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A Neutropenic Patient With Rapidly Progressive Lung Lesion
roentgenogram of the month A Neutropenic Patient With Rapidly Progressive Lung Lesion* Darryl R. Pauls, MHA; James G. Ravenel, MD; and Marc A. Judson, MD, FCCP
(CHEST 2004; 126:1364 –1367)
African-American woman presented A to42-year-old an outpatient hematology-oncology clinic for
follow-up after a bone marrow transplant with a chief complaint of pain in her extremities. Her medical history was remarkable for acute lymphoblastic leukemia positive for CD10, CD19, CD34, and Philadelphia chromosome. Ten weeks previously, she underwent a matched allogeneic unrelated donor bone marrow transplant. Her immediate posttransplant course was uneventful, and she was discharged to home 4 days prior to the current presentation. A physical examination revealed severe desquamation of her hands, legs, and scalp. She was subsequently admitted to the oncology ward with an initial diagnosis of graft-vs-host disease. Her treatment of graft-vs-host disease included dexamethasone, 12 mg/d; cyclosporin, 100 mg bid; and pimecrolimus 1% cream. The inpatient stay was lengthy with many complications, including both cutaneous and hepatic manifestations of graft-vs-host disease, cytomegalovirus infection, and pancytopenia. She was profoundly neutropenic and thrombocytopenic, with an absolute neutrophil count ranging from 0.243 to 1.134, and a platelet count consistently below 30/L and a low value of 6/L. On hospital day 41, hemoptysis developed and a CT scan revealed diffuse ground-glass opacities and regions of consolidation consistent with diffuse alveolar hemorrhage. The diagnosis of diffuse alveolar hemorrhage was confirmed by BAL, which recovered many
*From the Departments of Radiology (Mr. Pauls and Dr. Ravenel) and Pulmonary Medicine (Dr. Judson), Medical University of South Carolina, Charleston, SC. Manuscript received October 2, 2003; revision accepted January 23, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: James G. Ravenel, MD, Medical University of South Carolina, Box 250322, 169 Ashley Ave, Room 297, Charleston, SC 29425; e-mail: [email protected]
1364
Figure 1. Axial CT, lung window setting reveal a 9-mm groundglass nodule (arrow) superimposed on milder, generalized ground-glass opacity from resolving diffuse alveolar hemorrhage.
hemosiderin-laden macrophages seen on Prussian Blue staining. Culture findings from the BAL were negative for bacterial and fungal organisms. A followup CT obtained 4 days later revealed a marked improvement in diffuse alveolar hemorrhage, but also showed a new 0.9 ⫻ 1.0-cm nodule in the left upper lung (Fig 1). Because of her immunocompromised status, voriconazole, 200 mg bid, was begun. Despite treatment, a chest radiograph obtained 1 week later revealed a left upper lobe pneumonia (Fig 2). A CT scan was repeated with the left upper lobe lesion now measuring 6.6 ⫻ 5.1 cm (Fig 3). This lesion was of heterogeneous density with ill-defined margins and a halo of ground-glass opacity. Bronchoscopy was repeated, this time with transbronchial lung biopsy (Fig 4, 5) in addition to BAL. What is the diagnosis?
Roentgenogram of the Month
Figure 2. Frontal chest radiograph obtained 1 week after the image in Figure 1 reveals left upper lobe airspace disease consistent with pneumonia.
Figure 4. Transbronchial biopsy specimen (hematoxylin-eosin stain, original ⫻ 40) reveals multiple broad ribbon-like hyphae forms with few septations (arrowheads).
Figure 3. Axial CT, lung window setting at same time as chest radiography reveals parenchymal consolidation with central lower attenuation suggesting early necrosis. Note the halo of groundglass opacity surrounding the lesion (arrows).
Figure 5. Coned-down view of transbronchial biopsy (hematoxylineosin, original ⫻ 40) better delineates the fungal elements within necrotic debris (arrows).
www.chestjournal.org
CHEST / 126 / 4 / OCTOBER, 2004
1365
Diagnosis: Pulmonary mucormycosis
Discussion Bone marrow transplantation is widely used as a means of treatment for a variety of hematologic diseases including acute lymphoblastic leukemia. The most common complications arising from bone marrow transplantation are infection and graft-vshost disease.1 Patients with graft-vs-host disease have a greater predisposition to infection, as graft-vs-host disease reflects a prolonged immunodeficient state and requires high-dose immunosuppressive medications.1 In addition to bacterial infections, atypical organisms such as Nocardia and fungal infections, particularly Aspergillus, and Mucormycosis must be considered as potential etiologies. Mucormycosis is an opportunistic fungal infection of the order Mucorales, characterized by broad, nonseptated hyphae that randomly branch at right angles.2 Mucormycosis causes several distinct forms of clinical disease, most commonly rhinocerebral and pulmonary infection.2 Infections of skin, GI tract, cardiac tissue, and bone have also been described.2 There are four distinct risk factors associated with pulmonary mucormycosis: diabetes mellitus (56%), hematologic cancer (32%), renal insufficiency (13%), and organ transplantation (11%).3 The unifying feature of all these conditions is neutropenia and/or impaired phagocytosis.4 In this case, the patient was at risk due to prolonged and profound neutropenia. The most common clinical manifestations of pulmonary mucormycosis include fever, cough, hemoptysis, dyspnea, and chest pain.2,3,5 These symptoms are obviously nonspecific and can be seen with any infectious agent. However, early suspicion and diagnosis of pulmonary mucormycosis is vital because it often causes a rapidly progressive disease that is locally invasive and may disseminate hematogenously with a fatal course in ⬎ 50% of cases.2,3 The radiographic presentation of pulmonary mucormycosis can be diverse, and there are no pathognomonic radiographic features. In general, lobar or multilobar pneumonia is the most common manifestation on the chest radiograph, found in 39 to 66% of cases, followed by solitary or multiple pulmonary nodules and masses.2,3 Cavitation occurs in 26 to 40% of cases.2,3 An air-crescent sign formed by sloughed necrotic lung tissue with the cavity centrally can be seen in 5 to 12.5% of cases, and is highly suggestive of an invasive fungal infection.2– 4 Pleural effusions, fistulas to the chest wall, and hilar masses are rare presentations.2 CT can demonstrate findings not suspected on chest radiography in ⬎ 50% of cases.2 In the setting 1366
of immunosuppression, the CT halo sign, a ring of ground-glass opacity surrounding a region of focal consolidation, is highly suggestive of an angioinvasive fungal pneumonia.6 A CT scan performed 1 week after the image in Figure 3 revealed progression of the disease, now with a well-circumscribed outer rim of ground-glass opacities surrounding an area of increased density within the midportion of the mass. An area of central lucency was noted that represents necrotic change and is compatible with the diagnosis of mucormycosis. Pathologically, these transformations reflect the invasion of the pulmonary vasculature that leads to pulmonary hemorrhage and ischemic necrosis secondary to infarction.2 As such, the CT halo sign may be seen in a number of other conditions, including other infections, bland pulmonary infarcts, and vasculitis such as Wegener granulomatosis.7 Definitive diagnosis of mucormycosis often evades initial noninvasive techniques such as sputum and blood cultures. The organism may be recovered by bronchoscopy with BAL or transbronchial lung biopsy.4 However, because of the focal distribution of the disease, transthoracic CT-guided needle biopsy or open lung biopsy may be required to make the diagnosis.4 Mucormycosis can be identified with routine stains such as hematoxylin-eosin, Grocott methenamine stain, periodic acid Schiff, and KOH, and suspicion of fungal infection should be communicated to the laboratory so the appropriate culture media can be used. Because of the high mortality rate associated with pulmonary mucormycosis infection, early and aggressive treatment is imperative. Unfortunately, medical therapy (such as amphotericin B or an azole) alone in mucormycosis is associated with a high mortality, up to 68%.4 Compared to the high mortality for medical therapy alone, mortality was only 11% for patients treated with surgery alone or surgery in combination with medical therapy.4 Therefore, in patients who can tolerate surgery, the infected area of lung should be resected immediately because once the disease disseminates, the prognosis is dismal. Summary Pulmonary mucormycosis is a relatively rare but life-threatening disease that may become more common as the number of immunosuppressed patients, diabetics, and transplant recipients continue to rise. Because of the high mortality of pulmonary mucormycosis, early diagnosis is critical to initiate therapy of which surgery is the most effective. Though there are no definitive radiographic criteria for diagnosing pulmonary mucormycosis, a high clinical suspicion Roentgenogram of the Month
should be maintained because certain clues on chest radiography and CT may suggest mucormycosis as a possible etiology. References 1 Mori M, Galvin JR, Barloon TJ, et al. Fungal pulmonary infections after bone marrow transplant: evaluation with radiography and CT. Radiology 1991; 178:721–726 2 McAdams HP, Christenson MR, Strollo DC, et al. Pulmonary mucormycosis: radiologic findings in thirty two cases. Am J Radiol 1997; 198:1541–1547
www.chestjournal.org
3 Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last thirty years. Arch Intern Med 1999; 159:1301–1308 4 Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical treatment. Ann Thorac Surg 1994; 57:1044 –1050 5 Bigby TD, Serota ML, Tierney LM, et al. Clinical spectrum of pulmonary mucormycosis. Chest 1986; 89:435– 439 6 Jamadar D, D’Souza SP, Thomas EA, et al. Pulmonary zygomycosis: CT appearance. J Comput Assist Tomogr 1995; 19:733–738 7 Kim Y, Lee KS, Jung KJ, et al. Halo sign on high resolution CT: findings in spectrum of pulmonary diseases with pathologic correlation. J Comput Assist Tomogr 1999; 23:622– 626
CHEST / 126 / 4 / OCTOBER, 2004
1367
(CHEST 2004; 126:1364 –1367)
African-American woman presented A to42-year-old an outpatient hematology-oncology clinic for
follow-up after a bone marrow transplant with a chief complaint of pain in her extremities. Her medical history was remarkable for acute lymphoblastic leukemia positive for CD10, CD19, CD34, and Philadelphia chromosome. Ten weeks previously, she underwent a matched allogeneic unrelated donor bone marrow transplant. Her immediate posttransplant course was uneventful, and she was discharged to home 4 days prior to the current presentation. A physical examination revealed severe desquamation of her hands, legs, and scalp. She was subsequently admitted to the oncology ward with an initial diagnosis of graft-vs-host disease. Her treatment of graft-vs-host disease included dexamethasone, 12 mg/d; cyclosporin, 100 mg bid; and pimecrolimus 1% cream. The inpatient stay was lengthy with many complications, including both cutaneous and hepatic manifestations of graft-vs-host disease, cytomegalovirus infection, and pancytopenia. She was profoundly neutropenic and thrombocytopenic, with an absolute neutrophil count ranging from 0.243 to 1.134, and a platelet count consistently below 30/L and a low value of 6/L. On hospital day 41, hemoptysis developed and a CT scan revealed diffuse ground-glass opacities and regions of consolidation consistent with diffuse alveolar hemorrhage. The diagnosis of diffuse alveolar hemorrhage was confirmed by BAL, which recovered many
*From the Departments of Radiology (Mr. Pauls and Dr. Ravenel) and Pulmonary Medicine (Dr. Judson), Medical University of South Carolina, Charleston, SC. Manuscript received October 2, 2003; revision accepted January 23, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: James G. Ravenel, MD, Medical University of South Carolina, Box 250322, 169 Ashley Ave, Room 297, Charleston, SC 29425; e-mail: [email protected]
1364
Figure 1. Axial CT, lung window setting reveal a 9-mm groundglass nodule (arrow) superimposed on milder, generalized ground-glass opacity from resolving diffuse alveolar hemorrhage.
hemosiderin-laden macrophages seen on Prussian Blue staining. Culture findings from the BAL were negative for bacterial and fungal organisms. A followup CT obtained 4 days later revealed a marked improvement in diffuse alveolar hemorrhage, but also showed a new 0.9 ⫻ 1.0-cm nodule in the left upper lung (Fig 1). Because of her immunocompromised status, voriconazole, 200 mg bid, was begun. Despite treatment, a chest radiograph obtained 1 week later revealed a left upper lobe pneumonia (Fig 2). A CT scan was repeated with the left upper lobe lesion now measuring 6.6 ⫻ 5.1 cm (Fig 3). This lesion was of heterogeneous density with ill-defined margins and a halo of ground-glass opacity. Bronchoscopy was repeated, this time with transbronchial lung biopsy (Fig 4, 5) in addition to BAL. What is the diagnosis?
Roentgenogram of the Month
Figure 2. Frontal chest radiograph obtained 1 week after the image in Figure 1 reveals left upper lobe airspace disease consistent with pneumonia.
Figure 4. Transbronchial biopsy specimen (hematoxylin-eosin stain, original ⫻ 40) reveals multiple broad ribbon-like hyphae forms with few septations (arrowheads).
Figure 3. Axial CT, lung window setting at same time as chest radiography reveals parenchymal consolidation with central lower attenuation suggesting early necrosis. Note the halo of groundglass opacity surrounding the lesion (arrows).
Figure 5. Coned-down view of transbronchial biopsy (hematoxylineosin, original ⫻ 40) better delineates the fungal elements within necrotic debris (arrows).
www.chestjournal.org
CHEST / 126 / 4 / OCTOBER, 2004
1365
Diagnosis: Pulmonary mucormycosis
Discussion Bone marrow transplantation is widely used as a means of treatment for a variety of hematologic diseases including acute lymphoblastic leukemia. The most common complications arising from bone marrow transplantation are infection and graft-vshost disease.1 Patients with graft-vs-host disease have a greater predisposition to infection, as graft-vs-host disease reflects a prolonged immunodeficient state and requires high-dose immunosuppressive medications.1 In addition to bacterial infections, atypical organisms such as Nocardia and fungal infections, particularly Aspergillus, and Mucormycosis must be considered as potential etiologies. Mucormycosis is an opportunistic fungal infection of the order Mucorales, characterized by broad, nonseptated hyphae that randomly branch at right angles.2 Mucormycosis causes several distinct forms of clinical disease, most commonly rhinocerebral and pulmonary infection.2 Infections of skin, GI tract, cardiac tissue, and bone have also been described.2 There are four distinct risk factors associated with pulmonary mucormycosis: diabetes mellitus (56%), hematologic cancer (32%), renal insufficiency (13%), and organ transplantation (11%).3 The unifying feature of all these conditions is neutropenia and/or impaired phagocytosis.4 In this case, the patient was at risk due to prolonged and profound neutropenia. The most common clinical manifestations of pulmonary mucormycosis include fever, cough, hemoptysis, dyspnea, and chest pain.2,3,5 These symptoms are obviously nonspecific and can be seen with any infectious agent. However, early suspicion and diagnosis of pulmonary mucormycosis is vital because it often causes a rapidly progressive disease that is locally invasive and may disseminate hematogenously with a fatal course in ⬎ 50% of cases.2,3 The radiographic presentation of pulmonary mucormycosis can be diverse, and there are no pathognomonic radiographic features. In general, lobar or multilobar pneumonia is the most common manifestation on the chest radiograph, found in 39 to 66% of cases, followed by solitary or multiple pulmonary nodules and masses.2,3 Cavitation occurs in 26 to 40% of cases.2,3 An air-crescent sign formed by sloughed necrotic lung tissue with the cavity centrally can be seen in 5 to 12.5% of cases, and is highly suggestive of an invasive fungal infection.2– 4 Pleural effusions, fistulas to the chest wall, and hilar masses are rare presentations.2 CT can demonstrate findings not suspected on chest radiography in ⬎ 50% of cases.2 In the setting 1366
of immunosuppression, the CT halo sign, a ring of ground-glass opacity surrounding a region of focal consolidation, is highly suggestive of an angioinvasive fungal pneumonia.6 A CT scan performed 1 week after the image in Figure 3 revealed progression of the disease, now with a well-circumscribed outer rim of ground-glass opacities surrounding an area of increased density within the midportion of the mass. An area of central lucency was noted that represents necrotic change and is compatible with the diagnosis of mucormycosis. Pathologically, these transformations reflect the invasion of the pulmonary vasculature that leads to pulmonary hemorrhage and ischemic necrosis secondary to infarction.2 As such, the CT halo sign may be seen in a number of other conditions, including other infections, bland pulmonary infarcts, and vasculitis such as Wegener granulomatosis.7 Definitive diagnosis of mucormycosis often evades initial noninvasive techniques such as sputum and blood cultures. The organism may be recovered by bronchoscopy with BAL or transbronchial lung biopsy.4 However, because of the focal distribution of the disease, transthoracic CT-guided needle biopsy or open lung biopsy may be required to make the diagnosis.4 Mucormycosis can be identified with routine stains such as hematoxylin-eosin, Grocott methenamine stain, periodic acid Schiff, and KOH, and suspicion of fungal infection should be communicated to the laboratory so the appropriate culture media can be used. Because of the high mortality rate associated with pulmonary mucormycosis infection, early and aggressive treatment is imperative. Unfortunately, medical therapy (such as amphotericin B or an azole) alone in mucormycosis is associated with a high mortality, up to 68%.4 Compared to the high mortality for medical therapy alone, mortality was only 11% for patients treated with surgery alone or surgery in combination with medical therapy.4 Therefore, in patients who can tolerate surgery, the infected area of lung should be resected immediately because once the disease disseminates, the prognosis is dismal. Summary Pulmonary mucormycosis is a relatively rare but life-threatening disease that may become more common as the number of immunosuppressed patients, diabetics, and transplant recipients continue to rise. Because of the high mortality of pulmonary mucormycosis, early diagnosis is critical to initiate therapy of which surgery is the most effective. Though there are no definitive radiographic criteria for diagnosing pulmonary mucormycosis, a high clinical suspicion Roentgenogram of the Month
should be maintained because certain clues on chest radiography and CT may suggest mucormycosis as a possible etiology. References 1 Mori M, Galvin JR, Barloon TJ, et al. Fungal pulmonary infections after bone marrow transplant: evaluation with radiography and CT. Radiology 1991; 178:721–726 2 McAdams HP, Christenson MR, Strollo DC, et al. Pulmonary mucormycosis: radiologic findings in thirty two cases. Am J Radiol 1997; 198:1541–1547
www.chestjournal.org
3 Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last thirty years. Arch Intern Med 1999; 159:1301–1308 4 Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical treatment. Ann Thorac Surg 1994; 57:1044 –1050 5 Bigby TD, Serota ML, Tierney LM, et al. Clinical spectrum of pulmonary mucormycosis. Chest 1986; 89:435– 439 6 Jamadar D, D’Souza SP, Thomas EA, et al. Pulmonary zygomycosis: CT appearance. J Comput Assist Tomogr 1995; 19:733–738 7 Kim Y, Lee KS, Jung KJ, et al. Halo sign on high resolution CT: findings in spectrum of pulmonary diseases with pathologic correlation. J Comput Assist Tomogr 1999; 23:622– 626
CHEST / 126 / 4 / OCTOBER, 2004
1367