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Bronchiectasis in a patient with CREST syndrome
Joint Bone Spine 2002 ; 69 : 515-8 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X02004414/SCO
CASE REPORT
Bronchiectasis in a patient with CREST syndrome Frédéric Lavie, Sylvie Rozenberg, Anne Coutaux, Anne-Claude Koeger, Pierre Bourgeois, Bruno Fautrel* Department of Rheumatology, School of Medicine Pitié-Salpêtrière and University Pierre & Marie Curie, Paris VI, PitiéSalpêtrière Teaching Hospital, 83, boulevard de l’Hôpital, 75651 Paris cedex 13, France (Submitted for publication April 17, 2001; accepted in revised form October 24, 2001)
Summary – Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis (SSc). We report the case of a 70-year-old woman with CREST syndrome and vasculitis who developed multifocal symptomatic bronchiectasis. The bronchiectasis and immunosuppressive therapy precipitated severe lower respiratory tract infection, which was fatal within a few months. The concomitant occurrence of bronchiectasis and SSc raises the possibility of a pathophysiological relationship. Several hypotheses can be put forward to explain the occurrence of bronchial wall damage leading to bronchiectasis. Whatever the mechanism, cases of bronchiectasis in patients with SSc should be reported to make physicians aware of the substantial risk associated with this combination. Joint Bone Spine 2002 ; 69 : 515-8. © 2002 Éditions scientifiques et médicales Elsevier SAS bronchiectasis / lung / scleroderma / systemic sclerosis
INTRODUCTION Pulmonary arterial hypertension (PAH) and interstitial fibrosis are the most common pulmonary manifestations in patients with systemic sclerosis (SSc). A few other manifestations have been reported in small numbers of patients, but systemic sclerosis is not a classical cause of bronchiectasis. We report a case of symptomatic bronchiectasis in a patient with CREST syndrome. CASE REPORT A 70-year-old Caucasian woman was admitted in December 1998 for stage II dyspnea (NYHA classification). Since 1986, she had been receiving follow-up at our department for CREST syndrome with calcinosis, * Correspondence and reprints. E-mail address: [email protected] (B. Fautrel).
Raynaud’s phenomenon, sclerodactyly, and telangiectasias of the hands and face. She had sicca syndrome with xerophthalmia proven by Schirmer’s test and with xerostomia responsible for frequent nocturnal arousals to drink water. She had no hypertension or renal involvement. Immunological investigations revealed a high titer of antinuclear antibodies (1/2580) and the presence of anti-centromere antibodies, without anti-SSa anibodies. She was given low-dose oral prednisone (10 mg/d) and colchicine, as well as the calcium channel inhibitor nifedipine for disabling Raynaud’s phenomenon. At admission, she had no cyanosis or respiratory distress. There was no history of pulmonary disease or smoking. Blood pressure and pulmonary examination were normal; cardiac auscultation disclosed a systolic aortic ejection murmur. A chest radiograph was normal. Spirometry showed a marked decrease in the diffusing capacity of carbon monoxide (DLCO), which
516
F. Lavie et al.
was 48% of predicted, and a moderate increase in residual volume, to 112% of predicted. Vital capacity, total lung capacity, and forced expiratory flow rate (FEFR) were normal. Echocardiography revealed severe aortic stenosis with left ventricular hypertrophy and pulmonary arterial pressure elevation to 43 mm Hg. In April 1999, she underwent aortic valvular replacement because of progressive heart failure. Her dyspnea improved but her spirometry results remained unchanged. An echocardiogram showed only a slight decrease in pulmonary arterial pressure (37 mm Hg). In September 1999, she reported worsening of leg paresthesia and dysesthesia that had been present for 2 years. A neurologist diagnosed vasculitis, but a nerve biopsy was not done because of severe skin fragility related to long-term steroid therapy. She was given high-dose oral prednisone (1.5 mg/kg/d) and monthly cyclophosphamide infusions (1 g/month). After 2 months, while on 65 mg/d of prednisone and after receiving two 1-g cyclophosphamide infusions, she experienced rapid worsening of her dyspnea. Clinical examination showed respiratory distress with a breathing rate of 35/min and a nonproductive cough. She had peripheral leukocytosis (11 000/mm3), with a predominance of neutrophils and with lymphopenia (156/mm3). The serum gammaglobulin level was low (5 g/L). There was no fever or evidence of heart failure, and pulmonary auscultation was normal. Blood gas values at rest and chest radiograph findings were normal. FEFR and DLCO were 70% and 32% of normal values, respectively. Pulmonary arterial pressure was 42 mm Hg by echocardiography, and left ventricular ejection fraction was normal. Thoracic high-resolution computed tomography (HRCT) revealed plurifocal bronchiectasis (figure 1) without interstitial fibrosis. The patient had no personal or family history of bronchiectasis or recurrent infectious bronchitis. No mutation of the Cystic Fibrosis Transmembrane Regulator (CFTR) gene was found. In late December 1999, while still receiving cyclophosphamide and prednisone, she started experiencing fever and chills. Serratia marcescens was identified in sputum and blood specimens. Despite prompt intravenous administration of targeted antibiotics, septicemia developed and she died a few days later. DISCUSSION This case emphasizes the complexity of the pulmonary lesions seen in SSc patients. PAH was probably the
cause of the early respiratory symptoms experienced by our patient in December 1998. PAH was first ascribed to the aortic stenosis. However, the clinical symptoms did not resolve fully after valvular replacement, and the pulmonary arterial pressure remained elevated by echocardiography, suggesting SSc-related PAH. PAH is common in SSc with presence of anti-centromere antibodies and seems related to pulmonary vasospasm, or ‘pulmonary Raynaud’s phenomenon’ [1-4]. This mechanism is difficult to demonstrate but is consistent with the DLCO decrease seen with cold weather in SSc patients [4]. In some patients, PAH may also be related to mutilating interstitial fibrosis, which can decrease the diameter of pulmonary arteries, resulting in increased pulmonary arterial pressure. This was not observed in our patient. The present case is one of the first reports of concomitant bronchiectasis and SSc. Bronchiectasis has been reported in SSc patients with advanced interstitial fibrosis, which causes parenchymal retraction, thereby producing bronchial distortion and bronchiectasis [5]. This mechanism cannot explain the findings in our patient given that no interstitial fibrosis was noted by HRCT. Nevertheless, a role of SSc in the development of bronchiectasis is not excluded. One possible explanation may be impairment of bronchial immune function caused either by the autoimmune process or by the immunosuppressive agents used to treat SSc [6]. Immune function impairment may lead to chronic infection and inflammation responsible for airway damage and bronchial dystrophy. This sequence occurs in cystic fibrosis, another disease characterized by immune deficiency. Although our patient had no history of recurrent pulmonary infection, she had low gammaglobulin levels and received aggressive immunosuppressive treatment. Another explanation may be the development of sclerosis within the bronchial walls, thus compromising the contractility of the ciliary apparatus and the clearance of pathogens. Nevertheless, this phenomenon has not been described in SSc patients. Very recently, a preliminary HRCT study found a high rate of nonsymptomatic bronchiectasis in SSc patients [7]; these results require confirmation. Other autoimmune diseases have been associated with bronchiectasis, with no clear causal relationship. Primary Sjögren’s syndrome and vasculitis seem to be the autoimmune diseases most often associated with bronchiectasis [8-14]. In Sjögren’s syndrome, the replacement of glandular tissue by fibrosis leads to decreased mucus secretion, especially in the bronchial tree, with
Bronchiectasis and systemic sclerosis
517
Figure 1. High-resolution CT of the lungs. Multifocal bronchiectasis of the dorsal and apical segments of the right superior lobe. Ground-glass densities in the anterior segment of the right superior lobe.
plugging of the respiratory tract by inspissated secretions and, finally, development of bronchiectasis. Since our patient had sicca syndrome, this hypothesis is plausible. Among vasculitides, Wegener granulomatosis is the disease most commonly reported in association with bronchiectasis [11-14]. In Wegener granulomatosis, anti-neutrophil cytoplasm antibodies (ANCA) can compromise immune responses. However, tests for serum ANCA were negative in our patient, suggesting that the bronchiectasis may have been unrelated to vasculitis. Rheumatoid arthritis is another systemic disease classically associated with bronchiectasis [8, 15, 16]. A role for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutation has been suggested in this association. Our patient did not have the ∆F508 mutation or other known CFTR mutations. Other genes, most notably HLA genes, have been studied. HLA DQB1*0601 was increased in patients with bronchiectasis and rheumatoid arthritis [17]. More
recently, an association with HLA DR1*0401 was reported in these patients [18]. Our patient had none of these HLA alleles. In SSc, respiratory symptoms may have several causes. Bronchiectasis should be added to the list of pulmonary manifestations observed in patients SSc. Bronchiectasis predisposes to severe pulmonary or systemic infection in these patients whose disease and treatment are associated with immune defense impairment. REFERENCES 1 Minai OA, Dweik RA, Arroliga AC. Manifestations of scleroderma pulmonary disease. Clin Chest Med 1998 ; 19 : 713-31. 2 Youssem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990 ; 21 : 467-74. 3 Ungerer RG, Tashkin DP, Furst D. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983 ; 75 : 65-74. 4 Silver RM. Clinical problems. The lungs. Rheum Disease Clin North Am 1996 ; 22 : 825-40.
518
F. Lavie et al.
5 D’Angelo WA, Fries JF, Masi AT. Pathologic observations in systemic sclerosis (scleroderma). Am J Med 1969 ; 46 : 428-40. 6 Cole PJ. Inflammation: a two-edged sword--the model of bronchiectasis. Eur J Respir Dis 1986 ; 69 (Suppl 147) : 6-15. 7 Bounas A, Yarmenitis S, Georgiou P, Vlahanastasi C, Andonopoulos Rio AP. Bronchiectasis in progressive systemic sclerosis. A study using high resolution computed tomography abstract. Arthritis Rheum 2000 ; 9 (Suppl) : S318. 8 Cohen M, Sahn SA. Bronchiectasis in systemic diseases. Chest 1999 ; 116 : 1063-74. 9 Cain HC, Noble PW, Matthay RA. Pulmonary manifestations of Sjögren’s syndrome. Clin Chest Med 1998 ; 19 : 687-99. 10 Robinson DA, Meyer CF. Primary Sjögren’s syndrome associated with recurrent sinopulmonary infections and bronchiectasis. J Allergy Clin Immunol 1994 ; 94 : 263-4. 11 Woywodt A, Goebel U. Bronchial stenosis and extensive bronchiectasis due to Wegener’s granulomatosis. Nephron 2000 ; 85 : 366-7. 12 Matsuyama W, Wakimoto J, Watanabe A, Kubota I, Hirotsu Y, Mizoguchi A, et al. Bronchiectasis with myeloperoxidase antineutrophil cytoplasmic antibody and bactericidal/
13
14 15 16 17
18
permeability-increasing protein antineutrophil cytoplasmic antibody. Intern Med 1999 ; 38 : 813-6. Dunn AC, Walmsley RS, Dedrick RL, Wakefield AJ, Lockwood CM. Anti-neutrophil cytoplasmic autoantibodies (ANCA) to bactericidal/permeability-increasing protein recognize the carboxyl terminal domain. J Infect 1999 ; 39 : 81-7. Forde AM, Feighery C, Jackson J. Anti-phagocyte antibodies and infection. Autoimmunity 1998 ; 28 : 5-14. Walker WC. The lung in rheumatoid arthritis thesis: University of Edinburgh; 1966. Solanki T, Neville E. Bronchiectasis and rheumatoid disease: is there an association? Br J Rheum 1992 ; 31 : 691-3. Hillarby MC, McMahon MJ, Grennan DM, Cooper RG, Clarkson RWE, Davies EJ, et al. HLA associations in subjects with rheumatoid arthritis and bronchiectasis but not with other pulmonary complications of rheumatoid disease. Br J Rheum 1993 ; 32 : 794-7. Toussirot E, Despaux J, Wendling D. Increased frequency of HLA DR1*0401 in subjects with rheumatoid arthritis and bronchiectasis abstract. Arthritis Rheum 2000 ; 9 (Suppl) : S185.
CASE REPORT
Bronchiectasis in a patient with CREST syndrome Frédéric Lavie, Sylvie Rozenberg, Anne Coutaux, Anne-Claude Koeger, Pierre Bourgeois, Bruno Fautrel* Department of Rheumatology, School of Medicine Pitié-Salpêtrière and University Pierre & Marie Curie, Paris VI, PitiéSalpêtrière Teaching Hospital, 83, boulevard de l’Hôpital, 75651 Paris cedex 13, France (Submitted for publication April 17, 2001; accepted in revised form October 24, 2001)
Summary – Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis (SSc). We report the case of a 70-year-old woman with CREST syndrome and vasculitis who developed multifocal symptomatic bronchiectasis. The bronchiectasis and immunosuppressive therapy precipitated severe lower respiratory tract infection, which was fatal within a few months. The concomitant occurrence of bronchiectasis and SSc raises the possibility of a pathophysiological relationship. Several hypotheses can be put forward to explain the occurrence of bronchial wall damage leading to bronchiectasis. Whatever the mechanism, cases of bronchiectasis in patients with SSc should be reported to make physicians aware of the substantial risk associated with this combination. Joint Bone Spine 2002 ; 69 : 515-8. © 2002 Éditions scientifiques et médicales Elsevier SAS bronchiectasis / lung / scleroderma / systemic sclerosis
INTRODUCTION Pulmonary arterial hypertension (PAH) and interstitial fibrosis are the most common pulmonary manifestations in patients with systemic sclerosis (SSc). A few other manifestations have been reported in small numbers of patients, but systemic sclerosis is not a classical cause of bronchiectasis. We report a case of symptomatic bronchiectasis in a patient with CREST syndrome. CASE REPORT A 70-year-old Caucasian woman was admitted in December 1998 for stage II dyspnea (NYHA classification). Since 1986, she had been receiving follow-up at our department for CREST syndrome with calcinosis, * Correspondence and reprints. E-mail address: [email protected] (B. Fautrel).
Raynaud’s phenomenon, sclerodactyly, and telangiectasias of the hands and face. She had sicca syndrome with xerophthalmia proven by Schirmer’s test and with xerostomia responsible for frequent nocturnal arousals to drink water. She had no hypertension or renal involvement. Immunological investigations revealed a high titer of antinuclear antibodies (1/2580) and the presence of anti-centromere antibodies, without anti-SSa anibodies. She was given low-dose oral prednisone (10 mg/d) and colchicine, as well as the calcium channel inhibitor nifedipine for disabling Raynaud’s phenomenon. At admission, she had no cyanosis or respiratory distress. There was no history of pulmonary disease or smoking. Blood pressure and pulmonary examination were normal; cardiac auscultation disclosed a systolic aortic ejection murmur. A chest radiograph was normal. Spirometry showed a marked decrease in the diffusing capacity of carbon monoxide (DLCO), which
516
F. Lavie et al.
was 48% of predicted, and a moderate increase in residual volume, to 112% of predicted. Vital capacity, total lung capacity, and forced expiratory flow rate (FEFR) were normal. Echocardiography revealed severe aortic stenosis with left ventricular hypertrophy and pulmonary arterial pressure elevation to 43 mm Hg. In April 1999, she underwent aortic valvular replacement because of progressive heart failure. Her dyspnea improved but her spirometry results remained unchanged. An echocardiogram showed only a slight decrease in pulmonary arterial pressure (37 mm Hg). In September 1999, she reported worsening of leg paresthesia and dysesthesia that had been present for 2 years. A neurologist diagnosed vasculitis, but a nerve biopsy was not done because of severe skin fragility related to long-term steroid therapy. She was given high-dose oral prednisone (1.5 mg/kg/d) and monthly cyclophosphamide infusions (1 g/month). After 2 months, while on 65 mg/d of prednisone and after receiving two 1-g cyclophosphamide infusions, she experienced rapid worsening of her dyspnea. Clinical examination showed respiratory distress with a breathing rate of 35/min and a nonproductive cough. She had peripheral leukocytosis (11 000/mm3), with a predominance of neutrophils and with lymphopenia (156/mm3). The serum gammaglobulin level was low (5 g/L). There was no fever or evidence of heart failure, and pulmonary auscultation was normal. Blood gas values at rest and chest radiograph findings were normal. FEFR and DLCO were 70% and 32% of normal values, respectively. Pulmonary arterial pressure was 42 mm Hg by echocardiography, and left ventricular ejection fraction was normal. Thoracic high-resolution computed tomography (HRCT) revealed plurifocal bronchiectasis (figure 1) without interstitial fibrosis. The patient had no personal or family history of bronchiectasis or recurrent infectious bronchitis. No mutation of the Cystic Fibrosis Transmembrane Regulator (CFTR) gene was found. In late December 1999, while still receiving cyclophosphamide and prednisone, she started experiencing fever and chills. Serratia marcescens was identified in sputum and blood specimens. Despite prompt intravenous administration of targeted antibiotics, septicemia developed and she died a few days later. DISCUSSION This case emphasizes the complexity of the pulmonary lesions seen in SSc patients. PAH was probably the
cause of the early respiratory symptoms experienced by our patient in December 1998. PAH was first ascribed to the aortic stenosis. However, the clinical symptoms did not resolve fully after valvular replacement, and the pulmonary arterial pressure remained elevated by echocardiography, suggesting SSc-related PAH. PAH is common in SSc with presence of anti-centromere antibodies and seems related to pulmonary vasospasm, or ‘pulmonary Raynaud’s phenomenon’ [1-4]. This mechanism is difficult to demonstrate but is consistent with the DLCO decrease seen with cold weather in SSc patients [4]. In some patients, PAH may also be related to mutilating interstitial fibrosis, which can decrease the diameter of pulmonary arteries, resulting in increased pulmonary arterial pressure. This was not observed in our patient. The present case is one of the first reports of concomitant bronchiectasis and SSc. Bronchiectasis has been reported in SSc patients with advanced interstitial fibrosis, which causes parenchymal retraction, thereby producing bronchial distortion and bronchiectasis [5]. This mechanism cannot explain the findings in our patient given that no interstitial fibrosis was noted by HRCT. Nevertheless, a role of SSc in the development of bronchiectasis is not excluded. One possible explanation may be impairment of bronchial immune function caused either by the autoimmune process or by the immunosuppressive agents used to treat SSc [6]. Immune function impairment may lead to chronic infection and inflammation responsible for airway damage and bronchial dystrophy. This sequence occurs in cystic fibrosis, another disease characterized by immune deficiency. Although our patient had no history of recurrent pulmonary infection, she had low gammaglobulin levels and received aggressive immunosuppressive treatment. Another explanation may be the development of sclerosis within the bronchial walls, thus compromising the contractility of the ciliary apparatus and the clearance of pathogens. Nevertheless, this phenomenon has not been described in SSc patients. Very recently, a preliminary HRCT study found a high rate of nonsymptomatic bronchiectasis in SSc patients [7]; these results require confirmation. Other autoimmune diseases have been associated with bronchiectasis, with no clear causal relationship. Primary Sjögren’s syndrome and vasculitis seem to be the autoimmune diseases most often associated with bronchiectasis [8-14]. In Sjögren’s syndrome, the replacement of glandular tissue by fibrosis leads to decreased mucus secretion, especially in the bronchial tree, with
Bronchiectasis and systemic sclerosis
517
Figure 1. High-resolution CT of the lungs. Multifocal bronchiectasis of the dorsal and apical segments of the right superior lobe. Ground-glass densities in the anterior segment of the right superior lobe.
plugging of the respiratory tract by inspissated secretions and, finally, development of bronchiectasis. Since our patient had sicca syndrome, this hypothesis is plausible. Among vasculitides, Wegener granulomatosis is the disease most commonly reported in association with bronchiectasis [11-14]. In Wegener granulomatosis, anti-neutrophil cytoplasm antibodies (ANCA) can compromise immune responses. However, tests for serum ANCA were negative in our patient, suggesting that the bronchiectasis may have been unrelated to vasculitis. Rheumatoid arthritis is another systemic disease classically associated with bronchiectasis [8, 15, 16]. A role for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutation has been suggested in this association. Our patient did not have the ∆F508 mutation or other known CFTR mutations. Other genes, most notably HLA genes, have been studied. HLA DQB1*0601 was increased in patients with bronchiectasis and rheumatoid arthritis [17]. More
recently, an association with HLA DR1*0401 was reported in these patients [18]. Our patient had none of these HLA alleles. In SSc, respiratory symptoms may have several causes. Bronchiectasis should be added to the list of pulmonary manifestations observed in patients SSc. Bronchiectasis predisposes to severe pulmonary or systemic infection in these patients whose disease and treatment are associated with immune defense impairment. REFERENCES 1 Minai OA, Dweik RA, Arroliga AC. Manifestations of scleroderma pulmonary disease. Clin Chest Med 1998 ; 19 : 713-31. 2 Youssem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990 ; 21 : 467-74. 3 Ungerer RG, Tashkin DP, Furst D. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983 ; 75 : 65-74. 4 Silver RM. Clinical problems. The lungs. Rheum Disease Clin North Am 1996 ; 22 : 825-40.
518
F. Lavie et al.
5 D’Angelo WA, Fries JF, Masi AT. Pathologic observations in systemic sclerosis (scleroderma). Am J Med 1969 ; 46 : 428-40. 6 Cole PJ. Inflammation: a two-edged sword--the model of bronchiectasis. Eur J Respir Dis 1986 ; 69 (Suppl 147) : 6-15. 7 Bounas A, Yarmenitis S, Georgiou P, Vlahanastasi C, Andonopoulos Rio AP. Bronchiectasis in progressive systemic sclerosis. A study using high resolution computed tomography abstract. Arthritis Rheum 2000 ; 9 (Suppl) : S318. 8 Cohen M, Sahn SA. Bronchiectasis in systemic diseases. Chest 1999 ; 116 : 1063-74. 9 Cain HC, Noble PW, Matthay RA. Pulmonary manifestations of Sjögren’s syndrome. Clin Chest Med 1998 ; 19 : 687-99. 10 Robinson DA, Meyer CF. Primary Sjögren’s syndrome associated with recurrent sinopulmonary infections and bronchiectasis. J Allergy Clin Immunol 1994 ; 94 : 263-4. 11 Woywodt A, Goebel U. Bronchial stenosis and extensive bronchiectasis due to Wegener’s granulomatosis. Nephron 2000 ; 85 : 366-7. 12 Matsuyama W, Wakimoto J, Watanabe A, Kubota I, Hirotsu Y, Mizoguchi A, et al. Bronchiectasis with myeloperoxidase antineutrophil cytoplasmic antibody and bactericidal/
13
14 15 16 17
18
permeability-increasing protein antineutrophil cytoplasmic antibody. Intern Med 1999 ; 38 : 813-6. Dunn AC, Walmsley RS, Dedrick RL, Wakefield AJ, Lockwood CM. Anti-neutrophil cytoplasmic autoantibodies (ANCA) to bactericidal/permeability-increasing protein recognize the carboxyl terminal domain. J Infect 1999 ; 39 : 81-7. Forde AM, Feighery C, Jackson J. Anti-phagocyte antibodies and infection. Autoimmunity 1998 ; 28 : 5-14. Walker WC. The lung in rheumatoid arthritis thesis: University of Edinburgh; 1966. Solanki T, Neville E. Bronchiectasis and rheumatoid disease: is there an association? Br J Rheum 1992 ; 31 : 691-3. Hillarby MC, McMahon MJ, Grennan DM, Cooper RG, Clarkson RWE, Davies EJ, et al. HLA associations in subjects with rheumatoid arthritis and bronchiectasis but not with other pulmonary complications of rheumatoid disease. Br J Rheum 1993 ; 32 : 794-7. Toussirot E, Despaux J, Wendling D. Increased frequency of HLA DR1*0401 in subjects with rheumatoid arthritis and bronchiectasis abstract. Arthritis Rheum 2000 ; 9 (Suppl) : S185.