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A Patient With Myelodyplastic Syndrome, Pulmonary Nodules, and Worsening Infiltrates
pulmonary and critical care pearls A Patient With Myelodyplastic Syndrome, Pulmonary Nodules, and Worsening Infiltrates* Juliette L. Wohlrab, MD; Eric D. Anderson, MD, FCCP; Charles A. Read, MD, FCCP
(CHEST 2001; 120:1014 –1017)
63-year-old white man with stage IIA Hodgkin A disease and myelodysplastic syndrome was ad-
mitted to the hospital with fevers and chills. The Hodgkin disease was diagnosed 3 years previously, and he received treatment with MOPP/ABV (nitrogen mustard, vincristine, procarbazine, prednisone, doxorubicin, vinblastine, bleomycin). The myelodysplastic syndrome developed 1 year prior to hospital admission and was thought to be secondary to his chemotherapy. His medical history was also significant for bronchiolitis obliterans organizing pneumonia (BOOP) diagnosed 2 years earlier using transbronchial biopsy. The BOOP responded to steroids, but diffuse infiltrates subsequently developed during treatment. Open-lung biopsy results showed Pneumocystis carinii pneumonia, which resolved after treatment with trimethoprim/sulfamethoxazole. Prior to hospital admission, the patient was noted to have new bilateral pulmonary nodules on surveillance CT, for which he was scheduled to undergo CT-guided biopsy. He was asymptomatic from a pulmonary standpoint and had no localizing infectious symptoms to account for his fever. Medications prior to hospital admission included dexamethasone, 4 mg/d; folic acid; filgrastim; aminocaproic acid; and omeprazole. He also received periodic platelet and RBC transfusions.
ration rate was 22 breaths/min, and pulse oximetry was 97% on 2 L of oxygen via nasal cannula. Bibasilar crackles and left posterior egophony were evident on chest examination. Cardiovascular examination findings were normal without murmurs. The abdomen was normal, and the extremities had 1⫹ edema and petechiae around the ankles. A Groshong catheter (Bard Access Systems; Murray Hill, NJ) was present in the right anterior chest wall, and the site was without erythema or tenderness. Laboratory Findings The WBC count was 10,400/L, with 48% neutrophils and 37% bands. Hematocrit was 23%; platelet count, 2,000/L; creatinine, 1.7 mg/dL (baseline, 0.9 mg/dL); bicarbonate, 24 mmol/L; glucose, 135 mg/dL; and lactate dehydrogenase, 287 IU/L. Blood culture results were positive for Gram-negative rods. Chest radiographic findings were significant for the known
Physical Examination The patient’s temperature was 39.3°C, BP was 110/58 mm Hg, pulse rate was 86 beats/min, respi*From the Division of Pulmonary and Critical Care Medicine, Georgetown University Medical Center, Washington, DC. Manuscript received February 28, 2001; revision accepted April 17, 2001. Correspondence to: Juliette L. Wohlrab, MD, Division of Pulmonary and Critical Care Medicine, Georgetown University Medical Center, B100 Kober-Cogan, 3800 Reservoir Rd, NW, Washington, DC 20007; e-mail: [email protected] 1014
Figure 1. Anteroposterior chest radiograph showing bilateral nodules and a worsening lingular infiltrate. Pulmonary and Critical Care Pearls
Figure 2. CT scan of the chest with a cavitary infiltrate in the left upper lobe with interstitial changes and effusions bilaterally (nodules not demonstrated in this image).
nodules, which were unchanged, and a new lingular infiltrate. Urinalysis and culture findings were negative for infection.
revealed Escherichia coli. Treatment with antibiotics was then tailored to piperacillin/tazobactam. Stress-dose steroids with hydrocortisone were administered, 100 mg q8h. It was thought that this was likely a line-related infection, as this was his second episode of bacteremia with the same organism in the past month and no other source could be identified. The Groshong catheter was removed. Flexible bronchoscopy was performed to rule out a pulmonary infection given the new lingular infiltrate. BAL demonstrated only alveolar macrophages and lymphonuclear cells. All culture and stain results were negative. No transbronchial biopsy was performed secondary to his underlying thrombocytopenia. The patient’s oxygenation progressively deteriorated over the following week. Subsequent radiographs showed worsening of the lingular infiltrate with cavitation and interstitial changes bilaterally (Fig 1), which were confirmed by CT (Fig 2). IV liposomal amphotericin B, trimethoprim/sulfamethoxazole, and azithromycin were added to cover possible fungus, P carinii pneumonia, and atypical organisms, respectively.
Hospital Course The patient received treatment with vancomycin and ceftazidime empirically until culture findings
What diagnosis should be considered in evaluating this patient?
CHEST / 120 / 3 / SEPTEMBER, 2001
1015
Figure 3. Photomicrograph showing vascular invasion and hemorrhagic infarct with fungal overgrowth within vessels. Areas of BOOP are also seen (hematoxylin-eosin, original ⫻ 20).
Diagnosis: Pulmonary mucormycosis, BOOP Mucor is a zygomycete of the order Mucorales. Mucorales infections are generally rapidly progressive and often fatal. The organisms are ubiquitous saprophytes and can be found on fruits and moist bread, in soil, and on decaying organic matter. In contrast to Aspergillus, Mucor is generally not found in hospital environments. It has worldwide distribution and affects patients with underlying conditions such as diabetes mellitus, lymphoid and hematologic malignancies, burns, trauma, cirrhosis, renal failure, and transplantation and other immunodeficiency states. It is also seen in patients receiving deferoxamine and long-term steroid therapy. Hyperglycemia and metabolic acidosis provide an environment conducive to fungal growth. Normal macrophage and lymphocyte function usually provide immune protection against clinical infection. A reduction in phagocytosis by bronchoalveolar macrophages has been demonstrated in animals with diabetes or receiving steroid therapy. These macrophages normally inhibit spore germination and tissue invasion. Infection is likely initiated by inhalation of asexual spores that settle in the nasal passages and sinuses. It can then extend to the retro-orbital tissues, cerebrum, and lower respiratory tract. These fungi have a predilection for blood vessel invasion and can lead to arterial and venous thrombosis and subsequent tissue infarction. Rhinocerebral disease is the most common manifestation and occurs almost exclusively in the setting of diabetic ketoacidosis. Isolated pulmonary mucormycosis occurs and can lead to pneumonia, abscess, hemorrhage, and infarction. Pulmonary infection can be complicated by massive hemoptysis and superinfection with bacterial organisms. Lymphatics can also be involved and lead to a more indolent process. Other clinical manifestations 1016
Figure 4. Photomicrograph showing nonseptated hyphae with wide-angle branching consistent with Mucor (Gomori’s methenamine-silver, original ⫻ 40).
include GI, cutaneous, cardiac, and bone involvement. Disseminated disease occurs when two or more organ systems are involved. The disease course is usually acute and fulminant but can be subacute. The overall mortality is 80% for isolated pulmonary involvement and 95% for disseminated disease. The radiographic appearance is usually a patchy infiltrate that consolidates and leads to cavity formation despite antibiotic therapy. Other radiographic features include lobar or multilobar consolidation, solitary or multiple nodules, and adenopathy. The presence of an air-crescent sign appears to be associated with an increased risk of hemoptysis. Mucor has a predilection for the upper lobes. Diagnosis is rarely made using sputum culture or Gram’s stain. Bronchoscopy with BAL and transbronchial biopsy is often required. A recent report on the role of BAL for diagnosis of pulmonary mucormycosis suggests that given the appropriate clinical setting, demonstration of Mucor in BAL fluid can be diagnostic of invasive disease when transbronchial biopsy or open biopsy is contraindicated. Open-lung biopsy may be needed if bronchoscopy is nondiagnostic. Histologic examination reveals large, broad, nonseptated hyphae with wide-angle branching. Direct plating on blood or Sabouraud agar at 37°C increases culture yield, but it is generally poor. The differential diagnosis includes other infectious agents that are more likely to affect an immunocompromised host, such as Aspergillus and Nocardia, and would produce similar clinical syndromes. Pneumocystis and cytomegalovirus can lead to pulmonary symptoms in the immunocompromised patient, but cavitation would be rare. Legionella can also lead to cavitation, but this would be uncommon. Prompt initiation of therapy with IV amphotericin B should begin as soon as Mucor is suspected. Generally between 1 g and 2 g is administered, but Pulmonary and Critical Care Pearls
the total dose needed for cure is not known. Surgical resection is usually necessary for cure and has been shown to reduce mortality to 45% vs 70 to 80% with medical management alone for isolated pulmonary disease. BOOP is defined as granulation tissue within the lumen of small airways, with fibrinous exudates and accumulation of foamy macrophages. It can be a primary or secondary disease. Secondary BOOP is seen in association with connective tissue disorders, myelodysplastic syndrome, AIDS, solid organ and bone marrow transplantation, radiation, drugs, or viruses. Secondary BOOP requires treatment of the underlying disorder. Idiopathic BOOP generally responds favorably to treatment with corticosteroids. Radiographic appearance includes diffuse, bilateral, alveolar infiltrates with peripheral predominance. Linear or nodular opacities occur less commonly. Pleural effusions, pleural thickening, and cavitation are rare. This patient had a history of BOOP that responded to steroid therapy with radiographic resolution. He had a known underlying associated disease, myelodysplastic syndrome. This syndrome appeared to be well controlled, and the recrudescence of BOOP could be related to the Mucor infection. Given the fact that the patient’s clinical and radiographic course deteriorated during treatment with high-dose steroids, the BOOP was likely secondary in nature. Hospital Course The patient was referred for open-lung biopsy. His lingula and left upper lobe were resected, and pathology findings are demonstrated in Figures 3, 4. After surgical resection, he improved considerably with antifungal therapy. Treatment with trimethoprim/sulfamethoxazole was changed to prophylactic doses, and the steroids were rapidly tapered. A CT scan of the sinuses showed no rhinocerebral involvement. Despite his initial improvement, his hospital course was complicated by
recurrent sepsis and renal deterioration. He wished no further aggressive care and eventually died. Clinical Pearls 1. Fungal infection should be considered in the differential diagnosis of any immunocompromised patient with worsening radiographic changes or fevers despite treatment with broadspectrum antibiotics. 2. Prompt referral for open-lung biopsy should be made if bronchoscopy is nondiagnostic in the setting of a deteriorating clinical picture. 3. Overall mortality in isolated pulmonary mucormycosis can be reduced with surgical resection in combination with amphotericin B. 4. Mucormycosis can be isolated to the pulmonary parenchyma or disseminated, and the extent of disease affects overall mortality. 5. BOOP can be a primary or secondary disease process. Suggested Readings Epler GA. Bronchiolitis obliterans organizing pneumonia: definition and clinical features. Chest 1992; 102:2S– 6S Glazer M, Nusair S, Brewer R, et al. The role of BAL in the diagnosis of pulmonary mucormycosis. Chest 2000; 117:279 – 282 Harada M, Manabe T, Yamashita K, et al. Pulmonary mucormycosis with fatal hemoptysis. Acta Pathol Jpn 1992; 42:49 –55 Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med 1999; 159:1301–1309 McAdams H, Rosado de Christenson M, Strollo D, et al. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol 1997; 168:1541–1548 Meyers BR, Gurtman AC. Phycomycetes. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia, PA: W.B. Saunders, 1994; 1941–1945 Murphy RA, Miller WT. Pulmonary mucormycosis. Semin Roentgenol 1996; 31:83– 87 Tedder M, Spratt J, Anstadt M, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994; 57:1044 –1050 Waldorf AR, Levitz SM, Diamond RD. In vivo bronchoalveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J Infect Dis 1984; 150:752–760
CHEST / 120 / 3 / SEPTEMBER, 2001
1017
(CHEST 2001; 120:1014 –1017)
63-year-old white man with stage IIA Hodgkin A disease and myelodysplastic syndrome was ad-
mitted to the hospital with fevers and chills. The Hodgkin disease was diagnosed 3 years previously, and he received treatment with MOPP/ABV (nitrogen mustard, vincristine, procarbazine, prednisone, doxorubicin, vinblastine, bleomycin). The myelodysplastic syndrome developed 1 year prior to hospital admission and was thought to be secondary to his chemotherapy. His medical history was also significant for bronchiolitis obliterans organizing pneumonia (BOOP) diagnosed 2 years earlier using transbronchial biopsy. The BOOP responded to steroids, but diffuse infiltrates subsequently developed during treatment. Open-lung biopsy results showed Pneumocystis carinii pneumonia, which resolved after treatment with trimethoprim/sulfamethoxazole. Prior to hospital admission, the patient was noted to have new bilateral pulmonary nodules on surveillance CT, for which he was scheduled to undergo CT-guided biopsy. He was asymptomatic from a pulmonary standpoint and had no localizing infectious symptoms to account for his fever. Medications prior to hospital admission included dexamethasone, 4 mg/d; folic acid; filgrastim; aminocaproic acid; and omeprazole. He also received periodic platelet and RBC transfusions.
ration rate was 22 breaths/min, and pulse oximetry was 97% on 2 L of oxygen via nasal cannula. Bibasilar crackles and left posterior egophony were evident on chest examination. Cardiovascular examination findings were normal without murmurs. The abdomen was normal, and the extremities had 1⫹ edema and petechiae around the ankles. A Groshong catheter (Bard Access Systems; Murray Hill, NJ) was present in the right anterior chest wall, and the site was without erythema or tenderness. Laboratory Findings The WBC count was 10,400/L, with 48% neutrophils and 37% bands. Hematocrit was 23%; platelet count, 2,000/L; creatinine, 1.7 mg/dL (baseline, 0.9 mg/dL); bicarbonate, 24 mmol/L; glucose, 135 mg/dL; and lactate dehydrogenase, 287 IU/L. Blood culture results were positive for Gram-negative rods. Chest radiographic findings were significant for the known
Physical Examination The patient’s temperature was 39.3°C, BP was 110/58 mm Hg, pulse rate was 86 beats/min, respi*From the Division of Pulmonary and Critical Care Medicine, Georgetown University Medical Center, Washington, DC. Manuscript received February 28, 2001; revision accepted April 17, 2001. Correspondence to: Juliette L. Wohlrab, MD, Division of Pulmonary and Critical Care Medicine, Georgetown University Medical Center, B100 Kober-Cogan, 3800 Reservoir Rd, NW, Washington, DC 20007; e-mail: [email protected] 1014
Figure 1. Anteroposterior chest radiograph showing bilateral nodules and a worsening lingular infiltrate. Pulmonary and Critical Care Pearls
Figure 2. CT scan of the chest with a cavitary infiltrate in the left upper lobe with interstitial changes and effusions bilaterally (nodules not demonstrated in this image).
nodules, which were unchanged, and a new lingular infiltrate. Urinalysis and culture findings were negative for infection.
revealed Escherichia coli. Treatment with antibiotics was then tailored to piperacillin/tazobactam. Stress-dose steroids with hydrocortisone were administered, 100 mg q8h. It was thought that this was likely a line-related infection, as this was his second episode of bacteremia with the same organism in the past month and no other source could be identified. The Groshong catheter was removed. Flexible bronchoscopy was performed to rule out a pulmonary infection given the new lingular infiltrate. BAL demonstrated only alveolar macrophages and lymphonuclear cells. All culture and stain results were negative. No transbronchial biopsy was performed secondary to his underlying thrombocytopenia. The patient’s oxygenation progressively deteriorated over the following week. Subsequent radiographs showed worsening of the lingular infiltrate with cavitation and interstitial changes bilaterally (Fig 1), which were confirmed by CT (Fig 2). IV liposomal amphotericin B, trimethoprim/sulfamethoxazole, and azithromycin were added to cover possible fungus, P carinii pneumonia, and atypical organisms, respectively.
Hospital Course The patient received treatment with vancomycin and ceftazidime empirically until culture findings
What diagnosis should be considered in evaluating this patient?
CHEST / 120 / 3 / SEPTEMBER, 2001
1015
Figure 3. Photomicrograph showing vascular invasion and hemorrhagic infarct with fungal overgrowth within vessels. Areas of BOOP are also seen (hematoxylin-eosin, original ⫻ 20).
Diagnosis: Pulmonary mucormycosis, BOOP Mucor is a zygomycete of the order Mucorales. Mucorales infections are generally rapidly progressive and often fatal. The organisms are ubiquitous saprophytes and can be found on fruits and moist bread, in soil, and on decaying organic matter. In contrast to Aspergillus, Mucor is generally not found in hospital environments. It has worldwide distribution and affects patients with underlying conditions such as diabetes mellitus, lymphoid and hematologic malignancies, burns, trauma, cirrhosis, renal failure, and transplantation and other immunodeficiency states. It is also seen in patients receiving deferoxamine and long-term steroid therapy. Hyperglycemia and metabolic acidosis provide an environment conducive to fungal growth. Normal macrophage and lymphocyte function usually provide immune protection against clinical infection. A reduction in phagocytosis by bronchoalveolar macrophages has been demonstrated in animals with diabetes or receiving steroid therapy. These macrophages normally inhibit spore germination and tissue invasion. Infection is likely initiated by inhalation of asexual spores that settle in the nasal passages and sinuses. It can then extend to the retro-orbital tissues, cerebrum, and lower respiratory tract. These fungi have a predilection for blood vessel invasion and can lead to arterial and venous thrombosis and subsequent tissue infarction. Rhinocerebral disease is the most common manifestation and occurs almost exclusively in the setting of diabetic ketoacidosis. Isolated pulmonary mucormycosis occurs and can lead to pneumonia, abscess, hemorrhage, and infarction. Pulmonary infection can be complicated by massive hemoptysis and superinfection with bacterial organisms. Lymphatics can also be involved and lead to a more indolent process. Other clinical manifestations 1016
Figure 4. Photomicrograph showing nonseptated hyphae with wide-angle branching consistent with Mucor (Gomori’s methenamine-silver, original ⫻ 40).
include GI, cutaneous, cardiac, and bone involvement. Disseminated disease occurs when two or more organ systems are involved. The disease course is usually acute and fulminant but can be subacute. The overall mortality is 80% for isolated pulmonary involvement and 95% for disseminated disease. The radiographic appearance is usually a patchy infiltrate that consolidates and leads to cavity formation despite antibiotic therapy. Other radiographic features include lobar or multilobar consolidation, solitary or multiple nodules, and adenopathy. The presence of an air-crescent sign appears to be associated with an increased risk of hemoptysis. Mucor has a predilection for the upper lobes. Diagnosis is rarely made using sputum culture or Gram’s stain. Bronchoscopy with BAL and transbronchial biopsy is often required. A recent report on the role of BAL for diagnosis of pulmonary mucormycosis suggests that given the appropriate clinical setting, demonstration of Mucor in BAL fluid can be diagnostic of invasive disease when transbronchial biopsy or open biopsy is contraindicated. Open-lung biopsy may be needed if bronchoscopy is nondiagnostic. Histologic examination reveals large, broad, nonseptated hyphae with wide-angle branching. Direct plating on blood or Sabouraud agar at 37°C increases culture yield, but it is generally poor. The differential diagnosis includes other infectious agents that are more likely to affect an immunocompromised host, such as Aspergillus and Nocardia, and would produce similar clinical syndromes. Pneumocystis and cytomegalovirus can lead to pulmonary symptoms in the immunocompromised patient, but cavitation would be rare. Legionella can also lead to cavitation, but this would be uncommon. Prompt initiation of therapy with IV amphotericin B should begin as soon as Mucor is suspected. Generally between 1 g and 2 g is administered, but Pulmonary and Critical Care Pearls
the total dose needed for cure is not known. Surgical resection is usually necessary for cure and has been shown to reduce mortality to 45% vs 70 to 80% with medical management alone for isolated pulmonary disease. BOOP is defined as granulation tissue within the lumen of small airways, with fibrinous exudates and accumulation of foamy macrophages. It can be a primary or secondary disease. Secondary BOOP is seen in association with connective tissue disorders, myelodysplastic syndrome, AIDS, solid organ and bone marrow transplantation, radiation, drugs, or viruses. Secondary BOOP requires treatment of the underlying disorder. Idiopathic BOOP generally responds favorably to treatment with corticosteroids. Radiographic appearance includes diffuse, bilateral, alveolar infiltrates with peripheral predominance. Linear or nodular opacities occur less commonly. Pleural effusions, pleural thickening, and cavitation are rare. This patient had a history of BOOP that responded to steroid therapy with radiographic resolution. He had a known underlying associated disease, myelodysplastic syndrome. This syndrome appeared to be well controlled, and the recrudescence of BOOP could be related to the Mucor infection. Given the fact that the patient’s clinical and radiographic course deteriorated during treatment with high-dose steroids, the BOOP was likely secondary in nature. Hospital Course The patient was referred for open-lung biopsy. His lingula and left upper lobe were resected, and pathology findings are demonstrated in Figures 3, 4. After surgical resection, he improved considerably with antifungal therapy. Treatment with trimethoprim/sulfamethoxazole was changed to prophylactic doses, and the steroids were rapidly tapered. A CT scan of the sinuses showed no rhinocerebral involvement. Despite his initial improvement, his hospital course was complicated by
recurrent sepsis and renal deterioration. He wished no further aggressive care and eventually died. Clinical Pearls 1. Fungal infection should be considered in the differential diagnosis of any immunocompromised patient with worsening radiographic changes or fevers despite treatment with broadspectrum antibiotics. 2. Prompt referral for open-lung biopsy should be made if bronchoscopy is nondiagnostic in the setting of a deteriorating clinical picture. 3. Overall mortality in isolated pulmonary mucormycosis can be reduced with surgical resection in combination with amphotericin B. 4. Mucormycosis can be isolated to the pulmonary parenchyma or disseminated, and the extent of disease affects overall mortality. 5. BOOP can be a primary or secondary disease process. Suggested Readings Epler GA. Bronchiolitis obliterans organizing pneumonia: definition and clinical features. Chest 1992; 102:2S– 6S Glazer M, Nusair S, Brewer R, et al. The role of BAL in the diagnosis of pulmonary mucormycosis. Chest 2000; 117:279 – 282 Harada M, Manabe T, Yamashita K, et al. Pulmonary mucormycosis with fatal hemoptysis. Acta Pathol Jpn 1992; 42:49 –55 Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med 1999; 159:1301–1309 McAdams H, Rosado de Christenson M, Strollo D, et al. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol 1997; 168:1541–1548 Meyers BR, Gurtman AC. Phycomycetes. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia, PA: W.B. Saunders, 1994; 1941–1945 Murphy RA, Miller WT. Pulmonary mucormycosis. Semin Roentgenol 1996; 31:83– 87 Tedder M, Spratt J, Anstadt M, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994; 57:1044 –1050 Waldorf AR, Levitz SM, Diamond RD. In vivo bronchoalveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J Infect Dis 1984; 150:752–760
CHEST / 120 / 3 / SEPTEMBER, 2001
1017