Case Letter

Mucous Membrane Involving the Trachea and Bronchi: An Extremely Rare and Life-Threatening Presentation

Elizabeth Wilder, MD; Martin P. Fernandez, MD; Jennifer Krejci-Manwaring, MD

PRACTICE POINTS • Mucous membrane pemphigoid (MMP) can present with diverse clinical manifestations, making the diagnosis challenging for many clinicians, including experienced dermatologists. • If not treated early and aggressively, MMP can lead to scarring and iscopy a potentially life-threatening disease.

not To the Editor: A 37-year-old man presented to his primary care Mucous membrane pemphigoid (MMP) is an auto- physician with a chief concern of a sore throat and immune blistering disorder that causes subepithelial oral ulcers. The patient was treated with a course of damage and scarring of mucosal surfaces withDo or antibiotics followed by a nystatin oral solution. He without involvement.1 The clinical presenta- continued to develop ulcerative on the soft tion is highly variable. The oropharynx is the most palate, posterior pharynx, and nasal mucosae. He common site of initial presentation, followed by ocu- sought treatment from 2 otolaryngologists (ENTs) lar, nasopharyngeal, anogenital, skin, laryngeal, and and a gastroenterologist, and continued to be treated esophageal involvement.2 Patients often present to a with multiple oral antibiotics, fluconazole, and topi- variety of specialists depending on initial symptoms, cal nystatin. Despite treatment, the patient devel- and due to the diverse clinical manifestations, MMP oped pansinusitis and laryngitis and presented to often is misdiagnosed. Our CUTISpatient presented an even the ENT department at our institution with severe greater challenge because the disease progressed to hoarseness and dyspnea on exertion. Examination tracheal and bronchial involvement. by the ENT department revealed ulcerative lesions of the nares with stenosis and ulcers along the soft palate. Videolaryngostroboscopy showed remarkable supraglottic edema with thick endolaryngeal mucus. The patient worked as a funeral director and had notable formaldehyde exposure. He also hunted wild game and performed taxidermy regularly. The patient was admitted and treated with Dr. Wilder is from Baylor University Medical Center, Dallas, Texas. intravenous dexamethasone for a compromised Dr. Fernandez is from the Section of Dermatopathology, Scott & airway. Subsequently, he was taken to the operat- White Memorial Hospital, Temple, Texas. Dr. Krejci-Manwaring is ing room and had biopsies performed of the pos- from the University of Texas Health Science Center at San Antonio, terior pharynx. Given his exposure history, the Division of and Cutaneous Surgery, and Audie Murphy infectious disease department was consulted and Veteran’s Hospital, San Antonio. The authors report no conflict of interest. he was evaluated for multiple viral, bacterial, and Correspondence: Jennifer Krejci-Manwaring, MD, 7400 Merton fungal suspects including leishmania and tularemia. Minter Blvd, San Antonio, TX 78229-3900 ([email protected]). Age-appropriate screening, physical examination,

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and review of systems were negative for an underlying and topical mitomycin C. Subsequently, the patient neoplasm. Histopathologic examination revealed a regained some use of his voice. Although the next subepithelial vesicular mucositis with a mixed infil- several laryngoscopes showed improvement in the trate of and histiocytes. Direct immuno- patient’s epiglottis and glottis, the trachea continued fluorescence microscopy demonstrated strong linear to require debridement and dilation. fluorescence along the epithelial-subepithelial junc- Despite maximal medical therapy and surgical tion with IgG and C3. Based on these findings, the interventions, the patient had little improvement in diagnosis of MMP was made. his voice and large clots of blood obstructed his trache- Further testing for anti- ostomy daily. He was unable to sleep in his preferred gen 1 (BP230) and bullous pemphigoid antigen 2 position on the stomach (prone) due to dyspnea but (BP180) were negative. On one occasion the patient had less distress sleeping on his back (supine). The tested positive for anti-BP230 IgG, but it was at patient was referred to the pulmonology department a level judged to be insignificant (7.5 [reference for an endotracheobronchoscopy to further evalu- range, <9]). The patient also was negative for ate the airway. It was discovered that the mucosa against desmoglein 1 and 3. Indirect of the trachea from the level of the tracheostomy using rat bladder epithelium to the carina was friable with active erosions and was not performed. thick bloody secretions (Figure 1). Lesions extended The patient was started on and as far as the scope was able to visualize to the left oral by the rheumatology department, upper lobe takeoff and the right mainstem bronchus but after 1 week, he presented in respiratory distress (Figure 2). Biopsies of the carinal mucosa showed and was taken for an emergency tracheostomy. The 3+/3+ linear fluorescence with IgG along the der- patient eventually was referred to the dermatology moepidermal junction.copy Salt-split studies were per- department where methotrexate was discontinued formed, but because the specimen was fragmented, and the patient was started on titrating doses of it was not possible to assess if the fluorescence was prednisone and mycophenolate mofetil. Eight weeks present at the floor or at the roof of the split. later, the patient became completely aphonic and notGiven the severity of disease and failure to was taken by ENT for dilation of the supraglottic, respond to other aggressive immunosuppressive ther- glottic, and subglottic stenosis with mucosal tri- apies as well as having been with a tracheostomy amcinolone injections. Doxycycline 100 mg twice for 22 months, the patient was started on 2 doses of daily and nicotinamide 500 mg twice daily was initiDo- intravenous rituximab 1 g 2 weeks apart along with ated in addition to mycophenolate mofetil 3 g and trimethoprim-sulfamethoxazole (3 times weekly) prednisone 80 mg, but again the patient developed for pneumocystis pneumonia prophylaxis. No com- near-complete tracheal stenosis just proximal to the plications were observed during infusions. After tracheostomy entry site. At 16 weeks, balloon dila- 2 rituximab infusions, he was weaned off of predni- tion was repeated with dexamethasone injections sone and a repeat bronchoscopy showed no airway CUTIS

Figure 1. Bronchoscopy revealed a 2-cm area of Figure 2. Blood clots were removed with suction stenosis in the upper third of the trachea causing up and forceps to reveal irregular mucosa with to 90% narrowing. mild nodularity.

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ulcers beyond the distal trachea or endobronchial reports, each patient also presented with involvement obstruction. However, the subglottic space and area of the eyes or skin.4,5,7-11 Four of these cases were fatal above the tracheostomy showed remarkable ste- secondary to cardiopulmonary arrest.5,7,9,10 In the pro- nosis with a cobblestone pattern and granulation spective study, 110 consecutive patients with clinical, tissue with continued narrowing of the subglottic histologic, and immunologic criteria of MMP were area. The ENT performed further dilation and after examined with a flexible nasopharyngolaryngoscope.6 34 months, the tracheostomy was removed and a Thirty-eight patients had nose or throat symptoms but T-tube was placed. The patient required cleaning only 10 had laryngeal involvement and 5 had acute dys- out of the T-tube approximately every 3 months, pnea. The nasal valves, choanae, pharynx, and/or larynx and after 2 years the original T-tube was replaced were severely scarred in 7 patients, which was fatal in 3.6 with a new one. At the time of this report, the ENT Medical treatment should be based on the fol- recommended removing the T-tube, but the patient lowing factors of the patient’s disease: site, sever- was reluctant to do so; therefore, a second T-tube ity, and rapidity of progression.3 High-risk patients replacement is planned. He continues to do well can be defined as those who have lesions at any of without relapse and has been off all medical therapy the following sites: ocular, genital, nasopharyngeal, for nearly 4 years. esophageal, and laryngeal mucosae. As our patient Mucous membrane pemphigoid is an acquired had involvement at several high-risk sites, in par- autoimmune subepithelial blistering disease that ticular sites only visualized by various scoping proce- predominantly affects mucous membranes with or dures, a team of physicians including dermatologists, without skin involvement. This condition has been ENT physicians, pulmonologists, and oncologists referred to as cicatricial pemphigoid, oral pemphi- was necessary to facilitate his care. Scarring is the goid, and ocular cicatricial pemphigoid, among other hallmark of MMPcopy and prevention of scarring is names. It is characterized by linear deposition of the most important aspect of treatment of MMP. IgG, IgA, or C3 along the epithelial basement mem- Surgical repair of the previously involved mucosa is brane zone. According to the international consen- difficult, as the tissue is prone to re-scarring and dif- sus on MMP, the target antigens identified in the ficultnot to heal. Over the last several years, there has epithelial basement membrane zone include bullous been increasing evidence for the use of rituximab in pemphigoid antigen 1 (BP230), bullous pemphigoid autoimmune bullous skin diseases including pem- antigen 2 (BP180), 5 (α3, β3, γ2 chains), phigus vulgaris, acquisita, and laminin 6 (α3 chain), type VII , Doand MMP. 12-14 After 2 infusions of rituximab, our patient integrin β4 subunit.3 Not all patients with MMP had clearance of his disease and currently is doing will have circulating autoantibodies to the above well with a T-tube. components, and although our patient did have detectable anti-BP230 IgG, it was not consid- Acknowledgments—We thank Kim Yancey, MD ered clinically significant. Furthermore, the type of (Dallas, Texas), for providing access to the patient’s does not impact decisions regarding diagnostic laboratory immunology and reviewing therapy selection.3 biopsy specimens; Luis Angel, MD (San Antonio, Although rare, MMP CUTISis well-known to derma - Texas), for providing bronchoscopy photographs; tologists and ophthalmologists who manage a large and C. Blake Simpson, MD (San Antonio, Texas), majority of MMP patients depending on which for co-managing this challenging case. mucosa is involved. Mucous membrane pemphi- goid is extremely rare in the lower respiratory tract, REFERENCES and when these lesions are discovered, it often is 1. James WD, Berger TG, Elston D. Chronic in the face of life-threatening respiratory distress. blistering diseases. In: James WD, Berger Mucous membrane pemphigoid is a challenging TG, Elston D. Andrews’ Diseases of the Skin: Clinical disease to treat, even more so when the primary Dermatology. 11th ed. Philadelphia, PA: Sanders Elsevier; specialty physician is unable to visualize the affected 2010:448-467. areas. Our patient’s disease was limited primarily 2. Neff AG, Turner M, Mutasim DF. Treatment strate- to the pharynx, larynx, trachea, and bronchi with gies in mucous membrane pemphigoid. Ther Clin Risk few oral lesions. According to a PubMed search Manag. 2008;4:617-626. of articles indexed for MEDLINE using the terms 3. Chan LS, Ahmed AR, Anhalt GJ, et al. The first inter- mucous membrane , cicatricial pemphigoid, national consensus on mucous membrane pemphigoid: trachea, bronchus, and fatal, 8 reports (7 case reports definition, diagnostic criteria, pathogenic factors, medi- and 1 prospective study) of MMP involving the lower cal treatment, and prognostic indicators. Arch Dermatol. respiratory tract have been published.4-11 Of the case 2002;138:370-379.

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4. Kato K, Moriyama Y, Saito H, et al. A case of mucous 10. Derbes VJ, Pitot HC, Chernosky ME. Fatal cicatricial membrane pemphigoid involving the trachea and bron- mucous membrane pemphigoid of the trachea. Dermatol chus with autoantibodies to β3 subunit of laminin-332. Trop Ecol Geogr. 1962;1:114-117. Acta Derm Venereol. 2014;94:237-238. 11. Wieme N, Lambert J, Moerman M, et al. Epidermoly- 5. Gamm DM, Harris A, Mehran RJ, et al. Mucous mem- sis bullosa acquisita with combined features of bullous brane pemphigoid with fatal bronchial involvement in a pemphigoid and cicatricial pemphigoid. Dermatology. seventeen-year-old girl. Cornea. 2006;25:474-478. 1999;198:310-313. 6. Alexandre M, Brette MD, Pascal F, et al. A prospec- 12. Taylor J, McMillan R, Shephard M, et al. World tive study of upper aerodigestive tract manifestations of Workshop on Oral Medicine VI: a systematic review of mucous membrane pemphigoid. Medicine (Baltimore). the treatment of mucous membrane pemphigoid [pub- 2006;85:239-252. lished online March 11, 2015]. Oral Surg Oral Med Oral 7. de Carvalho CR, Amato MB, Da Silva LM, et al. Pathol Oral Radiol. 2015;120:161.e20-171.e20. Obstructive respiratory failure in cicatricial pemphigoid. 13. Sobolewska B, Deuter C, Zierhut M. Current medical Thorax. 1989;44:601-602. treatment of ocular mucous membrane pemphigoid [pub- 8. Müller LC, Salzer GM. Stenosis of left mainstem bronchus lished online July 9, 2013]. Ocul Surf. 2013;11:259-266. in a case of cicatricial pemphigoid. Eur J Cardiothorac 14. Maley A, Warren M, Haberman I, et al. Rituximab com- Surg. 1988;2:284-286. bined with conventional therapy versus conventional 9. Camisa C, Allen CM. Death from CP in a young woman therapy alone for the treatment of mucous membrane with oral, laryngeal, and bronchial involvement. Cutis. pemphigoid (MMP) [published online February 28, 2016]. 1987;40:426-429. J Am Acad Dermatol. 2016;74:835-840. copy

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