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Organizing Diffuse Alveolar Damage Associated With Progressive Systemic Sclerosis

      Diffuse alveolar damage (DAD) is a relatively nonspecific pattern of acute lung injury that can be observed in a wide range of clinical circumstances. DAD has often been recognized in association with various connective tissue diseases; however, to our knowledge, it has not been previously reported in the setting of progressive systemic sclerosis. Herein we describe two patients with established diagnoses of progressive systemic sclerosis who had development of the acute respiratory distress syndrome. Open-lung biopsy specimens from both patients showed a histologic pattern of DAD with no identifiable cause other than their progressive systemic sclerosis. Our results suggest that DAD should be added to the list of pleuro-pulmonary complications of progressive systemic sclerosis.
      ARDS (acute respiratory distress syndrome), CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), DAD (diffuse alveolar damage), ILD (interstitial lung disease), PSS (progressive systemic sclerosis), PSS-DS (diffuse variant of PSS)
      Progressive systemic sclerosis (PSS) is often classified into two clinical categories: the diffuse variant of scleroderma (PSS-DS) and the more indolent type of scleroderma, the CREST variant characterized by calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. PSS-DS is characterized by multisystem involvement, with vascular and connective tissue fibrosis and inflammation manifesting most prominently in the skin, gastrointestinal tract, lungs, and kidneys. Although interstitial lung disease (ILD) has been described in patients with both types of PSS,
      • Hara I
      • Miyake H
      A case of progressive systemic sclerosis complicated by crescentic glomerulonephritis and diffuse pulmonary hemorrhage.
      • Yousem SA
      The pulmonary pathologic manifestations of the CREST syndrome.
      it is usually a late feature and is generally not a major cause of morbidity or mortality. PSS-DS has a 7-year mortality rate of 50%,
      • Lee P
      • Langevitz P
      • Alderdice CA
      • Aubrey M
      • Baer PA
      • Baron M
      Mortality in systemic sclerosis (scleroderma).
      and the most frequent causes of death are pulmonary hypertension, heart failure, renal failure, and bronchopneumonia. Herein we describe two patients with PSS-DS who had development of fulminant, fatal ILD, an unusual complication of PSS-DS.

      REPORT OF CASES

      Case 1.—A previously healthy 53-year-old woman sought medical attention because of swelling of her right hand 16 months before hospital admission. Subsequently, pain and swelling developed in her right ankle. Serologic test results for antinuclear antibodies, rheumatoid factor, and Scl-70 antibody were negative. Ten months before admission, she complained of skin tightening, and a repeated Scl-70 antibody test was positive. PSS was diagnosed, and she was treated with 250 mg of penicillamine per day. Findings on echocardiography, pulmonary function studies, esophageal motility studies, and complete blood cell counts were normal 6 months before admission. Five months before admission, however, her clinical status began to decline: her arthralgias became more severe, she had dyspnea, an echocardiogram showed a new pericardial effusion with an enlarged heart, and pulmonary function tests revealed a restrictive pattern with decreased vital capacity. The dosage of penicillamine was increased, and cyclophosphamide and methotrexate were added to the regimen. The arthralgias diminished, but her skin tightness continued to worsen. Two months before admission, a chest roentgenogram showed bilateral reticular infiltrates. Two weeks before admission, she had pancytopenia; therefore, her medications were discontinued, and she received transfusions. On admission to the hospital, she had severe dyspnea, and an interval increase was noted in the pericardial effusion. Pericardiocentesis and open-lung biopsy were performed. Routine cultures of this material for bacteria, viruses, and fungi were negative. Antibiotic therapy was initiated; however, within 4 days, she died of progressive respiratory failure.
      Case 2.—A 70-year-old woman with a 50-pack-year history of smoking and a 2-year history of Raynaud's phenomenon had development of systemic hypertension 7 months before admission; she was treated with lisinopril. Two months before admission, she had increasing shortness of breath that was accompanied by a nonproductive cough. One month before admission, she had hand, arm, back, and chest pain. Physical examination demonstrated clear lung fields and acrosclerosis. Findings on chest roentgenography were normal. Laboratory studies yielded an increased leukocyte count (17 × 109L) and platelet count (772 × 109/L), an increased creatinine level (3.0 mg/dL) and erythrocyte sedimentation rate (58 mm in 1 hour), and a positive antinuclear antibody screen (1+ homogeneous). PSS was diagnosed, and prednisone was initiated. Other medications at that time included desipramine hydrochloride, lisinopril, levothyrox-ine sodium, nitroglycerin, and temazepam. Ten days before admission, repeated chest roentgenography showed a mild diffuse interstitial infiltrate throughout both lungs, with an area of dense consolidation in the apex of the right upper lobe and a slight amount of alveolar infiltrate in the right lower lobe (Fig. 1). On admission, she had severe dyspnea and tachypnea, with extensive, diffuse velcro rales in both lung fields. An arterial blood gas study revealed a partial oxygen tension of 41 torr, and ventilator therapy was initiated. A chest roentgenogram now showed diffuse bilateral interstitial and alveolar infiltrates (Fig. 2). She underwent open-lung biopsy 1 day later, and routine cultures of this material for bacteria, viruses, and fungi were negative. She requested extubation on the fourth postoperative day and died of respiratory failure within 3 days.
      Figure thumbnail gr1
      Fig. 1(case 2). Chest roentgenogram obtained 10 days before admission, showing mild diffuse interstitial infiltrate throughout both lungs, with area of dense consolidation in apex of right upper lobe and slight amount of alveolar infiltrate in right lower lobe
      Figure thumbnail gr2
      Fig. 2(case 2). Chest roentgenogram obtained at admission, demonstrating diffuse bilateral interstitial and alveolar infiltrates.

      PATHOLOGY

      Lung biopsy specimens from both patients were similar and showed acute and organizing diffuse alveolar damage (DAD). Eosinophilic hyaline membranes were present in both specimens and were most conspicuous along alveolar ducts and alveolar septa (Fig. 3). There was associated alveolar septal thickening due to a combination of edema and inflammation, intra-alveolar edema, patchy hyperplasia of type II pneumocytes, and early intra-alveolar and interstitial fibroblast proliferation. Special stains for organisms showed no evidence of infection with bacteria, mycobacteria, fungi, or Pneumocystis carinii. Neither case had evidence of viral inclusions, chronic fibrosis, honeycomb change, or pulmonary hypertension.
      Figure thumbnail gr3
      Fig. 3Photomicrograph of lung parenchyma, showing diffuse alveolar damage. Inset shows characteristic hyaline membranes (arrow). (Hematoxylin-eosin; original magnification: ×l60; inset, ×400.)
      Immunofluorescent studies in one patient (case 2) showed fibrin deposition predominantly in the intra-alveolar spaces, but no immunoglobulin, complement, or immune complex deposition was evident.

      DISCUSSION

      Our report of two patients with acute ILD associated with PSS and a histologic pattern of DAD suggests that DAD may be another manifestation of lung disease in patients with PSS. Unlike the other more common types of ILD (Table 1), however, DAD has a rapid, fulminant deteriorating course.
      Table 1Clinical and Pathologic Patterns of Lung Disease Associated With Progressive Systemic Sclerosis
      Clinical patternsPathologic findings
      PleuritisFibrinous pleuritis
      Effusions
      Pleural thickeningFibrous pleuritis
      Airway disease
      Airflow obstructionFollicular bronchiolitis
      Interstitial lung disease
      Acute interstitial pneumoniaDiffuse alveolar damage
      Alveolar hemorrhageHemorrhage
      Chronic interstitial pneumoniaUsual interstitial pneumonia
      Bronchiolitis obliteransBronchiolitis obliterans
      organizing pneumoniaorganizing pneumonia
      Vascular disease
      Pulmonary hypertensionIntimal proliferation and medial thickening
      VasculitisVasculitis
      Pulmonary parenchymal abnormalities are common in PSS, even in the absence of classic cutaneous involvement,
      • Lomeo RM
      • Cornelia RJ
      • Schabel SI
      • Silver RM
      Progressive systemic sclerosis sine scleroderma presenting as pulmonary interstitial fibrosis.
      and radiographic and high-resolution computed tomographic evidence of ILD has been reported in up to 90% of patients.
      • Weaver AL
      • Divertie MB
      • Titus JL
      Pulmonary scleroderma.
      • Schurawitzki H
      • Stiglbauer R
      • Graninger W
      • Herold C
      • Polzleitner D
      • Burghuber OC
      Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography.
      • Remy-Jardin M
      • Remy J
      • Wallaert B
      • Bataille D
      • Harton PY
      Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage.
      • Arroliga AC
      • Podell DN
      • Matthay RA
      Pulmonary manifestations of scleroderma.
      Symptomatic chronic pulmonary disease is less common and is typically associated with pleural thickening and fibrosis, interstitial fibrosis, and honeycomb change that mainly affects the periphery of the lower lobes.
      • Weaver AL
      • Divertie MB
      • Titus JL
      Pulmonary scleroderma.
      • Harmon KR
      • Leatherman JW
      Respiratory manifestations of connective tissue disease.
      In patients with the chronic variants of ILD, pulmonary function tests show either a restrictive or an obstructive pattern.
      • Weaver AL
      • Divertie MB
      • Titus JL
      Pulmonary scleroderma.
      • Guttadauria M
      • Ellman H
      • Emmanuel G
      • Kaplan D
      • Diamond H
      Pulmonary function in scleroderma.
      • Konig G
      • Luderschmidt C
      • Hammer C
      • Adelmann-Grill BC
      • Braun-Falco O
      • Fruhmann G
      Lung involvement in scleroderma.
      • Schneider PD
      • Wise RA
      • Hochberg MC
      • Wigley FM
      Serial pulmonary function in systemic sclerosis.
      In most reports, bronchoalveolar lavage has shown an increase in total leukocytes, with a high percentage of neutrophils in many cases.
      • Silver RM
      • Miller KS
      Lung involvement in systemic sclerosis.
      Pulmonary hypertension occurs in most patients with scleroderma and can coexist with other types of ILD as well as alveolar hemorrhage. Pulmonary hypertension can progress independently of associated ILD
      • Naeye RL
      Pulmonary vascular lesions in systemic scleroderma.
      and tends to be severe in the CREST variant.
      • Remy-Jardin M
      • Remy J
      • Wallaert B
      • Bataille D
      • Harton PY
      Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage.
      • Salerni R
      • Rodnan GP
      • Leon DF
      • Shaver JA
      Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma).
      Patients with pulmonary hypertension usually have a chronic progressive course, but occasionally they have a rapid clinical course with severe respiratory distress associated with pronounced right-sided heart failure and minimal interstitial disease.
      • Harmon KR
      • Leatherman JW
      Respiratory manifestations of connective tissue disease.
      • Young RH
      • Mark GJ
      Pulmonary vascular changes in scleroderma.
      Other less common patterns of lung disease have also been reported in patients with scleroderma. These include bronchiolitis obliterans organizing pneumonia, aspiration pneumonitis, and pleural effusions,
      • Bridges AJ
      • Hsu KC
      • Dias-Arias AA
      • Chechani V
      Bronchiolitis obliterans organizing pneumonia and scleroderma.
      • Taormina VJ
      • Miller WT
      • Gefter WB
      • Epstein DM
      Progressive systemic sclerosis subgroups: variable pulmonary features.
      • Choplin RH
      • Theros EG
      Pulmonary involvement in diseases of other systems.
      • Johnson DA
      • Drane WE
      • Curran J
      • Cattau Jr, EL
      • Ciarleglio C
      • Khan A
      Pulmonary disease in progressive systemic sclerosis: a complication of gastroesophageal reflux and occult aspiration?.
      • Wells AU
      • du Bois RM
      Bronchiolitis in association with connective tissue disorders.
      • Clements P
      Clinical aspects of localized and systemic sclerosis.
      all of which usually manifest as chronic or subacute processes. Systemic sclerosis complicated by alveolar hemorrhage
      • Alvarez Vega JL
      • Salazar Vallinas JM
      • Ortega Alberdi R
      • Munoz Sanz A
      • Turegano JM
      • Fernandez Alonso J
      Pulmonary haemorrhage and focal necrotizing glomerulonephritis in a case of systemic sclerosis.
      • Griffin MT
      • Robb JD
      • Martin JR
      Diffuse alveolar haemorrhage associated with progressive systemic sclerosis.
      • Bolster MB
      • Silver RM
      Lung disease in systemic sclerosis (scleroderma).
      may manifest with a more fulminant course that is characterized by the acute onset of dyspnea, tachypnea, and fever. Chest roentgenograms demonstrate widespread alveolar or alveolar-interstitial infiltrates that mimic the appearance of the adult respiratory distress syndrome (ARDS). Lung biopsy specimens from patients with pulmonary hemorrhage have a combination of acute and organizing hemorrhage and hemosiderosis.
      The histologic pattern of organizing DAD, as seen in the current cases, can be caused by various insults (Table 2)
      • Olson J
      • Colby TV
      • Elliott CG
      Hamman-Rich syndrome revisited.
      • Katzenstein A-LA
      • Askin FB
      and is the most common histologic finding in patients with ARDS.
      • Schurawitzki H
      • Stiglbauer R
      • Graninger W
      • Herold C
      • Polzleitner D
      • Burghuber OC
      Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography.
      • Olson J
      • Colby TV
      • Elliott CG
      Hamman-Rich syndrome revisited.
      The term “acute interstitial pneumonia” or “Hamman-Rich syndrome” is sometimes used to describe the clinicopathologic syndrome of idiopathic ARDS.
      • Katzenstein A-LA
      • Myers JL
      • Mazur MT
      Acute interstitial pneumonia: a clinicopathologic, ultrastructural, and cell kinetic study.
      Clinically, such patients have acute respiratory distress in conjunction with refractory hypoxemia and pulmonary edema, and usually they are dependent on a ventilator. The radiographic appearance is well defined, although not specific, and progresses through three stages. In stage 1 (the first 12 to 24 hours), the radiogram is clear unless the causative event is pulmonary in origin. Stage 2 corresponds to alveolar filling and shows patchy or diffuse interstitial opacification.
      • Morgan PW
      • Goodman LR
      Pulmonary edema and adult respiratory distress syndrome [published erratum appears in Radiol Clin North Am 1991 Nov; 29: ixl.
      In stage 3, the radiogram reveals a diffuse, bilateral ground-glass appearance.
      Table 2Common Causes of Adult Respiratory Distress Syndrome
      • Aspiration
      • Chemical inhalation
      • Connective tissue diseases
      • Drugs
      • Idiopathic
      • Infection
      • Radiation therapy
      • Shock
      • Transfusion
      Because the etiologie factors of DAD are diverse, causes other than PSS must be considered in our patients. One patient (case 1) was taking methotrexate and penicillamine, both of which have well-known lung toxicity
      • Katzenstein A-LA
      • Askin FB
      including DAD.
      • Camus P
      • Degat OR
      • Justrabo E
      • Jeannin L
      D-penicillamine-in-duced severe pneumonitis.
      • Carson CW
      • Cannon GW
      • Egger MJ
      • Ward JR
      • Clegg DO
      Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate.
      This patient, however, had discontinued use of these medications by the time she sought medical treatment for respiratory distress; therefore, they are unlikely causes of her acute illness. She also had undergone transfusions, another known cause of ARDS.
      • Popovsky MA
      • Abel MD
      • Moore SB
      Transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies.
      The transfusions, however, were 1 month before hospitalization, and the reports of transfusion-related lung injury have all occurred within hours after the transfusion. Our other patient (case 2) received oxygen treatment for several days, another well-known cause of DAD; however, her severe respiratory compromise occurred before the institution of oxygen therapy. In both our patients, possible infectious causes of DAD were excluded on the basis of negative cultures and special stains performed on lung biopsy specimens. An immune complex-mediated pathogenesis was ruled out based on negative results of immunofluorescent studies. Therefore, the cause of lung injury in these patients seems most likely to be related to their underlying PSS.
      To our knowledge, DAD that is not associated with infection or immune complex deposition has not been previously reported in association with scleroderma; however, it has been reported in conjunction with other connective tissue diseases, notably systemic lupus erythematosus,
      • Harmon KR
      • Leatherman JW
      Respiratory manifestations of connective tissue disease.
      • Hunninghake GW
      • Fauci AS
      Pulmonary involvement in the collagen vascular diseases.
      mixed connective tissue disease with systemic lupus erythematosus features, rheumatoid arthritis,
      • Yousem SA
      • Colby TV
      • Carrington CB
      Lung biopsy in rheumatoid arthritis.
      and polymyositis-dermato-myositis.
      • Tazelaar HD
      • Viggiano RW
      • Pickersgill J
      • Colby TV
      Interstitial lung disease in polymyositis and dermatomyositis: clinical features and prognosis as correlated with histologic findings.
      In our two patients, we believe that we ruled out treatment modalities, drugs, and infection as causes of the ILD. In light of the clinical and pathologic evidence in the two cases presented herein, we think that PSS should be included with other connective tissue diseases as a cause of DAD and that acute ILD associated with DAD should be added to the list of pulmonary diseases associated with PSS.
      Diffuse alveolar damage (DAD) is a relatively nonspecific pattern of acute lung injury that can be observed in a wide range of clinical circumstances. DAD has often been recognized in association with various connective tissue diseases; however, to our knowledge, it has not been previously reported in the setting of progressive systemic sclerosis. Herein we describe two patients with established diagnoses of progressive systemic sclerosis who had development of the acute respiratory distress syndrome. Open-lung biopsy specimens from both patients showed a histologic pattern of DAD with no identifiable cause other than their progressive systemic sclerosis. Our results suggest that DAD should be added to the list of pleuro-pulmonary complications of progressive systemic sclerosis.

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        Transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies.
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