Patients with Suspicion of Systemic Disease Require Ongoing Follow-Up for Diagnosis

A recent case report detailing multiple procedures and inconclusive biopsies underwent by a patient with unusual presentation of immunoglobulin G4-related disease before conclusive diagnosis emphasizes the importance of follow-up with patients with suspicion of systemic disease.

Close and ongoing follow-up of individuals with suspicion of systemic disease is needed to support accurate and timely diagnosis, according to a case reported published in Cureus.

The case report describes one patient’s unusual presentation of immunoglobulin G4-related disease (IgG4-RD), an immune-mediated condition that causes fibroinflammatory lesions that can affect multiple organs. Untreated IgG4-RD can lead to organ dysfunction, organ damage, and death.

The case highlights challenges to diagnosis, including tissue sample difficulties and limited knowledge on subglottic involvement in IgG4-RD, for a 30-year-old woman presenting with laryngeal subglottic involvement leading to stenosis and airway obstruction.

The patient presented to a laryngology clinic in 2017 after she was unable to be intubated for elective sinonasal surgery. She complained of nasal obstruction, crusting, nosebleeds, and difficulty breathing upon presentation to the laryngology clinic. She had been experiencing shortness of breath over the year prior to the initial visit and had been responsive to oral glucocorticoids and montelukast.

A flexible laryngoscopy was conducted, revealing subglottic stenosis. Due to observed symptoms and family history of autoimmune disease, rheumatology evaluation was requested. The report indicates that initial rheumatologic differential diagnoses included antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, IgG4-related disease, sarcoidosis, and relapsing polychondritis.

The patient’s laboratory workup revealed slightly elevated IgG4 subclass at 151 mg/dL (normal: 4-86 mg/dL) and slightly elevated ALT. However, the workup was considered otherwise normal, including basic metabolic panel, complete blood count, and serum protein electrophoresis.

A CT of the chest, abdomen, and pelvis revealed a 7 mm subpleural left upper lobe nodule with calcification, but no other findings suggested ANCA vasculitis or other organ involvement of IgG4-RD.

Despite the pathology of the laryngeal and subglottic tissues showing a small focus of chronic inflammation with stromal fibrosis/hyalinization and a few IgG4 cells present, the findings were not conclusive for IgG4-R due to the limited size of the sample and only the presence of a small number of IgG4 cells.

From 2017 through 2018, the patient underwent multiple operations including endoscopic procedures, a microlaryngoscopy, and a cystoscopy. All biopsies over this period returned normal and negative for IgG4 staining.

In 2019, a CT abdomen/pelvis scan noted some urothelial thickening of the renal collecting system, potentially indicated retroperitoneal fibrosis, which can be seen in the setting of IgG-RD. In 2020, the patient had repeat CT imaging of the chest, abdomen, and pelvis, revealing some scattered benign-appearing pulmonary nodules.

She was then treated with serial awake, office intralesional steroid injections. Though she experienced some improvement, her symptoms recurred, along with 60% stenosis. The patient then began systemic glucocorticoid therapy because her response to local treatment for a shorter period before recurrence suggested systemic disease. Treatment with prednisone led to improvement in nasal and laryngotracheal symptoms.

In 2020, the patient underwent a repeat microlaryngoscopy and bronchoscopy. This time, a larger excisional biopsy was taken, showing dense subepithelial storiform fibrosis and chronic inflammation with increased IgG4 positive plasma cells (33 per high power field at 40x) with less than 50% IgG4/IgG.

These findings helped make the diagnosis of IgG4-RD more definitive based on the 2019 ACR/EULAR classification criteria for IgG4-RD. After 2 weeks of laryngitis treatment and endoscopic assessment, she experienced improvement in hoarseness and had no dyspnea, dysphagia, and sore throat. Her subglottic stenosis was significantly improved.

Overall, it took nearly 3 years of follow-up, multiple procedures, and 3 biopsies to confidently characterize this patient’s disease and therefore determine appropriate treatment. The authors concluded that this case exemplifies the need for ongoing follow-up in patients with suspicion of systemic disease, particularly for those with presentation in a location in which it is challenging to obtain a large tissue sample.

They suggest that this case specifically highlights the importance of keeping IgG4-RD in mind when diagnosing and treating upper airway stenosis, given that tracheal and laryngeal involvement can develop insidiously and progress to critical airway obstruction. This is especially important for patients who become refractory to local treatments.

They also encourage awareness of factors influencing biopsy and the possibility of false negatives.

“If the clinical picture lends strong suspicion for IgG4-RD, then biopsy should be repeated to provide more definitive results,” they wrote.

Due to the rarity of laryngotracheal involvement in IgG4-RD and limited knowledge of the entity in its infancy, the authors suggest it may also be underrecognized, further emphasizing the importance of follow-up with these patients.

Reference

Nallani P, Guo W, Mayerhoff RM, Meysami A. An Unusual Presentation of Immunoglobulin G4-Related Diseases (IgG4-RD) Causing Subglottic Stenosis. Cureus. 2022;14(6):e26250. https://www.cureus.com/articles/100701-an-unusual-presentation-of-immunoglobulin-g4-related-disease-igg4-rd-causing-subglottic-stenosis. Published Jun 23, 2022. Accessed July 8, 2022.