Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disease, with a highly variable course in individual patients. Episodes of rapid deterioration are not uncommon, often following a period of stability. In cases of uncertain etiology, with typical clinical and high-resolution computed tomography (HRCT) features, the term ‘acute exacerbation of IPF' (AE-IPF) has been coined to describe a combination of diffuse alveolar damage and preexisting usual interstitial pneumonia. In 2007, a consensus definition and diagnostic criteria were proposed. Although the presence of overt infection is currently an exclusion criterion, it appears likely that occult infection, reflux and thoracic surgical procedures are all trigger factors for AE-IPF. The development of new, usually bilateral infiltrates (ground-glass attenuation with variable admixed consolidation) is a defining HRCT feature. The outcome is poor with a short-term mortality in excess of 50% despite therapy. A number of pathophysiologic pathways are activated, with immunologic dysregulation, epithelial damage and circulating fibrocytes all believed to play a pathogenetic role. Acute exacerbations are less prevalent in other fibrotic lung diseases than in IPF and may have a better outcome, with the exception of acute exacerbations of rheumatoid lung. In AE-IPF, the exclusion of alternative causes of rapid deterioration, including heart failure and infection, is the main goal of investigation. Empirical high-dose corticosteroid steroid therapy is generally used in AE-IPF, without proven benefit.

Keywords:
Idiopathic pulmonary fibrosis, Acute exacerbations, High-resolution computed tomography
1.
Mukhopadhyay S, Parambil JG: Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS). Semin Respir Crit Care Med 2012;33:476-485.
2.
Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K: Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993;103:1808-1812.
3.
Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Müller-Quernheim J, Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ, Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators: Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636-643.
4.
Papiris SA, Manali ED, Kolilekas L, Kagouridis K, Triantafillidou C, Tsangaris I, Roussos C: Clinical review: idiopathic pulmonary fibrosis acute exacerbations - unravelling Ariadne's thread. Crit Care 2010;14:246.
5.
Song JW, Hong SB, Lim CM, Koh Y, Kim DS: Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011;37:356-363.
6.
Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK: The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963-967.
7.
Daniels CE, Yi ES, Ryu JH: Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis. Eur Respir J 2008;32:170-174.
8.
Antoniou KM, Cottin V: The challenge of acute exacerbation of pulmonary fibrosis. Respiration 2012;83:13-16.
9.
Tachikawa R, Tomii K, Ueda H, Nagata K, Nanjo S, Sakurai, A, Otsuka K, Kaji R, Hayashi M, Katakami N, Imai Y: Clinical features and outcome of acute exacerbation of interstitial pneumonia: collagen vascular diseases-related versus idiopathic. Respiration 2012;83:20-27.
10.
Simon-Blancal V, Freynet O, Nunes H, Bouvry D, Naggara N, Brillet P-Y, Denis D, Cohen Y, Vincent F, Valeyre D, Naccache J-M: Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration 2012;83:28-35.
11.
Cottin V, Le Pavec J, Prévot G, Mal H, Humbert M, Simonneau G, Cordier JF, GERM'O'P: Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J 2010;35:105-111.
12.
Antoniou KM, Hansell DM, Rubens MB, Marten K, Desai SR, Siafakas NM, Nicholson AG, du Bois RM, Wells AU: Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med 2008;177:190-194.
13.
Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, Revel D, Valeyre D, Cordier JF: Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease. Arthritis Rheum 2011;63:295-304.
14.
Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T: Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006;27:143-150.
15.
Cottin V: Interstitial lung disease. Eur Respir Rev 2013;22:26-32.
16.
Swigris JJ, Brown KK: Acute interstitial pneumonia and acute exacerbations of idiopathic pulmonary fibrosis. Semin Respir Crit Care Med 2006;27:659-667.
17.
Judge EP, Fabre A, Adamali HI, Egan JJ: Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis. Eur Respir J 2012;40:93-100.
18.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schunemann HJ: An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.
19.
Rice AJ, Wells AU, Bouros D, du Bois RM, Hansell DM, Polychronopoulos V, Vassilakis D, Kerr JR, Evans TW, Nicholson AG: Terminal diff use alveolar damage in relation to interstitial pneumonias. An autopsy study. Am J Clin Pathol 2003;119:709-714.
20.
Akira M, Kozuka T, Yamamoto S, Sakatani M: Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;178:372-378.
21.
Ichikado K, Suga M, Muranaka H, Gushima Y, Miyakawa H, Tsubamoto M, Johkoh T, Hirata N, Yoshinaga T, Kinoshita Y, Yamashita Y, Sasaki Y: Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology 2006;238:321-329.
22.
Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, Sumikawa H, Ogura T, Kataoka K, Endo T, Kawaguchi A, Müller NL: Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol 2012;22:83-92.
23.
Corte TJ, Wells AU: Diffuse alveolar damage in idiopathic pulmonary fibrosis: does aetiology matter? Respirology 2010;15:873-875.
24.
Huie TJ, Olson AL, Cosgrove GP, Janssen WJ, Lara AR, Lynch DA, Groshong SD, Moss M, Schwarz MI, Brown KK, Frankel SK: A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: aetiology and outcomes. Respirology 2010;15:909-917.
25.
Parambil JG, Myers JL, Aubry MC, Ryu JH: Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy. Chest 2007;132:50-57.
26.
Kakugawa T, Yokota SI, Ishimatsu Y, Hayashi T, Nakashima S, Hara S, Sakamoto N, Kubota H, Mine M, Matsuoka Y, Mukae H, Nagata K, Kohno S: Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones 2013;18:581-590.
27.
Kahloon RA, Xue J, Bhargava A, Csizmadia E, Otterbein L, Kass DJ, Bon J, Soejima M, Levesque MC, Lindell KO, Gibson KF, Kaminski N, Banga G, Oddis CV, Pilewski JM, Sciurba FC, Donahoe M, Zhang Y, Duncan SR: Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses. Am J Respir Crit Care Med 2013;187:768-775.
28.
Kurosu K, Takiguchi Y, Okada O, Yumoto N, Sakao S, Tada Y, Kasahara Y, Tanabe N, Tatsumi K, Weiden M, Rom WN, Kuriyama T: Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis. J Immunol 2008;181:756-767.
29.
Wells AU, Kelleher WP: Idiopathic pulmonary fibrosis pathogenesis and novel approaches to immunomodulation: we must not be tyrannized by the PANTHER data. Am J Respir Crit Care Med 2013;187:677-679.
30.
Gomperts BN, Strieter RM: Fibrocytes in lung disease. J Leukoc Biol 2007;82:449-456.
31.
Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, O'Byrne PM, Strieter RM, Kolb M: Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179:588-594.
32.
Konishi K, Gibson KF, Lindell KO, Richards TJ, Zhang Y, Dhir R, Bisceglia M, Gilbert S, Yousem SA, Song JW, Kim DS, Kaminski N: Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;180:167-175.
33.
Collard HR, Calfee CS, Wolters PJ, Song JW, Hong SB, Brady S, Ishizaka A, Jones KD, King TE Jr, Matthay MA, Kim DS: Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010;299:L3-L7.
34.
Satoh H, Kurishima K, Ishikawa H, Ohtsuka M: Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med 2006;260:429-434.
35.
Lasithiotaki I, Antoniou KM, Vlahava VM, Karagiannis K, Spandidos DA, Siafakas NM, Sourvinos G: Detection of herpes simplex virus type-1 in patients with fibrotic lung diseases. PLoS One 2011;6:e27800.
36.
Wootton SC, Kim DS, Kondoh Y, Chen E, Lee JS, Song JW, Huh JW, Taniguchi H, Chiu C, Boushey H, Lancaster LH, Wolters PJ, DeRisi J, Ganem D, Collard HR: Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:1698-1702.
37.
Zhang Y, Kaminski N: Biomarkers in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2012;18:441-446.
38.
Tachibana K, Inoue Y, Nishiyama A, Sugimoto C, Matsumuro A, Hirose M, Kitaichi M, Akira M, Arai T, Hayashi S, Inoue Y: Polymyxin-B hemoperfusion for acute exacerbation of idiopathic pulmonary fibrosis: serum IL-7 as a prognostic marker. Sarcoidosis Vasc Diffuse Lung Dis 2011;28:113-122.
39.
Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H: Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475-1482.
40.
Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA: Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:88-95.
41.
Tzouvelekis A, Margaritopoulos G, Loukides S, Bouros D: Warfarin in idiopathic pulmonary fibrosis: friend or foe, is it a matter of genes and heparin? Am J Respir Crit Care Med 2013;187:213-214.
42.
Raghu G, Meyer KC: Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012;39:242-245.
43.
Tcherakian C, Cottin V, Brillet PY, Freynet O, Naggara N, Carton Z, Cordier JF, Brauner M, Valeyre D, Nunes H: Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease. Thorax 2011;66:226-231.
44.
Lee JS, Song JW, Wolters PJ, Elicker BM, King TE Jr, Kim DS, Collard HR: Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 2012;39:352-358.
45.
Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C: Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res 2013;14:73.
46.
Ling VY, Mortimore M, Serisier DJ: Suspected acute exacerbation of idiopathic pulmonary fibrosis associated with interferon alpha therapy for hepatitis C: case report. Springerplus 2013;2:101.
47.
Malouf MA, Hopkins P, Snell G, Glanville AR, Everolimus in IPF Study Investigators: An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis. Respirology 2011;16:776-783.
48.
Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, Pego-Reigosa JM, Retamozo S, Bove A, Brito-Zeron P, Bosch X, Ramos-Casals M: Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum 2011;41:256-264.
49.
Park IN, Kim DS, Shim TS, Lim CM, Lee SD, Koh Y, Kim WS, Kim WD, Jang SJ, Colby TV: Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest 2007;132:214-220.
50.
Olson AL, Huie TJ, Groshong SD, Cosgrove GP, Janssen WJ, Schwarz MI, Brown KK, Frankel SK: Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series. Chest 2008;134:844-885.
51.
Suda T, Kaida Y, Nakamura Y, Enomoto N, Fujisawa T, Imokawa S, Hashizume H, Naito T, Hashimoto D, Takehara Y, Inui N, Nakamura H, Colby TV, Chida K: Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases. Respir Med 2009;103:846-853.
52.
Churg A, Wright JL, Tazelaar HD: Acute exacerbations of fibrotic interstitial lung disease. Histopathology 2011;58:525-530.
53.
Baughman RP: Use of bronchoscopy in the diagnosis of infection in the immunocompromised host. Thorax 1994;49:3-7.
54.
Wells AU: The clinical utility of bronchoalveolar lavage in diffuse parenchymal lung disease. Eur Respir Rev 2010;19:237-241.
55.
Richter AG, Stockley RA, Harper L, et al: Pulmonary infection in Wegener granulomatosis and idiopathic pulmonary fibrosis. Thorax 2009;64:692-697.
56.
Shimizu Y, Sunaga N, Dobashi K, et al: Serum markers in interstitial pneumonia with and without Pneumocystis jirovecii colonization: a prospective study. BMC Infect Dis 2009;9:47.
57.
Shulgina L, Cahn AP, Chilvers ER, et al: Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial. Thorax 2013;68:155-162.
58.
Maher TM, Wells AU: If it was good enough for Aristotle... Thorax 2011;66:183-184.
59.
Suzuki H, Sekine Y, Yoshida S, Suzuki M, Shibuya K, Yonemori Y, Hiroshima K, Nakatani Y, Mizuno S, Takiguchi Y, Yoshino I: Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography. Surg Today 2011;41:914-921.
60.
Sakamoto K, Taniguchi H, Kondoh Y, Wakai K, Kimura T, Kataoka K, Hashimoto N, Nishiyama O, Hasegawa Y: Acute exacerbation of IPF following diagnostic bronchoalveolar lavage procedures. Respir Med 2012;106:436-442.
61.
Churg A, Müller NL, Silva CI, Wright JL: Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol 2007;31:277-284.
62.
Bhatti H, Girdhar A, Usman F, Cury J, Bajwa A: Approach to acute exacerbation of idiopathic pulmonary fibrosis. Ann Thorac Med 2013;8:71-77.
63.
Morawiec E, Tillie-Leblond I, Pansini V, Salleron J, Remy-Jardin M, Wallaert B: Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J 2011;38:1487-1489.
64.
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klüglich M, du Bois RM: Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079-1087.
65.
Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts R, Yow E, Raghu G: Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomized controlled trials. Lancet Respir Med 2013;1:369-376.
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