneumatoceles, bronchiectasis, or bronchopleural fistulas after lung resection).³ We report a case of a young STAT3 LOF patient with severe pulmonary infections and multiple surgical complications.

Case Presentation

We describe the case of an 11-year-old Peruvian female who was born full term without complications. She is the second daughter of nonconsanguineous parents and had a paternal uncle who died before 1 year of age from an unknown cause. There is no reported history of recurrent infections, autoimmune disease, or cancer in her family. At 7 days of life, she developed diffuse impetiginized atopic dermatitis on her extremities and scalp; however, it was partially responsive to oral antibiotics. She also developed oral candidiasis, which was treated with nystatin. During her first 2 years of life, she presented with multiple episodes of otitis media and persistent diarrhea, for which she received treatment on an outpatient basis.

At 2 years old, she was hospitalized for the first time in a rural hospital with left-sided community-acquired pneumonia (CAP) and empyema with methicillin-sensitive Staphylococcus aureus (MSSA) detected by culture. Tube thoracostomy and thoracentesis (TTT) were performed, and she was treated with intravenous antibiotics (IVAs). In addition, she presented with scalp abscesses (wound cultures positive for MSSA), which were drained and treated with IVAs. Owing to her clinical presentation and IgE level (>2,500 IU/mL), a clinical diagnosis of HIES was made. She developed right pneumatocele and acute respiratory failure 2 weeks later and consequently required mechanical ventilation for 1 month. When no clinical improvement was evident, she was referred to the National Pediatric Reference Center, where a right pneumatocele resection was performed, and she was hospitalized for 1 month for IVAs.

The patient was hospitalized ∼6 times every year due to CAP until the age of 4 years. She developed postoperative bronchopleural fistulas in the right hemithorax during this period, which were managed with supportive therapy. At age 4 years, she was again hospitalized in a rural hospital for an episode of right CAP, empyema, and left pneumothorax. TTT was performed and she was treated with IVAs; however, she developed acute respiratory failure and again required mechanical ventilation for 1 month. After clinical improvement, she was referred to a hospital in Lima, where a left pleuropulmonary decortication and bullectomy were performed, and she remained hospitalized for 2 months. During this hospitalization, immunoglobulin replacement therapy (IRT) was started every 3 weeks, and the bronchopleural fistulas became cutaneous fistulas.

Over the next 2 years, the frequency of infections and hospitalizations decreased to ∼3 per year. However, she only received IRT until 7 years of age due to a change in her health insurance, after which, she was only given supportive treatment for her cutaneous–bronchopleural fistulas.

At 8 years of age, she presented with hemoptysis, bilateral CAP, right pneumatocele (with a positive culture for Pseudomonas aeruginosa and Acinetobacter spp.), and oral candidiasis at a rural hospital. She was subsequently hospitalized and treated with IVAs. As no clinical improvement was seen, she was hospitalized in the pulmonology service of the National Pediatric Reference Center, and, given her previous clinical diagnosis, our unit was consulted. We performed an immunological (Table 1) and a clinical evaluation using the National Institutes of Health (NIH) criteria for HIES (total score: 67 points).⁴ The relevant clinical and laboratory findings were pneumatocele, recurrent pneumonia, newborn rash, scoliosis, retained primary teeth, characteristic face, and high eosinophil count and IgE level (Fig. 1A, B). Based on these results, IRT was restarted.

FIG. 1.

Clinical and radiological findings of the patient. (A) Characteristic face (broad nasal base, prominent forehead, and facial asymmetry). (B) Bilateral surgical scar, scoliosis. (C, D) Thorax CT scan. Right middle lobe and left upper lobe consolidation. Bilateral pneumatocele, pleural thickening, and bronchiectasis. CT, computed tomography.

Table 1.

Immunological Profile of the Patient

	Normal range	Patient
Eosinophil count ( × 10⁶/mL)	0 − 0.46	1.08
Lymphocyte subsets (10³ cells/μL)
CD3⁺	0.9 − 4.5	2.7
CD3⁺CD4⁺	0.5 − 2.4	1.4
CD3⁺CD8⁺	0.3 − 1.6	1.1
CD19⁺	0.2 − 2.1	0.3
CD3⁻CD56⁺	0.1 − 1.0	0.1
Immunoglobulins
IgE (IU/mL)	<52	>2,000
IgG (mg/dL)	580 − 1,080	1,495
IgM (mg/dL)	54 − 153	164
IgA (mg/dL)	49 − 157	136
Complement (mg/dL)
C3	90 − 180	117
C4	10 − 40	37

IgE, immunoglobulin E.

Targeted next-generation sequencing of 264 genes associated with primary immunodeficiency (Supplementary Table S1) revealed a heterozygous mutation of the STAT3 gene (c.1144C>T; p.R382W) that had previously been described as a cause of STAT3 LOF.

After 1 month, she developed a left pneumatocele, which was managed with TTT (Fig. 1C, D); 1 week later, she presented with acute abdomen and subcutaneous emphysema. A laparotomy was performed, which showed evidence of sigmoid colon perforation and generalized peritonitis. Consequently, surgical resection of the sigmoid colon was made. As there was no clinical improvement, she was hospitalized in the intensive care unit, treated with IVAs, and remained on mechanical ventilation for 2 weeks. Once clinical improvement was evident, surgical closure of the cutaneous–bronchopleural fistulas was performed. After 1 month, pleural effusion was evident in the left hemithorax with carbapenem-resistant Achromobacter xylosoxidans shown by culture. Intravenous colistin was administered, and she remained hospitalized for 6 months during this episode.

During the following 3 years, the patient has continued with monthly IRT, in addition to antibiotic prophylaxis with trimethoprim–sulfamethoxazole. The frequency of infections and hospitalizations has decreased to once a year, and the patient has reported an improvement in her quality of life.

Discussion

Herein, we describe a patient with STAT3 LOF as a result of a missense heterozygous STAT3 mutation in the DNA binding domain (p.R382W). Despite limited data, it is estimated that the annual incidence of HIES is 1/100,000, and is equally distributed among males and females.⁵ In Latin America, there have been 185 cases of AD-HIES reported by the Latin American Society for Immunodeficiencies (LASID) by 2020, of which Peru has reported 8 cases, although not all are supported by genomic studies.^6,7

Recurrent pneumonia is the most common pulmonary manifestation of STAT3 LOF.^1,2 Signs of lung disease appear typically in the first year of life and are frequently caused by infectious agents such as S. aureus, Streptococcus pneumoniae, and Haemophilus influenzae.^3,8–10 Recurrent pneumonia and abnormal healing lead to severe destruction of the lung parenchyma, together with bronchiectasis, pneumatoceles, abscesses, and cyst formation, which are frequently infected with P. aeruginosa or Aspergillus fumigatus.^8–11 For this reason, STAT3 LOF patients with parenchymal lung disease may need surgical intervention, which is a significant source of complications in more than half of the cases.^10,11

The most commonly reported surgeries reported are single or multiple lobe resections, partial lobectomies, and pleural interventions. Prolonged bronchopleural fistula is the most common complication and frequently leads to empyema, which often leads to the requirement for additional surgery.^10,11

Interestingly, our patient presented with empyema caused by the rarely reported A. xylosoxidans bacteria. A. xylosoxidans are aerobic, opportunistic, gram-negative bacilli, and an important emergent nosocomial pathogen in immunocompromised patients.^12,13 Several studies performed in tertiary health centers have demonstrated nosocomial bacteremia and pneumonia as the main infections, especially in medical and intensive care areas. The annual incidence of infections caused by Achromobacter spp. is <1.5/10,000 hospitalizations and mortality is seen in ∼20% of the cases, particularly high in patients with bacteremia and prior chemotherapy.^12,13 Underlying cystic fibrosis, cancer, cardiovascular disease, lymphopenia, neutropenia, long-term corticosteroid use, use of mechanical ventilation, or prior chemotherapy are risk factors of Achromobacter-related infection.^12,13

The presence of this infection in our patient could likely be related to the prolonged stay in intensive care. As far as we know, there has been no previous report of infections caused by A. xylosoxidans in STAT3 LOF patients. In addition, our patient presented a sigmoid colon perforation. Spontaneous perforations in the gastrointestinal (GI) tract have been reported in STAT3 LOF patients, although it is an infrequent complication.^14,15 A case series of 10 patients showed that the most frequent location was the sigmoid colon, all the patients were surgical treated, and there was no evidence of subsequent episodes.¹⁵ Other GI manifestations reported are dysphagia, gastroesophageal reflux disease, abdominal pain, constipation, food impaction, GI tract infections, and wall thickening diverticulosis and transaminitis.^14,15

STAT3 is a critical transcription factor in the differentiation of T helper 17 (Th17) lymphocytes, by mediating signal transduction of key cytokines, such as interleukin (IL)-6, IL-10, IL-11, IL-21, and IL-23. Th17 cells are known to mediate neutrophil chemotaxis and proliferation, and induce the release of inflammatory cytokines (eg, IL-6, IL-17, and IL-22) from a wide range of cells. Moreover, they also stimulate the release of antimicrobial peptides, such as β-defensins, from keratinocytes and epithelial cells through IL-17 and IL-22, which are essential in eliminating extracellular bacteria and fungi at epithelial surfaces.^2,5

Likewise, IL-22–activated STAT3 promotes epithelial proliferation and tissue repair in the lungs and skin.¹⁶ In addition, IL-21 and IL-10 are implicated in B cell proliferation, differentiation, and class switching, and have vital roles in antigen-specific antibody responses.¹⁷ Therefore, STAT3 mutation in HIES patients could explain recurrent staphylococcal infections, mucocutaneous candidiasis, severe lung involvement, and a high frequency of lung surgery and complications, as was observed in our patient.^5,16,17 Unfortunately, we could not evaluate the B cell population, antibody responses, and IL-17 level in our patient due to limited laboratory resources.

The NIH scoring system has become an essential clinical evaluation tool for suspected AD-HIES patients: scores >40 suggest AD-HIES, scores between 20 and 40 indicate a possible diagnosis, and scores <20 indicate that an AD-HIES is unlikely. Almost all AD-HIES patients (>95%) with dominant-negative STAT3 mutations have an NIH score >40, with pneumatocele, newborn rash, and characteristic facies as the most frequently reported findings.^8,9,18–20 Therefore, the detection of STAT3 mutations by next-generation sequencing is the only reliable approach to confirm the diagnosis; nevertheless, the scoring system is still useful in settings wherein genomic sequencing is difficult.^18,21 To the best of our knowledge, our case is the first STAT3 LOF case supported by genomic sequencing to be published in our country; previous studies were only based on clinical characterization and application of the NIH scoring system.²²

In an analysis of 4 cohorts of AD-HIES patients, the mean age at diagnosis was between 6 and 14 years, and the median age at symptom onset was newborn. The median age of delayed diagnosis was between 4 and 9 years, and the oldest was seen in a Chinese cohort.^8,9,20,21 A Peruvian study reported a median delay in diagnosis of 12.2 months in 45 PIDD patients; however, the number of AD-HIES cases was not mentioned, and the study only included clinical records of 1 immunology department.²³ Although our patient was diagnosed at 2 years, she did not receive appropriate and opportune treatment at that time; there was a delay of 2 years before the IRT treatment was started, and further 6 years before an immunologist performed a detailed evaluation and initiated appropriate management.

This delay could have been due to several reasons: immunology is a novel medical specialty in Peru, and there are only 6 specialized immunological centers, all of which are located in Lima, but not all have adequate infrastructure to perform the immunological tests required to make a definitive diagnosis of a PIDD. Furthermore, there is limited access to IRT and hematopoietic stem cell transplantation, and these treatment types require international support to provide an opportune treatment to PIDD patients.^23–25 Therefore, many Peruvian physicians do not have adequate education and available resources to diagnose and manage patients with PIDD, such as STAT3 LOF. This problem is even more evident in rural hospitals because of limited access to medications and diagnostic resources.

Previous studies have shown that AD-HIES patients die on average between 13 and 30 years old, the majority of whom had lung parenchymal disease with pneumonia-causing multiple organ failure as the leading cause of death.^8,20,26 Prophylaxis with antibiotics and antifungals, and IRT in patients with recurrent pulmonary infections and lung parenchymal disease decreases the annual incidence of infections and seems to increase survival.⁸ Likewise, the role of hematopoietic stem cell transplant is evolving and should be considered for those with recurrent infections despite prophylaxis.²⁷ In our case, after initiation of IRT 3 years ago, the patient has had fewer infections and less frequent hospitalizations.

In conclusion, we present the first case of STAT3 LOF diagnosed by genomic sequencing in Peru. The patient presented with severe lung infections and surgical complications. In addition, she was found to have an infection with an uncommon pathogen, likely due to the prolonged stay in the intensive care. Additional care must be taken in patients with this infection, due to the association with high mortality. Late diagnosis can further complicate the clinical course of STAT3 LOF patients. Despite the severity of her initial clinical presentation, she has been improving with fewer infections and well-controlled treatment.

Informed Consent

Informed consent was obtained from the child's mother.

Footnotes

Acknowledgments

We thank Drs. Raif Geha, Janet Chou, and Craig Platt, Division of Immunology, Boston Children's Hospital, Harvard Medical School for the genetic diagnosis.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

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