1. ¹Division of Hematology and Oncology, Department of Medicine, Akita University School of Medicine, Akita, Japan
2. ²Department of Otolaryngology, Akita University School of Medicine, Akita, Japan. E-mail: hirokawa@med.akita-u.ac.jp

Obstructive and restrictive pulmonary diseases are clinical manifestations of chronic graft-versus-host disease (GVHD) in the airway tract, and involvement of the upper respiratory tract is unusual. We present a case of glottic and subglottic stenosis that presented with extensive chronic GVHD.

A 22-year-old Japanese male was diagnosed with chronic myeloid leukemia in 1993. Interferon-alpha therapy effected complete hematological response but cytogenetic response was minimal. He had no HLA-matched siblings or family members. Two years after diagnosis, he was conditioned with fractionated total body irradiation (2 Gy twice daily for 3 days, total dose 12 Gy) and cyclophosphamide (120 mg/kg), followed by infusion of bone marrow from a serologically HLA-matched, ABO minor mismatched unrelated male donor. Cyclosporine and short-term methotrexate were given for the prophylaxis of acute GVHD. Engraftment was prompt and complete cytogenetic response was obtained. He developed grade 2 acute GVHD on day 10 of transplantation, which responded to corticosteroids. On day 47, he developed cytomegalovirus-associated interstitial pneumonia and ganciclovir resulted in resolution of the pneumonia. On day 100, he complained of persistent nausea and severe watery diarrhea, with normal bacterial flora and negative Clostridium toxins. Colonoscopic examination confirmed the diagnosis of intestinal GVHD and corticosteroid therapy ameliorated the gastrointestinal symptoms. As a result of persistent oral mucositis and depigmentation (vitiligo) over the face and fingers, cyclosporine and prednisolone were continued. On day 937, he complained of dysphagia persisting for a few months. Redness of the right vocal cord was found and diagnosed as chronic laryngitis. The symptom spontaneously disappeared. On day 1925, the patient again complained of dysphagia and a prolonged sore throat and visited the otolaryngology department. Fiberoptic laryngoscopy demonstrated a reddened arytenoid mucosa. Neither H2 receptor blockers nor long-term administration of antibiotics or antifungal drugs ameliorated the symptoms. His range of movement in both shoulders became limited, despite continued administration of cyclosporine and prednisolone, and stiffened fascial tissues were palpable over the sternocleidomastoid and trapezoid muscles. On day 2088, he consulted the emergency room for inspiratory dyspnea. Anteroposterior radiogram of the upper airway showed subglottic tracheal narrowing (Figure 1). Laryngoscopy demonstrated swelling and poor movement of the vocal cords, and magnetic resonance imaging of his neck revealed glottic stenosis with low intensity of the left vocal cord on T1-weighed images. As inhalation of corticosteroids was ineffective in improving his symptoms, tracheotomy was performed. Although a small tissue sample was taken from the tracheotomy site, only blood clot and degenerative collagen fibers were seen. As glottic and subglottic stenosis could be a presentation of chronic GVHD, immunosuppressive therapy consisting of tacrolimus and prednisolone was given. Although the glottic stenosis appears to have improved 4 years after starting tacrolimus therapy, closing the orifice of the tracheotomy cannula leads to the development of stridor. Therefore, decannulation has not yet been successful.

Figure 1.

Anteroposterior radiographs of the upper airway of the present case. The normal lateral convexities of the subglottic trachea were still present on day 937. Subglottic tracheal narrowing producing an inverted V configuration, known as the steeple sign, was evident on day 2088, when the patient complained dyspnea.

Full figure and legend (96K)

Laryngotracheal stenosis may be congenital or acquired, and the type of stenosis is classified into supraglottic, glottic, or subglottic stenosis based on the anatomic location. Acquired glottic and subglottic stenosis most commonly results from trauma secondary to endotracheal intubation.^{1, 2} Other causes include inflammation, infection and trauma and rarely neoplasms. The present patient had never been intubated. Rarely, glottic stenosis caused by granulomatous infections or inflammatory diseases including tuberculosis, sarcoidosis and Wegener's granulomatosis has been reported.^{3, 4} This patient had no history of symptoms, signs or evidence suggesting the presence of these diseases.

To our knowledge, this complication in the setting of hematopoietic stem cell transplantation has not been previously reported. Although the exact mechanisms of laryngeal stenosis remain uncertain, an inflammatory process in association with chronic GVHD may have contributed to the development of laryngeal stenosis in this case. Prolonged symptoms of the upper respiratory tract associated with extensive chronic GVHD may be an early sign of this complication, and intensive immunosuppressive therapy should be considered.