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Pulmonary hemorrhage Associated with Bullous pemphigoid of the lung
Pulmonary Hemorrhage Associated with Bullous Pemphigoid of the Lung STEVENT.KARIYA,M.D.,ROBERTS.STERN,M.D.,RICHARDM.SCHWARTZSTEIN,M.D., HOWARDFRANK,M.D., ROBERTS. BROWN,M.D.Boston, Massachusetts
W
e report herein an unusual case of bullous pemphigoid involving both the skin and lung that was discovered during an evaluation for massive hemoptysis.
CASE REPORT The patient was a 52-year-old white man referred for evaluation of recurrent severe hemoptysis. His past medical history was notable for long-standing endstage renal failure, attributed to long-term analgesic use and hypertension, for which he received a cadaveric renal transplant in 1980. In August of 1982, he noted a bullous eruption that progressed to crusted lesions, initially localized to the back of his hands but subsequently involving the oropharnyx, trunk, and lower extremities. A skin biopsy examination demonstrated a subepidermal split, but immunofluorescent studies were non-diagnostic. His bullous eruption would heal and recur intermittently over the next four years while the patient was taking azathioprine and prednisone for his renal transplant. However, chronic transplant rejection and subsequent renal failure developed, which was managed with fluid and dietary restrictions. In June 1986, he presented with progressive hemoptysis, dyspnea on exertion, a decrease in his hematocrit to 15 percent, and a chest radiograph that demonstrated diffuse alveolar infiltrates. Evaluation at that time revealed a blood urea nitrogen level (BUN) of 131 mg/dl and serum creatinine level of 12 mg/dl; a normal prothrombin time, partial thromboplastin time, platelet count, bleeding time, and serum complement level; negative serum studies for either anti-nuclear antibodies or anti-glomerular basement membrane antibodies; and a carbon monoxide diffusing capacity (DLCO) that was 280 percent of the predicted value. He received transfusions with packed red cells, and hemodialysis was restarted, with subsequent diminution in his hemoptysis, stabilization of his hematocrit, and partial clearing of his radiographic infiltrates. Azathioprine was discontinued, and prednisone was tapered off by September 1986. In October 1986, his skin disease flared with involvement of his trunk, extremities, and oropharynx, with the development of a hemorrhagic component to his cutaneous bullous lesions. Skin biopsy examination was initially non-diagnostic, but repeat biopsy examination of his bullous lesions demonstrated a subepidermal cleft with direct immunofluorescent staining in a linear pattern for both C3 and IgG at the basal lamina of the dermal-epidermal junction. These From the Departments of Medicine and Surgery, Beth Israel Hospital, Harvard Medical School and the Harvard Center for the Study of Kidney Diseases, Boston, Massachusetts. Requests for reprints should be addressed to Robert S. Brown, M.D., Renal Division, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts02215. Manuscript submitted April 12, 1988, and accepted October 19, 1988.
findings were those of bullous pemphigoid, and prednisone 60 mg daily was started with some stabilization of his skin lesions. In late November 1986, progressive and recurrent bouts of hemoptysis developed, one of which resulted in acute respiratory failure that required intubation and mechanical ventilation. His condition stabilized, and he underwent intensive hemodialysis; however, his chest radiograph continued to show a diffuse alveolar filling pattern and the DLCO value remained elevated at 260 percent of predicted. Further diagnostic studies included an open lung biopsy that revealed diffuse alveolar hemorrhage with otherwise normal bronchial, alveolar, and vascular structures on light microscopy. Immunofluorescent studies demonstrated linear staining for both C3 and IgG along the bronchial basal lamina. In addition, a fiberoptic bronchoscopy revealed two bullous lesions on the trachea, each approximately 3 mm in diameter (Figure 1). Neither lesion was observed to be bleeding. Inspection of the distal bronchial tree did not reveal any endobronchial lesions, but the bronchial walls were quite friable and bled easily with bronchoscopic suctioning. Because of concerns regarding hemostasis, no biopsy specimens of the tracheal bullous lesions were taken. Azathioprine (2 mglkglday) was restarted and resulted in a slow decrease of his hemoptysis and dyspnea coincident with resolution of his remaining skin lesions. By January 1987, he felt well while receiving azathioprine and prednisone 30 mg/day. He had no further episodes of hemoptysis, the DLCO value normalized, and there was slow radiographic improvement of his pulmonary infiltrates and good control of his skin lesions. He underwent repeat cadaveric renal transplant in February 1987 with the addition of cyclosporine to azathioprine and prednisone. He remains well without evidence of bullous pemphigoid or hemoptysis one year later.
COMMENTS Bullous pemphigoid lesions involving the mucous membrane of the upper airway and larnyx have been previously described [I]. In a report of bullous pemphigoid complicated by larnygeal stenosis and requiring tracheostomy, bronchoscopic demonstration of involvement of the tracheobronchial tree is described, although no further details are provided [2]. Ours is thus the second documented case of bullous pemphigoid involving the lower respiratory tract, and the first one associated with life-threatening hemoptysis. Initially, our patient presented a dermatologic diagnostic dilemma. When he presented in 1982, skin biopsy examination demonstrated a subepidermal split with positive immunofluorescent staining of the bullous cavity and stratum cornea for IgG, IgA, IgM, C3, and fibrinogen and a focal dispersed granular pattern January1989 TheAmericanJournalof Medicine Volume86
127
BULLOUS
PEMPHIGOID
OF THE LUNG
/ KARIYA
ET AL
Figure 1. Bronchoscopic photograph of one of two builous tracheal lesions (arrow). The view is from the proximal trachea toward the carina (which is faintly visible distally); the cartilaginous rings of the trachea can be seen. This bullous lesion was approximately 3 mm in diameter.
between keratocytes. At that time, his pathologic and clinical findings favored the diagnosis of bulious dermatosis of hemodialysis over bullous pemphigoid or porphyria cutanea tarda, although he was not undergoing dialysis at that time [3]. It was not until November 1986 when the characteristic immunofluorescent staining pattern was demonstrated that the diagnosis of bullous pemphigoid could be firmly established. Cutaneous bullous pemphigoid has been extensively investigated. It is characterized by autoantibodies reactive to an antigen located in the lamina lucida region of the basement membrane of skin [4]. Such autoantibodies activate the classic pathway of complement, attract neutrophils, lymphocytes, and eosinophils, and may activate mast cells. The significance of the immunofluorescent staining pattern observed on the open lung biopsy specimen is unclear. Some investigators have reported that the autoantibodies of bullous pemphigoid react with the basement membranes of a number of human stratified squamous epithelia, including human oral cavity mucosa and amnion epithelium [5,6]. Beutner and others [5] have also reported reactions with the basement membrane of a variety of monkey organs such as gallbladder, bladder, urethra, trachea, and bronchi. The linear deposition of IgG and complement along the bronchial basement membrane in our patient was similar to the immunofluorescent staining pattern observed on the last skin biopsy specimen. Although this
128
January
1989
The American
Journal
of Medicine
Volume
pattern would be consistent with circulating bullous pemphigoid autoantibodies reacting to an antigen common to both bronchial basement membrane and subepidermis in our patient, the specificity of this linear immunofluorescent staining pattern in the lung is unknown. The severe and recurrent hemoptysis in our patient was probably a result of multiple causes. Although we did not directly observe active bleeding by the tracheal bullous lesions, it is likely that rupture and hemorrhage can occur with these lesions in a manner similar to that observed with cutaneous lesions. In addition, the diffuse immunologic involvement demonstrated on the open limg biopsy specimen would be consistent with additional injuries throughout the lung, not simply the central tracheal bullous lesions that we observed bronchoscopically. The bleeding disorder associated with end-stage renal disease, primarily platelet dysfunction, could well have exacerbated hemorrhage from such lesions. Finally, the high-dose corticosteroid therapy may have contributed to the friable bronchial mucosa that we observed. Although others [7,8] have reported pulmonary infectious or neoplastic conditions associated with bullous pemphigoid, neither the bronchoscopy nor open lung biopsy was consistent with these concurrent conditions. In summary, the findings in our patient are consistent with bullous pemphigoid involving the lung. Physicians caring for such patients should be aware that life-threatening hemoptysis can develop, particularly if co-existent coagulopathy is present. It is interesting to note that our patient’s bullous pemphigoid, which had not been completely controlled when he was receiving both azathioprine and prednisone, greatly improved after the institution of cyclosporine therapy.
REFERENCES 1. Person JR. Rogers RS: Bullous and cicatricial oemohiaoid: clinical. histooathologic and immunopathologic correlation. Mayo Clin Pro; 1977; $2: 54-k. 2. Smith RJH, Sessions RB, Dean SF: Benign mucous membrane pemphigoid. Ann Otol 1982; 91: 142-144. 3. Gilchrest 8, Jowe JW, Mihm MC Jr: Bullous dermatosis of hemodialysis. Ann Intern Med 1975; 83: 480-483. 4. Jordan RE, Kawana S, Fritz KA: lmmunopathologic mechanisms in pemphigus and bullous pemphigoid. J Invest Dermatol 1985; 85: 725-785. 5. Beutner EH, Chorzelski TP, Jordan RE: Autosensitivity in pemphigus and bullous pemphigoid. Springfield, Illinois: Charles C. Thomas, 1970. 6. Robinson HN, Anhalt GJ, Pate1 HP, Takahashi Y, Labib RS, Diaz LA: Pemphigus and pemphigoid antigens are expressed in human amnion epithelium. J Invest Dermatol 1984; 83: 234-237. 7. Stein KM, Raque CR, Harrell DD, Samitz MH: Lung abscess: complication of high dose steroids in bullous pemphigoid. Arch Dermatol 1970; 102: 674-676. 6Takeuchi M, Okazaki A, Nakajima N. Saito Y, Nozaki M, Niibe H: A case of lung cancer with bullous pemphigoid. Gan No Rinsho 1986; 32: 529-533.
86
W
e report herein an unusual case of bullous pemphigoid involving both the skin and lung that was discovered during an evaluation for massive hemoptysis.
CASE REPORT The patient was a 52-year-old white man referred for evaluation of recurrent severe hemoptysis. His past medical history was notable for long-standing endstage renal failure, attributed to long-term analgesic use and hypertension, for which he received a cadaveric renal transplant in 1980. In August of 1982, he noted a bullous eruption that progressed to crusted lesions, initially localized to the back of his hands but subsequently involving the oropharnyx, trunk, and lower extremities. A skin biopsy examination demonstrated a subepidermal split, but immunofluorescent studies were non-diagnostic. His bullous eruption would heal and recur intermittently over the next four years while the patient was taking azathioprine and prednisone for his renal transplant. However, chronic transplant rejection and subsequent renal failure developed, which was managed with fluid and dietary restrictions. In June 1986, he presented with progressive hemoptysis, dyspnea on exertion, a decrease in his hematocrit to 15 percent, and a chest radiograph that demonstrated diffuse alveolar infiltrates. Evaluation at that time revealed a blood urea nitrogen level (BUN) of 131 mg/dl and serum creatinine level of 12 mg/dl; a normal prothrombin time, partial thromboplastin time, platelet count, bleeding time, and serum complement level; negative serum studies for either anti-nuclear antibodies or anti-glomerular basement membrane antibodies; and a carbon monoxide diffusing capacity (DLCO) that was 280 percent of the predicted value. He received transfusions with packed red cells, and hemodialysis was restarted, with subsequent diminution in his hemoptysis, stabilization of his hematocrit, and partial clearing of his radiographic infiltrates. Azathioprine was discontinued, and prednisone was tapered off by September 1986. In October 1986, his skin disease flared with involvement of his trunk, extremities, and oropharynx, with the development of a hemorrhagic component to his cutaneous bullous lesions. Skin biopsy examination was initially non-diagnostic, but repeat biopsy examination of his bullous lesions demonstrated a subepidermal cleft with direct immunofluorescent staining in a linear pattern for both C3 and IgG at the basal lamina of the dermal-epidermal junction. These From the Departments of Medicine and Surgery, Beth Israel Hospital, Harvard Medical School and the Harvard Center for the Study of Kidney Diseases, Boston, Massachusetts. Requests for reprints should be addressed to Robert S. Brown, M.D., Renal Division, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts02215. Manuscript submitted April 12, 1988, and accepted October 19, 1988.
findings were those of bullous pemphigoid, and prednisone 60 mg daily was started with some stabilization of his skin lesions. In late November 1986, progressive and recurrent bouts of hemoptysis developed, one of which resulted in acute respiratory failure that required intubation and mechanical ventilation. His condition stabilized, and he underwent intensive hemodialysis; however, his chest radiograph continued to show a diffuse alveolar filling pattern and the DLCO value remained elevated at 260 percent of predicted. Further diagnostic studies included an open lung biopsy that revealed diffuse alveolar hemorrhage with otherwise normal bronchial, alveolar, and vascular structures on light microscopy. Immunofluorescent studies demonstrated linear staining for both C3 and IgG along the bronchial basal lamina. In addition, a fiberoptic bronchoscopy revealed two bullous lesions on the trachea, each approximately 3 mm in diameter (Figure 1). Neither lesion was observed to be bleeding. Inspection of the distal bronchial tree did not reveal any endobronchial lesions, but the bronchial walls were quite friable and bled easily with bronchoscopic suctioning. Because of concerns regarding hemostasis, no biopsy specimens of the tracheal bullous lesions were taken. Azathioprine (2 mglkglday) was restarted and resulted in a slow decrease of his hemoptysis and dyspnea coincident with resolution of his remaining skin lesions. By January 1987, he felt well while receiving azathioprine and prednisone 30 mg/day. He had no further episodes of hemoptysis, the DLCO value normalized, and there was slow radiographic improvement of his pulmonary infiltrates and good control of his skin lesions. He underwent repeat cadaveric renal transplant in February 1987 with the addition of cyclosporine to azathioprine and prednisone. He remains well without evidence of bullous pemphigoid or hemoptysis one year later.
COMMENTS Bullous pemphigoid lesions involving the mucous membrane of the upper airway and larnyx have been previously described [I]. In a report of bullous pemphigoid complicated by larnygeal stenosis and requiring tracheostomy, bronchoscopic demonstration of involvement of the tracheobronchial tree is described, although no further details are provided [2]. Ours is thus the second documented case of bullous pemphigoid involving the lower respiratory tract, and the first one associated with life-threatening hemoptysis. Initially, our patient presented a dermatologic diagnostic dilemma. When he presented in 1982, skin biopsy examination demonstrated a subepidermal split with positive immunofluorescent staining of the bullous cavity and stratum cornea for IgG, IgA, IgM, C3, and fibrinogen and a focal dispersed granular pattern January1989 TheAmericanJournalof Medicine Volume86
127
BULLOUS
PEMPHIGOID
OF THE LUNG
/ KARIYA
ET AL
Figure 1. Bronchoscopic photograph of one of two builous tracheal lesions (arrow). The view is from the proximal trachea toward the carina (which is faintly visible distally); the cartilaginous rings of the trachea can be seen. This bullous lesion was approximately 3 mm in diameter.
between keratocytes. At that time, his pathologic and clinical findings favored the diagnosis of bulious dermatosis of hemodialysis over bullous pemphigoid or porphyria cutanea tarda, although he was not undergoing dialysis at that time [3]. It was not until November 1986 when the characteristic immunofluorescent staining pattern was demonstrated that the diagnosis of bullous pemphigoid could be firmly established. Cutaneous bullous pemphigoid has been extensively investigated. It is characterized by autoantibodies reactive to an antigen located in the lamina lucida region of the basement membrane of skin [4]. Such autoantibodies activate the classic pathway of complement, attract neutrophils, lymphocytes, and eosinophils, and may activate mast cells. The significance of the immunofluorescent staining pattern observed on the open lung biopsy specimen is unclear. Some investigators have reported that the autoantibodies of bullous pemphigoid react with the basement membranes of a number of human stratified squamous epithelia, including human oral cavity mucosa and amnion epithelium [5,6]. Beutner and others [5] have also reported reactions with the basement membrane of a variety of monkey organs such as gallbladder, bladder, urethra, trachea, and bronchi. The linear deposition of IgG and complement along the bronchial basement membrane in our patient was similar to the immunofluorescent staining pattern observed on the last skin biopsy specimen. Although this
128
January
1989
The American
Journal
of Medicine
Volume
pattern would be consistent with circulating bullous pemphigoid autoantibodies reacting to an antigen common to both bronchial basement membrane and subepidermis in our patient, the specificity of this linear immunofluorescent staining pattern in the lung is unknown. The severe and recurrent hemoptysis in our patient was probably a result of multiple causes. Although we did not directly observe active bleeding by the tracheal bullous lesions, it is likely that rupture and hemorrhage can occur with these lesions in a manner similar to that observed with cutaneous lesions. In addition, the diffuse immunologic involvement demonstrated on the open limg biopsy specimen would be consistent with additional injuries throughout the lung, not simply the central tracheal bullous lesions that we observed bronchoscopically. The bleeding disorder associated with end-stage renal disease, primarily platelet dysfunction, could well have exacerbated hemorrhage from such lesions. Finally, the high-dose corticosteroid therapy may have contributed to the friable bronchial mucosa that we observed. Although others [7,8] have reported pulmonary infectious or neoplastic conditions associated with bullous pemphigoid, neither the bronchoscopy nor open lung biopsy was consistent with these concurrent conditions. In summary, the findings in our patient are consistent with bullous pemphigoid involving the lung. Physicians caring for such patients should be aware that life-threatening hemoptysis can develop, particularly if co-existent coagulopathy is present. It is interesting to note that our patient’s bullous pemphigoid, which had not been completely controlled when he was receiving both azathioprine and prednisone, greatly improved after the institution of cyclosporine therapy.
REFERENCES 1. Person JR. Rogers RS: Bullous and cicatricial oemohiaoid: clinical. histooathologic and immunopathologic correlation. Mayo Clin Pro; 1977; $2: 54-k. 2. Smith RJH, Sessions RB, Dean SF: Benign mucous membrane pemphigoid. Ann Otol 1982; 91: 142-144. 3. Gilchrest 8, Jowe JW, Mihm MC Jr: Bullous dermatosis of hemodialysis. Ann Intern Med 1975; 83: 480-483. 4. Jordan RE, Kawana S, Fritz KA: lmmunopathologic mechanisms in pemphigus and bullous pemphigoid. J Invest Dermatol 1985; 85: 725-785. 5. Beutner EH, Chorzelski TP, Jordan RE: Autosensitivity in pemphigus and bullous pemphigoid. Springfield, Illinois: Charles C. Thomas, 1970. 6. Robinson HN, Anhalt GJ, Pate1 HP, Takahashi Y, Labib RS, Diaz LA: Pemphigus and pemphigoid antigens are expressed in human amnion epithelium. J Invest Dermatol 1984; 83: 234-237. 7. Stein KM, Raque CR, Harrell DD, Samitz MH: Lung abscess: complication of high dose steroids in bullous pemphigoid. Arch Dermatol 1970; 102: 674-676. 6Takeuchi M, Okazaki A, Nakajima N. Saito Y, Nozaki M, Niibe H: A case of lung cancer with bullous pemphigoid. Gan No Rinsho 1986; 32: 529-533.
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