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* From the Division of Pulmonary and Critical Care Medicine (Drs. Parambil and Ryu), Mayo Clinic, Rochester, MN; and Division of Anatomic Pathology (Dr. Myers), University of Michigan Health System, Ann Arbor, MI. Drs. Parambil, Myers, and Ryu have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Correspondence to: Jay H. Ryu, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; e-mail: ryu.jay{at}mayo.edu
Abstract
Background: Diffuse alveolar damage (DAD) is a relatively common finding on surgical lung biopsy and can result from a variety of causes.
Methods: We studied nine consecutive patients with connective tissue disease (CTD) and DAD diagnosed on surgical lung biopsy to examine this association and clinical implications.
Results: The median age was 63 years (range, 35 to 76 years), and seven of the patients were women (78%). Underlying CTDs included rheumatoid arthritis in five patients, polymyositis in two patients, and one patient each with systemic sclerosis and mixed CTD. In seven patients (78%), CTD had been diagnosed before the onset of DAD; six of these patients had a preexisting interstitial lung disease (ILD) related to their CTD. DAD was the presenting manifestation leading to a new CTD diagnosis in two patients (22%). CT of the chest revealed ground-glass opacities and/or consolidation bilaterally with or without honeycombing. In all patients, surgical lung biopsy revealed DAD for which no cause could be identified other than the underlying CTD. Seven patients (78%) were receiving mechanical ventilatory support at the time of the surgical lung biopsy. Four patients (44%) survived to hospital discharge and included one patient with preexisting ILD and all three patients without chronic ILD.
Conclusion: We conclude that DAD can complicate the clinical course of patients with CTD-related chronic ILD, or can occasionally occur as a presenting manifestation of CTDs. When DAD occurs in patients with CTDs, the outcome appears to be worse for those with preexisting chronic ILD compared to those without ILD.
Key Words: connective tissue disease • interstitial lung disease • interstitial pneumonia • lung biopsy • pulmonary fibrosis
Diffuse alveolar damage (DAD) is a relatively common finding on surgical lung biopsy and can result from a variety of causes.123 DAD can be seen in patients with pneumonias, sepsis, drug-induced lung diseases, inhalation injuries, and various other conditions that are associated with acute lung injury.1 It is the most common underlying histology seen in patients with ARDS.4
Acute respiratory deterioration due to DAD has been described as an uncommon manifestation of connective tissue diseases (CTDs), including polymyositis, dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis.5678910 The occurrence of DAD in these patients has been associated with a generally poor prognosis when a reversible cause for the acute lung injury cannot be identified. We examined a consecutive series of patients with CTDs who had DAD on surgical lung biopsy in an effort to more clearly define clinical implications of this infrequent complication.
Materials and Methods
A computer-aided search was conducted to identify all adults (
18 years old) seen at the Mayo Clinic in Rochester, MN, during a 7-year period from January 1, 1996, to December 31, 2002, with a CTD and DAD identified on surgical lung biopsy. Underlying CTDs included rheumatoid arthritis, polymyositis/dermatomyositis, scleroderma, systemic lupus erythematosus, primary Sjögren syndrome, and mixed CTD. We included patients if a previously unrecognized CTD was diagnosed within 3 months of lung biopsy. Of 13 patients identified to have DAD and a CTD, 4 patients had pulmonary infections or drug-induced lung diseases and were excluded from this study. The remaining nine patients had no identifiable cause for the DAD other than their underlying CTD, and they comprise the study group. Medical records were examined in detail to gather clinical, laboratory, radiologic, and pulmonary function data at presentation. Follow-up data were also extracted.
All lung biopsy specimens were reviewed by one of us (J.L.M.). Gram stains for bacteria, stains for acid-fast bacilli (auramine-rhodamine), and special stains for fungi and Pneumocystis jiroveci (Gomori-methenamine silver) were performed on all surgical lung biopsies. Pulmonary function data included plethysmographically determined total lung capacity (TLC), FVC, FEV1, ratio of FEV1 to FVC, and diffusing capacity of the lung for carbon monoxide (DLCO). Spirometry and measurements of lung volumes and DLCO were performed in our laboratory using standard techniques.11 Data are reported as mean ± SD unless otherwise stated. This study was approved by the Mayo Foundation institutional review board. Patients who did not authorize the use of their medical records for research were excluded from this study.
Results
Demographic Features and Clinical Presentation
Patient demographics and clinical characteristics are summarized in Table 1
. The median age at the time of surgical lung biopsy was 63 years (range, 35 to 76 years); seven of the nine patients (78%) were women. Four patients (44%) had a smoking history, including two current smokers. All patients presented with respiratory symptoms that included dyspnea (100%) and cough (89%) experienced for a median duration of 14 days (range, 3 to 21 days). Less common symptoms included fever (44%), flu-like symptoms (22%), and chest pain (11%). Inspiratory crackles were heard in all patients, and expiratory wheezes were noted in three patients (33%). Digital clubbing was evident in three patients (33%).
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At the time of the surgical lung biopsy, eight patients (89%) had been hospitalized for a median duration of 9 days (range, 5 to 16 days). These eight patients required ventilatory assistance that included invasive mechanical ventilation for six patients and noninvasive ventilatory support for the other two patients. One remaining patient was hospitalized following an elective surgical lung biopsy performed for evaluation of diffuse pulmonary infiltrates.
Preexisting Interstitial Lung Disease
A form of diffuse lung disease other than DAD had been previously diagnosed in six patients (67%) a median of 28 months (range, 10 months to 10 years) prior to the development of DAD (Table 1). All six patients had parenchymal infiltrates demonstrated on prior chest imaging studies. Previous transbronchoscopic (three patients) or surgical (one patient) lung biopsies demonstrated organizing pneumonia in three of them (two with rheumatoid arthritis, one with polymyositis) and nonspecific interstitial pneumonia in one patient (polymyositis). The two remaining patients (both with rheumatoid arthritis patients) had usual interstitial pneumonia (UIP) based on clinical and high-resolution CT (HRCT) findings that included subpleural honeycombing and reticular opacities with lower lung predominance as well as traction bronchiectasis.
Chest Radiography and CT
All patients underwent chest radiography at initial presentation and serially during their hospitalization. Diffuse alveolar-interstitial infiltrates were identified in all patients. HRCT of the chest was performed on all patients after a median interval of 3 days (range, 0 to 7 days) following presentation with acute respiratory symptoms. All patients had bilateral areas of ground-glass opacities and/or consolidation (Fig 1
). Reticular opacities were also noted in five patients (56%) and included peripheral honeycombing in three patients (33%). Eight patients (89%) underwent CT pulmonary angiography, and all were negative for pulmonary embolism.
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200. The mean arterial pH was 7.37 ± 0.05, and the mean PCO2 was 47.4 ± 9.4 mm Hg. Bronchoscopy was performed on all patients prior to surgical lung biopsy with a median interval of 4 days (range, 0 to 6 days) following initial presentation and included BAL in all patients and bronchoscopic lung biopsies in five patients. Neutrophils were the predominant cell type identified in BAL fluid, with a mean percentage of 56.1 ± 20.1%. Macrophages, lymphocytes, and eosinophils accounted for 29.4 ± 20.1%, 11.1 ± 10.6%, and 2.2 ± 1.5% of cells recovered by BAL, respectively. Bronchoscopic lung biopsies revealed organizing pneumonia in one patient (polymyositis). The specimens were without diagnostic findings in the remaining four patients. Microbiologic studies including cultures and immunoassays to identify potential infectious pathogens were performed on the BAL fluid as well as blood, sputum, and tracheal secretions for all patients, and results were negative.
Pulmonary Function Data
Seven patients (78%) had pulmonary function data obtained a median of 30 months (range, 16 to 81 months) prior to the current presentation. Pulmonary function results demonstrated a restrictive pattern of ventilatory limitation in six of these patients (86%), all of whom had diffuse lung diseases, and included a mean TLC of 67 ± 12% of predicted, FVC of 69 ± 11% of predicted, and DLCO of 45 ± 8% of predicted. Pulmonary function results were normal in the remaining patient.
Pulmonary function results were obtained in three of four survivors after a median interval of 7 months (range, 3 to 14 months) following DAD. A restrictive pattern of ventilatory limitation was seen in two patients with a mean TLC of 73 ± 9% of predicted, FVC of 72 ± 10% of predicted, and DLCO of 66 ± 18% of predicted. The remaining patient had normal pulmonary function results, including normal DLCO.
Echocardiography
All nine patients underwent transthoracic echocardiography performed after a median interval of 3 days (range, 0 to 5 days) of the current presentation. Left ventricular systolic function including the estimated ejection fraction was normal in all patients, as were morphologic assessments of the mitral and aortic valves. Right ventricular enlargement and hypertrophy was present in six patients (67%), and the right ventricular systolic function was impaired in five of these patients (56%). The mean calculated right ventricular systolic pressure was 51.5 ± 10.7 mm Hg (range, 32 to 69 mm Hg). Aside from annular dilatation, morphologic findings of the tricuspid and pulmonary valves were normal in all patients. Four patients (44%) had small pericardial effusions without evidence of cardiac tamponade.
Surgical Lung Biopsy
Surgical specimens were obtained by limited thoracotomy in five patients (55%) and by video-assisted thoracoscopic surgery in four patients (45%). No major complications occurred. Minor complications occurred in two patients (22%) and consisted of prolonged air leak in both. Both were managed conservatively with successful resolution of the air leak.
Pathology
All biopsies showed DAD characterized by diffuse alveolar septal thickening with marked hyperplasia of alveolar pneumocytes and eosinophilic, acellular hyaline membranes. In five cases, there was associated proliferation of fibroblasts and myofibroblasts in a pattern typical of the organizing phase of DAD. Underlying fibrosis with honeycomb change was seen in two patients and included features diagnostic of underlying UIP in a patient with rheumatoid arthritis who had an established diagnosis of chronic diffuse lung disease. Acute bronchopneumonia was also present in one patient who had negative special stain and culture findings.
Treatment
Systemic corticosteroid therapy was administered to all nine patients. After surgical lung biopsy, five patients (56%) received an IV bolus of methylprednisolone, 500 to 1,000 mg qd, for 3 days followed by 1 to 2 mg/kg/d administered in divided doses; the remaining four patients (44%) were treated with 1 to 2 mg/kg/d of IV methylprednisolone administered in divided doses without an initial bolus. The corticosteroid dose was tapered gradually over subsequent weeks. Five patients (56%) also received an IV dose of cyclophosphamide, 500 to 1,000 mg/m2. All patients received empiric broad-spectrum antibacterial therapy, and 5 patients (56%) received antifungal therapy until the results of the lung biopsy became available, which led to the discontinuation of the antibacterial agents in seven patients (78%) and antifungal agents in all five patients.
Outcome
Patients were hospitalized for an average of 27.8 ± 18.6 days (range, 7 to 63 days). Four patients (44%) survived to hospital discharge. Among six patients with preexisting CTD-related interstitial lung disease (ILD), five patients (83%) died. All three patients without preexisting CTD-related ILD survived to hospital discharge.
The mean duration of follow-up for the four survivors was 27 months (range, 4 to 76 months), during which time two additional patients died. These two patients died from acute respiratory failure caused by influenza A pneumonia and acute exacerbation of polymyositis-related ILD, respectively.
Discussion
Acute respiratory deterioration due to DAD occurs in patients with underlying CTD and occasionally represents the presenting feature of the illness. Pulmonary manifestations are common in patients with CTDs and comprise various forms of diffuse lung disease, including nonspecific interstitial pneumonia, organizing pneumonia, and UIP.121314 DAD has been described infrequently in association with CTDs.56910 Our study population indicates that DAD occurs in patients with or without preexisting CTD-related chronic ILD and is a de novo manifestation of CTD in some patients.
Clinical and radiologic findings in our patients with CTD-related DAD are indistinguishable from those seen in DAD in other clinical contexts.12315 Our patients with CTD-related DAD presented with worsening dyspnea, cough, and bilateral ground-glass or consolidative infiltrates on HRCT. In those patients with preexisting chronic ILD, reticular opacities or honeycombing were also present, a combination of findings also seen in patients with accelerated idiopathic pulmonary fibrosis (IPF).16
Rheumatoid arthritis was the most common underlying CTD in our small series, accounting for just over one half of our patients. One of these patients with rheumatoid arthritis was being treated with leflunomide, a drug that has been associated with an acute lung reaction termed acute interstitial pneumonia. This form of drug-induced lung disease has occurred rarely in the Western hemisphere (< 0.1% of those receiving leflunomide) and, to our knowledge, the underlying histopathologic pattern has not been defined.171819 The high proportion of patients with rheumatoid disease may reflect a referral bias; rheumatology colleagues at our institution have a strong interest in rheumatoid arthritis. CTD-associated DAD has been described most commonly in patients with polymyositis-dermatomyositis in whom DAD implies a poor prognosis.5672021 Most reported patients have died within a few months of the onset of DAD despite corticosteroid therapy. DAD has been described less commonly in patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus.89102122
Acute respiratory deterioration due to DAD was the presenting manifestation of CTD in two of our patients, including one with rheumatoid arthritis and another with mixed CTD. Although this form of acute respiratory illness usually occurs in patients with established histories of CTD, it had been previously reported as a presenting manifestation of disease in two patients with polymyositis-dermatomyositis.20
Patients with and without preexisting chronic CTD-related ILD are vulnerable to DAD.5672021 DAD occurring in patients with preexisting CTD-related ILD exhibits similarities to acute exacerbation described in patients with IPF.16212324 In both situations, acute worsening of respiratory symptoms is accompanied by new pulmonary infiltrates and worsened gas exchange in the absence of an identifiable cause other than the preexisting ILD. Although our study is too small to allow meaningful statistical analysis, it is interesting to note that survival appeared to be better in patients without preexisting chronic CTD-related ILD. Corticosteroid therapy has been reported to be effective in reversing the downhill clinical course in patients with acute exacerbation of IPF,2324 but corticosteroid therapy with or without cyclophosphamide showed little benefit for our patients with DAD superimposed on CTD-related chronic ILD. Similarly poor results in polymyositis have been reported by other authors.25 Case reports have described successful therapeutic use of cyclosporin A combined with prednisolone26 or cyclophosphamide27 in patients with acute worsening of CTD-related ILD. However, it is unclear whether these patients had DAD since a lung biopsy was not performed. Overall, the survival rate for our cohort of patients with CTD-related DAD was worse than that reported for acute interstitial pneumonia and ARDS from other causes.2829
In summary, we conclude that acute respiratory deterioration due to DAD can complicate the clinical course of patients with CTD with or without chronic ILD. This acute respiratory illness can occasionally be seen as a presenting manifestation of CTDs in some patients. When DAD occurs in patients with CTDs, the outcome appears to be worse for those with preexisting chronic CTD-related ILD compared to those without. There are similarities between DAD occurring in patients with CTD and acute exacerbation described in patients with IPF. The pathogenesis of these serious events needs to be better understood.
Footnotes
Abbreviations: CTD = connective tissue disease; DAD = diffuse alveolar damage; DLCO = diffusing capacity of the lung for carbon monoxide; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; TLC = total lung capacity; UIP = usual interstitial pneumonia
Received for publication January 9, 2006. Accepted for publication February 17, 2006.
References
This article has been cited by other articles:
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  J. G. Parambil, J. L. Myers, M.-C. Aubry, and J. H. Ryu Causes and Prognosis of Diffuse Alveolar Damage Diagnosed on Surgical Lung Biopsy Chest, July 1, 2007; 132(1): 50 - 57. [Abstract] [Full Text] [PDF]
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I-N. Park, D. S. Kim, T. S. Shim, C.-M. Lim, S. D. Lee, Y. Koh, W. S. Kim, W. D. Kim, S. J. Jang, and T. V. Colby Acute Exacerbation of Interstitial Pneumonia Other Than Idiopathic Pulmonary Fibrosis Chest, July 1, 2007; 132(1): 214 - 220. [Abstract] [Full Text] [PDF]
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