Table 4.

How we evaluate and manage STAT3-HIES

Clinical manifestations	How we evaluate	How we manage
Oral and dental manifestations
Dental abnormalities	Twice yearly dental evaluations to assess Retention of primary teeth and the appropriate timing of extraction. Decay of secondary teeth.	Antibiotic prophylaxis (e.g. amoxicillin/clavulanate) around tooth extractions and other oral surgeries, typically 48 hours for primary teeth and 5–7 days for secondary teeth. Referral to Orthodontics as indicated.
Mucocutaneous candidiasis	Obtain fungal culture with antifungal susceptibility testing in cases of persistent Candida infection despite antifungal therapy.	Consider suppressive antifungal therapy for Candida onychomycosis or recurrent oropharyngeal disease requiring repeated treatment. Fluconazole is typically the first line agent if no resistance; posaconazole can be used when there is concern for concurrent mold infection.
Aphthous ulcers	Obtain HSV PCR for initial episode or atypical appearance.	Symptomatic pain relief with Magic mouthwash or topical corticosteroids (e.g. triamcinolone dental ointment)
Non-allergic skin/soft tissue manifestations
Newborn rash	Obtain bacterial cultures from skin lesions or nose to assess S. aureus carriage and antibiotics susceptibility.	Use chlorhexidine washes to reduce S. aureus colonization. Initiate TMP/SMX prophylaxis around 2 months of age.
Recurrent skin abscesses	If breakthrough infections occur despite TMP/SMX prophylaxis, consider obtaining a nasal culture for S. aureus with antibiotics susceptibility testing to evaluate for resistance.	Use antiseptics to decrease S. aureus colonization (e.g., dilute bleach baths, chlorhexidine washes, or swimming in chlorinated pools). Initiate TMP/SMX prophylaxis at 5–6 mg/kg/day of the TMP component divided twice daily (max 160 mg TMP/dose). Consider dupilumab to improve skin barrier integrity and reduce the risk of secondary infections.
Allergic manifestations
Eczematous rash	Obtain clinical history and perform physical exam.	Use antiseptics (e.g. dilute bleach baths, chlorhexidine washes) in addition to antibiotic prophylaxis (e.g., TMP/SMX) and topical therapies. Low threshold to consider dupilumab.
Eosinophilic esophagitis	Obtain relevant clinical history (e.g., dysphagia, food impaction) and proceed with upper endoscopy as indicated.	Consider swallowed corticosteroids or dupilumab in biopsy-proven cases.
Food allergy	Obtain clinical history and only proceed with allergen-specific IgE testing if history is suggestive of an IgE-mediated hypersensitivity	In confirmed cases, avoid culprit food and prescribe epinephrine autoinjectors.
Lung manifestations
Recurrent pneumonia	Education regarding minimal systemic signs at start of pneumonia, and low clinical threshold to look for pneumonia with chest imaging.	Obtain sputum cultures (induced or bronchoscopy if needed) during infection to guide antibiotics use. Ensure compliance with TMP/SMX prophylaxis at 5–6 mg/kg/day of the TMP component divided twice daily (max 160 mg TMP/dose). Strong consideration for IgRT.
Bronchiectasis	Chest CT imaging every 1–2 years with PFTs and 6-minute walk test.	Sputum culture monitoring for bacteria, fungi and mycobacteria in patients with chronic infection/colonization, which can guide treatment choices during exacerbation. Airway clearance with oscillatory devices, albuterol, hypertonic saline aerosols, or aerobic exercise. Consider azithromycin (in adults, 250 mg daily), if no evidence of nontuberculous mycobacteria colonization.
Pneumatocele	Chest CT imaging to assess for thickened walls or debris suggestive of infection	If not infected, consider itraconazole antifungal prophylaxis. Minimize mold exposures (e.g., avoiding mulching and hay exposure).
Aspergillus lung infection	Chest CT imaging to assess for Aspergilloma.	Lifelong antifungals (e.g., posaconazole) typically due to increased risk of hemoptysis and further spread with local invasion.
Prolonged bronchopleural fistula	Awareness of the risk of this complication before lung surgery.	Consider endobronchial valves.
ABPA/M	Follow revised ISHAM-ABPA working group consensus criteria but emphasize the importance to look for compatible chest CT imaging findings.	Anti-mold antifungals (e.g., posaconazole) and initiate systemic corticosteroids. Low threshold for anti-type 2 biologies (e.g., dupilumab) as steroid-sparing agent, due to negative consequences of prolonged corticosteroid use with increased risk of fractures and potential worsening of infections.
Musculoskeletal manifestations
Scoliosis	Annual physical exam screen, more frequent if scoliosis is present. Low threshold to obtain radiographic evaluation.	Referral to Orthopedics. When surgical correction is needed, consider additional S. aureus prophylaxis (e.g., linezolid), starting pre-operatively and continuing for 7–10 days post-operatively.
Minor trauma fractures	Obtain DEXA scan and vitamin D levels	Optimize Vitamin D and calcium intake. Consider medical therapy (e.g. bisphosphonates) in patients with fractures or osteoporosis on DEXA scan.
Osteoarthritis	Low threshold for radiographic evaluation	Low threshold for physical therapy and orthopedics referral. With surgical correction/joint replacement, consider additional S. aureus prophylaxis (e.g., linezolid), starting 1–2 days pre-operatively and continuing 7–10 days post-operatively.
Other manifestations
Endemic mycoses	Low threshold to look for disseminated Coccidioides, Histoplasma and Cryptococcal disease.	Azole prophylaxis for patients traveling to or residing in Coccidioides endemic regions. Consideration of azole prophylaxis for those with high-risk activities for Histoplasma exposure (e.g. residing in highly endemic regions).
Vascular abnormalities: e.g., cerebral or coronary artery	Brain MRA and coronary artery screening (e.g., cardiac MRI) beginning in adolescence, with follow-up imaging every 3 years, unless clinical concerns warrant earlier evaluation.	Consider anti-platelet agents for coronary artery aneurysm. Optimize blood pressure management as appropriate. Avoid estrogen supplementation or other pro-thrombotic agents, when possible, particularly in patients with vascular abnormalities.
Clinical autoimmunity: e.g., lupus-like manifestations	Clinical assessment and yearly urinalysis screening for proteinuria.	Referral to Rheumatology.
Lymphoma	Low threshold for imaging, annual blood tests (e.g., LDH, uric acid), and biopsy if indicated.	Referral to Hematology/Oncology. Patients typically respond well to standard chemotherapy regimen.

Abbreviations: HSV, herpes simplex virus; PCR, polymerase chain reaction; TMP/SMX, trimethoprim/sulfamethoxazole; IgRT, immunoglobulin replacement therapy; PFT, pulmonary function test; CT, computed tomography; ABPA/M, allergic bronchopulmonary aspergillosis/mycosis; ISHAM, International Society for Human and Animal Mycology; DEXA, dual-energy X-ray absorptiometry; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; LDH, lactate dehydrogenase.