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A 61-Year-Old Man With Dyspnea
CHEST
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
A 61-Year-Old Man With Dyspnea Byung Hak Rho, MD; Diana Qama, MD; Won-Il Choi, MD; and Kun Young Kwon, MD
CHEST 2012; 142(5):1344–1347
man presented to the outpatient clinic A61-year-old with dyspnea. The patient reported a 2-week his-
tory of dry cough and mild dyspnea with chills and night sweats. He had been given a diagnosis of type 2 diabetes mellitus 5 years previously. He had a smoking history of . 30 years, but had stopped smoking 10 years previous. Physical Examination The patient’s vital signs were as follows: BP, 103/67 mm Hg; heart rate, 103 beats/min; respiratory rate, 22 breaths/min; and temperature, 36.7°C. Physical examination revealed no abnormalities. Laboratory Findings CBC, routine chemistry findings, serum amylase and lipase levels, and myocardial enzyme levels were normal, with the exception of glucose level (145 mg/dL). Blood gas analysis revealed a pH of 7.37; oxygen tension, 61 mm Hg; CO2 tension, 36.8 mm Hg; bicarbonate
Figure 1. Initial chest radiograph showing multiple ill-defined nodules at both lungs.
Figure 2. Thoracic CT scan showing multiple nodules, bilateral air-space consolidations, and ground glass opacities.
level, 20.9 mmol/L; and oxygen saturation, 91% while breathing nasal oxygen at 6 L/min. Radiographic and Bronchoscopic Findings Plain radiographic film of the chest is shown in Figure 1. A thoracic CT scan showed multiple nodules, bilateral air-space consolidations, and ground glass opacities (Fig 2). Interestingly, multiple nodules were distributed perilymphatically. A 2-cm low-density mass
Figure 3. There is a 2-cm-sized low-density mass in the head portion of the pancreas (arrow) on the abdominal CT scan.
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Postgraduate Education Corner
Figure 4. A, Lung tissue section obtained by video-assisted thoracic surgery showing a subpleural nodular lesion with central fibrotic nodule (asterisk) (hematoxylin and eosin stain, original magnification 3 40). B, High magnification of the rectangular lesion showing infiltration of lymphocytes and plasma cells (arrows) (hematoxylin and eosin stain, original magnification 3 400). C, Immunohistochemical stains showing high expression for IgG4 compared with IgG (original magnification 3 200).
was detected in the head of the pancreas on an abdominal CT scan (Fig 3). Subsequently, BAL was performed because we suspected malignant disease or TB. No endobronchial lesion was seen. The samples obtained showed negative results for cytology, acidfast bacilli stain, and TB polymerase chain reaction. BAL fluid culture was also negative. Influenza A, influenza B, parainfluenza types 1 to 3, respiratory syncytial virus, adenovirus, rhinovirus, and metapneumovirus were not detected by multiplex polymerase chain reaction.
1.85 g/L (normal range, 0.11-1.59 g/L), whereas the serum immune electrophoresis showed a decrease in IgG fraction. What is the diagnosis?
Lung Biopsy Specimen Findings The patient underwent a video-assisted thoracoscopic lung biopsy. The lung tissue had a lymphoplasmacytic infiltrate in the fibrotic subpleural nodule (Fig 4). The surrounding lung parenchyma also had a lymphoplasmacytic infiltrate and fibrosis of the patchy consolidated lesions. Immunohistochemical stains showed diffusely distributed IgG4-positive plasma cells in the nodular lesions, and the ratio of IgG4/IgG expression was . 1.5. The serum IgG4 level was Manuscript received March 3, 2012; revision accepted March 20, 2012. Affiliations: From the Department of Radiology (Dr Rho), Department of Internal Medicine (Drs Qama and Choi), and Department of Pathology (Dr Kwon), Keimyung University School of Medicine, Daegu, South Korea, and Regional Hospital (Dr Qama), Berat, Albania. Correspondence to: Won-Il Choi, MD, Department of Internal Medicine, Keimyung University School of Medicine, 216 Dalseong-ro, Jung-Gu, Daegu 700-712, South Korea; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-0594 journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
CHEST / 142 / 5 / NOVEMBER 2012
1345
Diagnosis: Acute respiratory failure due to IgG4-related sclerosing disease
Discussion IgG4-related sclerosing disease (ISD) is a systemic disease with extensive infiltration of IgG4-positive plasma cells and T lymphocytes in various organs along with tissue fibrosis and obstructive phlebitis. It was first reported in patients with autoimmune pancreatitis. However, ISD is now described in various organs, such as the liver, bile ducts, salivary and lacrimal glands, kidney, retroperitoneum, aorta, and lung. ISD is also associated with elevated serum IgG4 levels. It is found mainly in men and usually men aged a median of 60 to 65 years. Patients with ISD do not have specific clinical manifestations, and their symptoms are mostly related to the organs that are involved. Systemic signs, such as fever and weight loss, can also be present, but they are uncommon in ISD. The histopathologic features of ISD may present as a diffuse lymphoplasmacytic infiltration, fibrosis, eosinophilic infiltration, and obliterative vasculitis. Immunohistochemical stains from these fibrous/inflammatory areas show increased infiltration of IgG4-positive plasma cells. The ratio of IgG4/IgG-positive plasma cells is . 30%. Although serum IgG4 level is elevated in most patients with ISD, the absence of this sign does not exclude this diagnosis. The pathogenesis of ISD remains unknown. Until now, the evidence suggests that the immune response is involved and that T helper 2 cytokines, regulatory T cells, IL-10, and transforming growth factor-b play important roles in IgG4-positive plasma cell infiltration and fibrogenesis. Steroid treatment often is chosen and is effective. Oral prednisone usually is the most recommended steroid, but the exact dose is not yet established. Physicians decide the dose according to the patient’s clinical history until the maximum starting dose of 1 mg/kg per day oral prednisone is reached. Steroid response is included in the diagnostic criteria of autoimmune pancreatitis. Steroids have been shown to be effective in improving the clinical and radiologic features of patients with ISD; they also decrease the serum IgG4 level. The diagnosis of ISD is complex, and a combination of clinical, biochemical, radiologic, and pathologic findings with the response to corticosteroid treatment is required to determine the correct diagnosis. Lung involvement is one of the intrathoracic patterns in patients with ISD. Intrathoracic involvement can develop before, during, or after the diagnosis of autoimmune pancreatitis or other extrathoracic
lesions in patients with ISD. The most common respiratory symptoms are cough, dyspnea, and chest pain; occasionally, the patient may be asymptomatic. Chest radiographs may show multiple round nodules, alveolar interstitial disease, tracheobronchial stenosis, pleural nodules, or a pleural effusion. Tissue biopsy specimens from lung parenchyma or pleural lesions are useful to differentiate ISD from other diseases with similar radiologic findings, such as lung cancer, lymphoma, or sarcoidosis. Biopsy specimens can be examined to detect the presence of a lymphoplasmacytic infiltrate. In addition, the presence of IgG4positive lymphoplasmacytic infiltration and an elevated ratio of IgG4/IgG-positive plasma cells in immunohistochemical examinations are helpful to correctly diagnose ISD. Patients with ISD with intrathoracic and extrathoracic manifestations generally respond well clinically to corticosteroid therapy. Steroid response can be seen in 1 to 2 weeks, and the treatment dose must be reduced thereafter. Initially, after radiologic results were reviewed in this patient, we suspected pneumonia underlying TB or metastatic malignancy. We performed BAL for confirmation. Empirical treatment was initiated with ceftriaxone (2 g every 24 h) and azithromycin (500 mg every 24 h). The results from BAL were normal, and the findings of chest radiography did not change significantly after 10 days of treatment with antibiotics. Histopathologic confirmation was required to determine the correct diagnosis. Therefore, we performed a video-assisted thoracoscopic lung biopsy. Examination of biopsy samples of lung parenchyma and subpleural nodules showed many lymphoplasmacytic infiltrates. Because we believed that ISD was a possible diagnosis, we performed immunohistochemical staining, which showed infiltration with many scattered IgG4 plasma cells and a high ratio of IgG4/IgG-positive plasma cells. In addition, we found an elevated serum IgG4 level. Moreover, an abdominal CT scan showed a mass in the pancreatic head portion, although the patient did not have any symptoms and the serum lipase and amylase levels were normal. However, we did not perform a biopsy of the pancreatic mass. We gave the patient a diagnosis of acute respiratory failure due to ISD. Clinical Course Corticosteroid treatment was initiated for the patient. Initially, he was given 0.5 mg/kg per day oral prednisone. After 1 week of treatment with corticosteroids, the respiratory symptoms rapidly resolved, and there was rapid resolution of multiple nodules (Fig 5). We decreased the dose to 0.25 mg/kg per day after 2 weeks. The patient is still being followed.
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Postgraduate Education Corner
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Suggested Readings
Figure 5. After 2 weeks of treatment, there is a rapid resolution of multiple nodules on follow-up chest CT scan.
Clinical Pearls 1. Differential diagnosis of multiple small nodules in the lung includes sarcoidosis, TB, and metastatic carcinoma. However, IgG4 sclerosis should also be taken into consideration. 2. IgG4 sclerosis usually presents as an asymptomatic mass or nodule. However, IgG4-related sclerosis can present with acute hypoxemic respiratory failure. 3. IgG4-related sclerosis of the lung may have abdominal pathology, such as sclerosing cholangitis and pancreatitis. If ISD is suspected, abdominal CT imaging may be helpful. 4. There is rapid resolution of symptoms and nodules after corticosteroid treatment.
Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40(7):1561-1568. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol. 2005;36(7):710-717. Hirano K, Kawabe T, Komatsu Y, et al. High-rate pulmonary involvement in autoimmune pancreatitis. Intern Med J. 2006; 36(1):58-61. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260-270. Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886-1893. Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol. 2010;76(2):228-238. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34(12):1812-1819. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23(1):74-79. Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J. 2012; 39(1):180-186.
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
CHEST / 142 / 5 / NOVEMBER 2012
1347
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
A 61-Year-Old Man With Dyspnea Byung Hak Rho, MD; Diana Qama, MD; Won-Il Choi, MD; and Kun Young Kwon, MD
CHEST 2012; 142(5):1344–1347
man presented to the outpatient clinic A61-year-old with dyspnea. The patient reported a 2-week his-
tory of dry cough and mild dyspnea with chills and night sweats. He had been given a diagnosis of type 2 diabetes mellitus 5 years previously. He had a smoking history of . 30 years, but had stopped smoking 10 years previous. Physical Examination The patient’s vital signs were as follows: BP, 103/67 mm Hg; heart rate, 103 beats/min; respiratory rate, 22 breaths/min; and temperature, 36.7°C. Physical examination revealed no abnormalities. Laboratory Findings CBC, routine chemistry findings, serum amylase and lipase levels, and myocardial enzyme levels were normal, with the exception of glucose level (145 mg/dL). Blood gas analysis revealed a pH of 7.37; oxygen tension, 61 mm Hg; CO2 tension, 36.8 mm Hg; bicarbonate
Figure 1. Initial chest radiograph showing multiple ill-defined nodules at both lungs.
Figure 2. Thoracic CT scan showing multiple nodules, bilateral air-space consolidations, and ground glass opacities.
level, 20.9 mmol/L; and oxygen saturation, 91% while breathing nasal oxygen at 6 L/min. Radiographic and Bronchoscopic Findings Plain radiographic film of the chest is shown in Figure 1. A thoracic CT scan showed multiple nodules, bilateral air-space consolidations, and ground glass opacities (Fig 2). Interestingly, multiple nodules were distributed perilymphatically. A 2-cm low-density mass
Figure 3. There is a 2-cm-sized low-density mass in the head portion of the pancreas (arrow) on the abdominal CT scan.
1344
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
Postgraduate Education Corner
Figure 4. A, Lung tissue section obtained by video-assisted thoracic surgery showing a subpleural nodular lesion with central fibrotic nodule (asterisk) (hematoxylin and eosin stain, original magnification 3 40). B, High magnification of the rectangular lesion showing infiltration of lymphocytes and plasma cells (arrows) (hematoxylin and eosin stain, original magnification 3 400). C, Immunohistochemical stains showing high expression for IgG4 compared with IgG (original magnification 3 200).
was detected in the head of the pancreas on an abdominal CT scan (Fig 3). Subsequently, BAL was performed because we suspected malignant disease or TB. No endobronchial lesion was seen. The samples obtained showed negative results for cytology, acidfast bacilli stain, and TB polymerase chain reaction. BAL fluid culture was also negative. Influenza A, influenza B, parainfluenza types 1 to 3, respiratory syncytial virus, adenovirus, rhinovirus, and metapneumovirus were not detected by multiplex polymerase chain reaction.
1.85 g/L (normal range, 0.11-1.59 g/L), whereas the serum immune electrophoresis showed a decrease in IgG fraction. What is the diagnosis?
Lung Biopsy Specimen Findings The patient underwent a video-assisted thoracoscopic lung biopsy. The lung tissue had a lymphoplasmacytic infiltrate in the fibrotic subpleural nodule (Fig 4). The surrounding lung parenchyma also had a lymphoplasmacytic infiltrate and fibrosis of the patchy consolidated lesions. Immunohistochemical stains showed diffusely distributed IgG4-positive plasma cells in the nodular lesions, and the ratio of IgG4/IgG expression was . 1.5. The serum IgG4 level was Manuscript received March 3, 2012; revision accepted March 20, 2012. Affiliations: From the Department of Radiology (Dr Rho), Department of Internal Medicine (Drs Qama and Choi), and Department of Pathology (Dr Kwon), Keimyung University School of Medicine, Daegu, South Korea, and Regional Hospital (Dr Qama), Berat, Albania. Correspondence to: Won-Il Choi, MD, Department of Internal Medicine, Keimyung University School of Medicine, 216 Dalseong-ro, Jung-Gu, Daegu 700-712, South Korea; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-0594 journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
CHEST / 142 / 5 / NOVEMBER 2012
1345
Diagnosis: Acute respiratory failure due to IgG4-related sclerosing disease
Discussion IgG4-related sclerosing disease (ISD) is a systemic disease with extensive infiltration of IgG4-positive plasma cells and T lymphocytes in various organs along with tissue fibrosis and obstructive phlebitis. It was first reported in patients with autoimmune pancreatitis. However, ISD is now described in various organs, such as the liver, bile ducts, salivary and lacrimal glands, kidney, retroperitoneum, aorta, and lung. ISD is also associated with elevated serum IgG4 levels. It is found mainly in men and usually men aged a median of 60 to 65 years. Patients with ISD do not have specific clinical manifestations, and their symptoms are mostly related to the organs that are involved. Systemic signs, such as fever and weight loss, can also be present, but they are uncommon in ISD. The histopathologic features of ISD may present as a diffuse lymphoplasmacytic infiltration, fibrosis, eosinophilic infiltration, and obliterative vasculitis. Immunohistochemical stains from these fibrous/inflammatory areas show increased infiltration of IgG4-positive plasma cells. The ratio of IgG4/IgG-positive plasma cells is . 30%. Although serum IgG4 level is elevated in most patients with ISD, the absence of this sign does not exclude this diagnosis. The pathogenesis of ISD remains unknown. Until now, the evidence suggests that the immune response is involved and that T helper 2 cytokines, regulatory T cells, IL-10, and transforming growth factor-b play important roles in IgG4-positive plasma cell infiltration and fibrogenesis. Steroid treatment often is chosen and is effective. Oral prednisone usually is the most recommended steroid, but the exact dose is not yet established. Physicians decide the dose according to the patient’s clinical history until the maximum starting dose of 1 mg/kg per day oral prednisone is reached. Steroid response is included in the diagnostic criteria of autoimmune pancreatitis. Steroids have been shown to be effective in improving the clinical and radiologic features of patients with ISD; they also decrease the serum IgG4 level. The diagnosis of ISD is complex, and a combination of clinical, biochemical, radiologic, and pathologic findings with the response to corticosteroid treatment is required to determine the correct diagnosis. Lung involvement is one of the intrathoracic patterns in patients with ISD. Intrathoracic involvement can develop before, during, or after the diagnosis of autoimmune pancreatitis or other extrathoracic
lesions in patients with ISD. The most common respiratory symptoms are cough, dyspnea, and chest pain; occasionally, the patient may be asymptomatic. Chest radiographs may show multiple round nodules, alveolar interstitial disease, tracheobronchial stenosis, pleural nodules, or a pleural effusion. Tissue biopsy specimens from lung parenchyma or pleural lesions are useful to differentiate ISD from other diseases with similar radiologic findings, such as lung cancer, lymphoma, or sarcoidosis. Biopsy specimens can be examined to detect the presence of a lymphoplasmacytic infiltrate. In addition, the presence of IgG4positive lymphoplasmacytic infiltration and an elevated ratio of IgG4/IgG-positive plasma cells in immunohistochemical examinations are helpful to correctly diagnose ISD. Patients with ISD with intrathoracic and extrathoracic manifestations generally respond well clinically to corticosteroid therapy. Steroid response can be seen in 1 to 2 weeks, and the treatment dose must be reduced thereafter. Initially, after radiologic results were reviewed in this patient, we suspected pneumonia underlying TB or metastatic malignancy. We performed BAL for confirmation. Empirical treatment was initiated with ceftriaxone (2 g every 24 h) and azithromycin (500 mg every 24 h). The results from BAL were normal, and the findings of chest radiography did not change significantly after 10 days of treatment with antibiotics. Histopathologic confirmation was required to determine the correct diagnosis. Therefore, we performed a video-assisted thoracoscopic lung biopsy. Examination of biopsy samples of lung parenchyma and subpleural nodules showed many lymphoplasmacytic infiltrates. Because we believed that ISD was a possible diagnosis, we performed immunohistochemical staining, which showed infiltration with many scattered IgG4 plasma cells and a high ratio of IgG4/IgG-positive plasma cells. In addition, we found an elevated serum IgG4 level. Moreover, an abdominal CT scan showed a mass in the pancreatic head portion, although the patient did not have any symptoms and the serum lipase and amylase levels were normal. However, we did not perform a biopsy of the pancreatic mass. We gave the patient a diagnosis of acute respiratory failure due to ISD. Clinical Course Corticosteroid treatment was initiated for the patient. Initially, he was given 0.5 mg/kg per day oral prednisone. After 1 week of treatment with corticosteroids, the respiratory symptoms rapidly resolved, and there was rapid resolution of multiple nodules (Fig 5). We decreased the dose to 0.25 mg/kg per day after 2 weeks. The patient is still being followed.
1346
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
Postgraduate Education Corner
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Suggested Readings
Figure 5. After 2 weeks of treatment, there is a rapid resolution of multiple nodules on follow-up chest CT scan.
Clinical Pearls 1. Differential diagnosis of multiple small nodules in the lung includes sarcoidosis, TB, and metastatic carcinoma. However, IgG4 sclerosis should also be taken into consideration. 2. IgG4 sclerosis usually presents as an asymptomatic mass or nodule. However, IgG4-related sclerosis can present with acute hypoxemic respiratory failure. 3. IgG4-related sclerosis of the lung may have abdominal pathology, such as sclerosing cholangitis and pancreatitis. If ISD is suspected, abdominal CT imaging may be helpful. 4. There is rapid resolution of symptoms and nodules after corticosteroid treatment.
Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40(7):1561-1568. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol. 2005;36(7):710-717. Hirano K, Kawabe T, Komatsu Y, et al. High-rate pulmonary involvement in autoimmune pancreatitis. Intern Med J. 2006; 36(1):58-61. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260-270. Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886-1893. Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol. 2010;76(2):228-238. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34(12):1812-1819. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23(1):74-79. Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J. 2012; 39(1):180-186.
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 11/09/2012
CHEST / 142 / 5 / NOVEMBER 2012
1347