British Journal of Radiology (2005) 78, 762-766
© 2005 British Institute of Radiology
doi: 10.1259/bjr/95651807
Fatal acute exacerbation of usual interstitial pneumonia in ulcerative colitis
K Marten, MD1,
F Fend, MD2,
H Hautmann, MD3,
M Kremer, MD2,
E J Rummeny, MD1 and
C Engelke, MD1
Departments of 1 Radiology, 2 Pathology and 3 Pneumology, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675 München, Germany
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Abstract
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Pulmonary involvement in ulcerative colitis may manifest as a variety of disorders. Ulcerative colitis-related interstitial lung disease is exceedingly rare and has been reported to be steroid-responsive. We describe the first case of a patient with acute exacerbation of ulcerative colitis-induced usual interstitial pneumonia, who did not respond to corticosteroid therapy and died 12 weeks after the onset of pulmonary symptoms. Early recognition of pulmonary disease in patients with ulcerative colitis is necessary to initiate further diagnostic work-up and may aid treatment decisions.
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Introduction
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Pulmonary complications of ulcerative colitis are very rare and may present as upper airway stenosis [1], tracheobronchitis [2, 3], bronchiectasis [4, 5], constrictive bronchiolitis [2], panbronchiolitis [6], cryptogenic organizing pneumonia (formerly bronchiolitis obliterans organizing pneumonia) [7], necrobiotic nodules [5], bullae [8], pulmonary vasculitis [9], or pulmonary eosinophilia [5]. Interstitial lung disease with varying histopathological appearances associated with ulcerative colitis has only been described in a small number of cases, all of them having been highly sensitive to corticosteroid treatment [10–13]. Herein we describe the first case of a patient with ulcerative colitis who developed rapidly progressive usual interstitial pneumonia (UIP) which was non-responsive to steroid treatment, and who died from respiratory failure 3 months after the onset of pulmonary symptoms.
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Case report
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A 70-year-old Caucasian male presented in August 2003 with increasing exertional dyspnoea. He was a retired businessman and an ex-smoker with a 20 pack-year history not known to have been exposed to any dusts, chemicals, or animals in the past. The patient had a 4 year history of chronic obstructive pulmonary disease (COPD), he had undergone right hemicolectomy for caecal cancer 11 years earlier and had biopsy confirmation of ulcerative colitis in 1999 at which time there was no evidence of extraintestinal colitis-associated disease. Medical treatment for ulcerative colitis had included prednisolone from February 1999 until June 2002 (initial dosage, 40 mg day–1, with subsequent gradual tapering of dose to 5 mg day–1) and sulfasalazine (varying dosages, 1–4 g day–1) from February 1999 through December 2002. Following termination of prednisolone therapy in June 2002, the patient had undergone surgical resection of the sigmoid colon for active colitis. COPD had been diagnosed during initial clinical admission in 1999, with isolated expiratory flow limitation in conjunction with moderate hypoxaemia and mild hyperventilation (vital capacity (VC)=4.5 l (109% of predicted), residual lung volume (RV)=3.39 l (143% of predicted), forced vital capacity (FVC)=4.1 l (102% of predicted), forced expiratory volume in 1 s (FEV1)=1.88 l (60% of predicted), partial oxygen pressure (PaO2)=70.4 mmHg and partial carbon dioxide pressure (PaCO2)=33.9 mmHg). A chest CT scan at that time had shown panacinar emphysema predominantly affecting the upper lobes and discrete reticular changes with intralobular and interlobular interstitial thickening in the dorsal subpleural region, chiefly of the right lower and upper lobes, findings which had been in keeping with established fibrosis. Traction bronchiectasis and honeycombing had been absent (Figure 1
). The patient had subsequently been treated with inhaled bronchodilators and inhaled steroids. Apart from occasional mild exertional dyspnoea, pulmonary symptoms were minimal until August 2003.
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Figure 1. Initial chest CT (5 mm section thickness) from July 2002 showing panacinar and paraseptal emphysema affecting the upper and middle lobes and the lingula (arrows). Note additional mild right-sided subpleural interlobular and intralobular interstitial thickening (arrowheads). Traction bronchiectasis and honeycombing are absent.
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On admission in August 2003, the patient presented with fatigue and breathlessness, but no cough or fever was present. The lungs were clear on auscultation. Laboratory test results showed a leucocytosis (14 400 µl–1, normal range: 4000–9000 µl–1) and elevation of c-reactive protein (20.1 mg dl–1, normal range: <0.5 mg dl–1). However, there were no clinical signs of pulmonary infection. Plain film chest radiography revealed bilateral hyperinflation consistent with pulmonary emphysema (Figure 2). Lung function testing now revealed new moderate pulmonary restrictive disease with mild hypoxaemia (VC=2.86 l (72% of predicted), RV=3.12 l (128% of predicted), FVC=2.37 l (62% of predicted), FEV1=1.27 l (43% of predicted), PaO2=72.6 mmHg, and PaCO2=32.2 mmHg. In the following 8 weeks, the patient's pulmonary function deteriorated. In October 2003 auscultation revealed bilateral crackles. A repeat chest radiograph revealed bilateral lower and mid-zone reticular opacities consistent with marked interstitial lung disease (Figure 3). Pulmonary function testing showed progressive restrictive pulmonary disease with a substantially aggravated severe hypoxaemia (VC=2.11 l (54% of predicted), RV=1.04 l (43% of predicted), FVC=1.83 l (48% of predicted), FEV1=1.57 l (53% of predicted), PaO2=37.4 mmHg, and PaCO2=30.4 mmHg). The patient's rapidly deteriorating pulmonary status prompted administration of high-dose intravenous corticosteroid therapy with a daily dose of 150 mg prednisolone. However, the patient's respiratory function did not improve. Subsequent high-resolution CT of the chest in the last week of October (12 weeks after admission) demonstrated typical features of usual interstitial pneumonia with severe architectural distortion including honeycombing, traction bronchiectasis and bronchiolectasis. In addition, multifocal areas of ground glass opacification were present, suggestive of an accelerated phase of the disease (Figure 4). The patient's clinical status further deteriorated, requiring mechanical ventilation with 100% oxygen. He developed acute right ventricular failure and died on November 1st 2003.
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Figure 2. Chest radiograph from July 2003. Note the bilateral lung hyperinflation indicating pulmonary emphysema. There is no evidence of interstitial lung disease.
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Figure 3. Chest radiograph from October 2003 showing bilateral lower and mid-zone reticular opacities consistent with major interstitial lung disease (arrows) in comparison with the previous chest radiograph (Figure 2 ).
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Figure 4. High-resolution CT in the last week of October demonstrated typical features of usual interstitial pneumonia with severe architectural distortion including honeycombing (arrowheads), massive traction bronchiectasis and bronchiolectasis (arrows). In addition, multifocal areas of ground glass opacification were present, suggestive of diffuse alveolar damage (asterisks).
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Autopsy revealed an increased weight of both lungs, with emphysematous changes, subpleural fibrosis, and marked bilateral honeycombing affecting predominantly the lung periphery. Histological examination showed a background pattern of usual interstitial pneumonia with a heterogeneous appearance of interstitial scarring with dense collagen deposits, thickening the alveolar septa and enlarged airspaces filled with a proteinanceous exudate containing sporadic inflammatory cells (Figure 5). Additionally, scattered foci of florid fibroblast proliferation, abundant buds of intra-alveolar organization and hyaline membranes as seen in the organizing phase of diffuse alveolar damage were present. Some thickened septae showed marked smooth muscle hyperplasia. Examination of the heart revealed right ventricular myocardial hypertrophy.
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Figure 5. Photomicrographs illustrating the most striking histological features of the usual interstitial pneumonia (Haematoxylin & Eosin stain, x 300): (a) Remodelled fibrotic cystic air spaces (arrowhead) are lined by bronchiolar epithelium containing mucinous debris and inflammatory cells (arrow). (b) A focus of organizing pneumonitis (asterisks) composed of spindled fibroblasts dispersed in pale oedematous-appearing stroma. (c) Area of diffuse alveolar damage with hyaline membranes (arrow) superimposed on a background of fibrotic lung parenchyma. (d) Prominent smooth muscle hyperplasia (arrowheads) in remodelled pulmonary septae.
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Discussion
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Pulmonary involvement of inflammatory bowel disease (either ulcerative colitis or Crohn's disease) is rare, with only three cases having been reported in an observational study of 1400 patients with inflammatory bowel disease [14]. However, systematic lung function testing and prospective clinical work-up was not performed, suggesting that the true prevalence of pulmonary involvement in patients with ulcerative colitis may be underestimated. This is particularly plausible in the light of the difficulty in recognizing concomitant pulmonary symptoms, which may be preceded by ulcerative colitis for years. Besides, pulmonary involvement may be asymptomatic, manifesting as mild pulmonary function abnormalities, and chest radiographs of these patients are usually normal [15]. Subsequently, in a more recent prospective observational series with 30 patients, lung function abnormalities were demonstrated in as many as 56.7% of patients with ulcerative colitis [15].
High resolution CT features related to a variety of ulcerative colitis-associated pulmonary disorders have been described only in a small number of patients [16]. They include bronchiectasis and pulmonary parenchymal mosaicism with evidence of air trapping indicative of constrictive bronchiolitis, centrilobular nodular densities and branching linear opacities with tree-in-bud appearance suggestive of cellular bronchiolitis or bronchiolectasis with mucoid impactations, as well as a predominantly subpleural reticular pattern consistent with fibrosis. However, correlations with corresponding histopathological findings, clinical follow-up or therapeutic response data are missing in most cases [16]. Furthermore, the occurrence of pulmonary toxic effects of sulfasalazine therapy that generally manifest as hypersensitivity reaction or chronic interstitial fibrosis often render a differentiation of colitis-related from drug-induced pulmonary pathology impossible [17–20].
We describe a patient with pulmonary involvement of ulcerative colitis who developed rapidly progressive UIP which was clearly unattributable to sulfasalazine therapy. To our knowledge, this is the first report of a case with a fatal non-steroid responsive course of such acute exacerbation of ulcerative colitis-induced UIP. Few well documented patients with ulcerative colitis-associated interstitial fibrosis, unattributable to sulfasalazine treatment, have been reported. Balestra et al described a patient with ulcerative colitis predating pulmonary interstitial disease by many years in whom the pulmonary symptoms improved after 7 days of prednisolone, followed by simultaneous continuous improvement of radiographic and functional parameters [10]. Three other patients with interstitial lung disease predating ulcerative colitis, all showing excellent responses of pulmonary symptoms to steroids, have been described [11–13]. Only a single case of corticosteroid-resistant advanced interstitial fibrosis with respiratory failure has been described in association with ulcerative colitis. However, this patient was treated with varying doses of sulfasalazine when pulmonary symptoms occurred [21]. After cessation of sulfasalazine therapy, his respiratory function did not improve, provoking the authors to conclude that in this case pulmonary disease most likely represented an extracolonic manifestation of ulcerative colitis [21]. However, pulmonary disease induced by sulfasalazine may have a fatal progressive course despite the cessation of therapy, and it is possible that McKee et al may have reported a case of sulfasalazine toxicity instead of true colitis-induced exacerbation of pulmonary disease [18, 19].
The high-resolution CT features in patients with UIP have been well described and include honeycombing, reticular opacities which are often associated with traction bronchiectasis, prominent architectural distortion with a patchy, basal and peripheral distribution and occasionally, ground glass opacities [22]. Our patient's histopathological and imaging features were in accordance with these findings. Nevertheless, our patient displayed an atypical clinical course, ultimately progressing to terminal respiratory failure only 2 months after presentation with pulmonary symptoms, consistent with superimposed acute exacerbation. Acute exacerbation is recognized as a rare and, if untreated, terminal event in patients with UIP, with histopathological features having been described in a small number of patients [23, 24]. Kondoh et al reported three patients with acute exacerbation of UIP displaying alveolar wall oedema with a mononuclear cell infiltrate and intra-alveolar organization without hyaline membrane formation. All patients rapidly responded to treatment with corticosteroids and antibiotics [24]. Rice et al reviewed autopsy material from patients with acute exacerbation of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA), and demonstrated UIP as the underlying histopathological pattern in 12 of 15 cases [23]. In our patient, autopsy revealed histopathological features of acute exacerbation of UIP, with hyaline membranes and intra-alveolar organization indicative of the organizing phase of diffuse alveolar damage.
Additional evidence for superimposition on UIP of an acute lung injury pattern can occasionally be found on high-resolution CT. Akira et al retrospectively evaluated CT findings of 17 patients with acutely exacerbating IPF and found peripheral, multifocal, and diffuse patterns of parenchymal opacification (either ground glass or consolidation), with a multifocal diffuse distribution corresponding to acute diffuse alveolar damage [25]. Interestingly, only 50% of the patients with multifocal parenchymal opacification responded to corticosteroid therapy [25]. Therefore, the presence of multifocal ground glass opacities in our patient's follow-up CT scan found in association with rapidly progressive honeycombing, traction bronchiectasis and architectural distortion is likely to be indicative of superimposed acute diffuse alveolar damage. By contrast, the differential diagnosis of acute pulmonary infection as a predisposing factor for lung function deterioration is unlikely in our patient. Despite a moderate leucocytosis on admission, he did not show any clinical symptoms of chest infection, and there was no radiological or histopathological evidence of bronchopneumonia. In our patient, the additional toxic effects of oxygen can be excluded as a cause of his acute UIP-exacerbation, because oxygen administration was initiated late in the terminal phase of the disease.
In conclusion, we present a case of acute fatal exacerbation of UIP as an extracolonic manifestation of ulcerative colitis which was not steroid-responsive. Early recognition and close follow-up of patients with ulcerative colitis-related pulmonary function abnormalities may help in the decision to perform further imaging and, potentially, to instigate or change treatment.
Received for publication June 7, 2004.
Revision received January 5, 2005.
Accepted for publication March 15, 2005.
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Abstract
Introduction
