Respiratory Medicine CME
Volume 1, Issue 1 , Pages 43-47, 2008

Initial presentation of idiopathic pulmonary fibrosis as an acute exacerbation

  • Krishna M. Sundar

      Affiliations

    • Department of Medicine, Utah Valley Pulmonary Clinic, 1055N, 300W, Suite 500, Provo, UT 84604, USA
    • Department of Medicine, University of Utah Medical Center, Salt Lake City, UT, USA
    • Corresponding Author InformationCorresponding author. Departments of Medicine, Utah Valley Pulmonary Clinic, 1055N, 300W, Suite 500, Provo, UT 84604, USA.
    • ,
  • Dixie L. Harris

      Affiliations

    • Department of Medicine, Utah Valley Pulmonary Clinic, 1055N, 300W, Suite 500, Provo, UT 84604, USA

Received 10 September 2007; accepted 1 November 2007.

Article Outline

Summary 

Two cases presenting as an acute exacerbation of idiopathic pulmonary fibrosis (IPF) are presented. Both patients had good response to corticosteroids and exhibited the underlying pathology of organizing pneumonia superimposed on usual interstitial pneumonia. The challenges with diagnosing an IPF exacerbation in patients with previously unknown IPF are discussed. The impact of underlying histopathology during an exacerbation on patient outcomes is also discussed.

Keywords: Idiopathic pulmonary fibrosis, Organizing pneumonia, Acute exacerbation

 

Rapid clinical deterioration in patients with idiopathic pulmonary fibrosis (IPF) has been increasingly recognized over the past decade.1, 2, 3, 4 This “acute exacerbation” of IPF is characterized by accelerated deterioration in lung function and is fatal in a significant proportion of affected patients.1, 2, 4 Most reports to date have emphasized the occurrence of acute exacerbations in patients with known IPF.4 This report highlights the initial presentation of IPF as an acute exacerbation discussing the diagnostic challenges encountered in this setting. It also discusses the impact of lung histopathology on patient outcomes from an acute IPF exacerbation.

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Case 1 

A 69-year old male was admitted with worsening shortness of breath and a dry nonproductive cough occurring over a 3-week period. He had complaints of mild exertional dyspnea for 2 years prior to this. The patient was a non-smoker but gave a history of diesel, asbestos and fiberglass exposure. His examination was remarkable for severe hypoxemia, tachypnea and bibasilar inspiratory crackles on chest auscultation. Laboratory studies revealed leucocytosis with normal hemoglobin and albumin levels. Antinuclear antigen (ANA), antineutrophilic cytoplasmic antibody (ANCA), Jo-1 antibody, Scl-70, anti-citrullinated antibody and mycoplasma titers were negative. Rheumatoid factor (RF) and C-reactive protein (CRP) levels were markedly elevated. Computed tomography (CT) of the chest showed bilateral ground-glass opacities with ill-defined reticular changes (Figure 1A). The patient declined to undergo a surgical or bronchoscopic biopsy and was empirically started on high-dose corticosteroids (methylprednisolone 240mg/day) and antibiotics for community-acquired pneumonia. His condition improved, and he was discharged on a tapering dose of prednisone over the next 8 weeks. CRP levels normalized and his RF titers fell from 27 to 17U (normal 0–14IU/mL).

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  • Figure 1. 

    Serial chest HRCT scans in Case 1. (A) During first acute IPF exacerbation. (B) Following resolution of first IPF exacerbation showing peripheral reticular opacities suggestive of UIP pattern. (C) During second IPF exacerbation showing new ground-glass opacities.

During follow-up, his respiratory status improved (Graph 1), and chest CT scans showed resolution of ground-glass opacities but peripheral reticular changes suggestive of an underlying usual interstitial pneumonia (UIP) were noted (Figure 1B). Nine months later, he presented with a weeklong history of exertional dyspnea and nonproductive cough. Chest CT scans showed superimposition of ground-glass opacities with peripheral honeycombing (Figure 1C). Laboratory studies showed elevation of CRP values and leucocytosis with a left shift. RF titers were increased to 45IU/mL and Chlamydia pneumoniae IgG titers were at 1:256. Bronchoalveolar lavage (BAL) revealed 48% lymphocytes, 35% macrophages and 10% neutrophils without any growth of a specific pathogen. He was treated with high-dose corticosteroids and intravenous azithromycin with an excellent response. On follow-up, he had an improvement in his pulmonary function tests (Graph 1). A video-assisted thoracoscopic surgical (VATS) biopsy done 3 months later showed changes of UIP with numerous fibroblastic foci and patchy organizing pneumonia (Figure 2A and B).

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  • Graph 1. 

    Pulmonary function tests (PFTs) showing improvement to baseline following resolution of first acute exacerbation and worsening during second IPF exacerbation. Arrows point to timing of the exacerbations.

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  • Figure 2. 

    Surgical biopsy from Case 1. Panel (A): At scanning magnification the characteristic temporal heterogeneity of UIP is evident, with fibrosis encircling lobules and normal lung present at lobule centers (nl). Fibroblast foci are present and there are areas with metaplastic bone (b), the latter a manifestation of chronicity. Panel (B): Scattered throughout the biopsy were areas of organizing pneumonia pattern (o) subacute lung injury, occupying lobules to variable degree and accompanied by squamous metaplasia of the terminal airways (m). Microscopic honeycombing is present (mhc). Hematoxylin and eosin stain. Panel (A): 12.5× original magnification; Panel (B): 40× original magnification.

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Case 2 

A 71-year old white female presented with increasing dyspnea and a nonproductive cough for a 3-week period. She was admitted with resting room air hypoxemia, and bilateral diffuse ground-glass opacities on chest radiographs. She denied any prior history of smoking or inhalational exposures. Laboratory studies revealed normal CBC, ESR of 46mm/h and a negative serological workup for connective tissue diseases and atypical pneumonia. CT scans of the chest showed interlobular septal thickening in lower lobes with diffuse patchy areas of ground-glass opacities (Figure 3). BAL from multiple lung lobes revealed 50–60% macrophages, 30–45% lymphocytes and 10% neutrophils. Pulmonary function tests revealed FVC of 1.67L (52% predicted), FEV1/FVC ratio of 87%, DLCO of 4.5mL/mmHg/min (18% predicted). A VATS biopsy revealed features of organizing pneumonia superimposed on a background of UIP (Figure 4A and B). Patient was placed on high-dose steroids with good clinical response, and follow-up pulmonary function tests a month later showed improvement in FVC to 1.96L and DLCO to 10.5mL/mmHg/min.

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  • Figure 4. 

    Surgical biopsy from Case 2. Panel (A): At scanning magnification the UIP pattern is evident with microscopic honeycomb remodeling (mhc) alternating with areas of uninvolved lung (nl). Patchy areas of organizing pneumonia pattern are present within lobules (o), accompanied by mild chronic inflammation. Panel (B): At higher magnification organizing pneumonia pattern is seen (o) with associated mild chronic inflammation (i) extending into adjacent alveolar walls. Hematoxylin and eosin stain. Panel (A): 12.5× original magnification; Panel (B): 100× original magnification.

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Discussion 

Acute exacerbations of IPF are characterized by the occurrence of acute lung injury superimposed on preexisting UIP.3 The exact nature of the acute injury appears to be variable, ranging from diffuse alveolar damage (DAD) to organizing pneumonia.5 Acute exacerbations impact the natural history of IPF significantly, and this has been better appreciated in the last decade. Based on historical data, patients with IPF live less than 2 years following their diagnosis, although considerable variation occurs in the disease course for individual patients.6 Progression of disease with development of honeycombed end-stage lung was traditionally believed to be the main reason for respiratory failure in a study that summarized the causes of death in 326 IPF patients from six studies.7 A recent study, however, showed that 47% of deaths in patients with early lung impairment (FVC>50%) occurred due to acute respiratory deteriorations.8 Because the concept of acute exacerbation of IPF has evolved relatively recently, it is difficult to say how many IPF deaths in previous analyses were due to acute exacerbations.7 Moreover, consensus-derived pathologic definitions of the idiopathic interstitial lung diseases have been agreed upon only in the last decade, making it difficult to adequately separate true IPF patients from other interstitial diseases in prior series.9 There is also no agreement on the clinical or pathologic definition of an acute IPF exacerbation. Currently used criteria include: (1) development of clinical deterioration over 1 month, (2) occurrence of new radiographic opacities and (3) exclusion of other possible etiologies such as infection, medication toxicity, thromboembolic disease and heart failure.1, 2, 3, 4

We describe two patients with previously undiagnosed IPF who presented with acute exacerbations. Both of these patients were diagnosed with underlying IPF only after adequate histopathological specimens were obtained after extensive workups for infectious and non-infectious causes had been performed. Although a prior history of chronic cough and dyspnea were elicited, no other clinical finding was found to suggest the possibility of preexisting IPF in either patient. Even though CT scans were suggestive of ill-defined reticular abnormalities, none of these patients had peripheral honeycombing or traction bronchiectasis.

In patients with IPF exacerbations, infectious pneumonia remains a particular concern. In the study by Panos et al. of 543 patients, only 2–4% of patients had documented respiratory infections.7 In other studies looking at the incidence of infection in IPF patients with acute respiratory failure, rates of infectious pneumonia have varied and it is unclear how many of these documented infections occurred nosocomially.10, 11 BAL is commonly performed to exclude infection in patients in those who can tolerate this procedure. Although one report has emphasized the predominance of neutrophils in the BAL of patients with acute IPF exacerbations,4 this was not present in either of our patients.

The pathology in both our cases was that of organizing pneumonia superimposed on underlying IPF. DAD has been the predominant superimposed abnormality in other published studies on patients with IPF exacerbations,3 although a recent study by Churg et al. has shown the occurrence of significant proportion of superimposed organizing pneumonia in patients with UIP.5 Although previous studies on IPF exacerbations showed a high mortality rate,2, 3, 4 this has not been borne out in reports on IPF exacerbations with the underlying pathology of superimposed organizing pneumonia on UIP.5, 12 Both our patients exhibited the pathology of UIP with superimposed organizing pneumonia with a good clinical response to corticosteroids. It can be argued that Case 1 could have started out with the pathology of superimposed DAD as the VATS lung biopsy was done quite late in the course of his exacerbation. However, his dramatic response to steroids, and the lack of corroborating features to suggest a fibroproliferative DAD, makes superimposed organizing pneumonia the likelier pathologic process underlying the exacerbation. Whether underlying histopathologic patterns during an acute exacerbation reflect different triggers and therefore different pathobiological bases remain unknown. A study looking at the finding of organizing pneumonia in transbronchial biopsies from patients with IPF found that patients exhibiting such change had a subacute disease onset, and a good response to steroids.13 Unfortunately, the lack of adequate surgical biopsy specimens and inadequate radiological information on these patients make interpretation of this study results difficult.13 Acute interstitial pneumonia (AIP) was an important diagnostic consideration in both of our patients. Unlike IPF exacerbations, patients with AIP tend to be younger and have a subacute course with a shorter duration of respiratory symptoms.14 Laboratory and radiological abnormalities are very similar in patients with AIP and IPF exacerbations, making their differentiation difficult, especially in patients without previously documented IPF.14 The finding of honeycombing has been reported in fibrotic late stages of AIP,15 and it may be difficult to distinguish AIP from acute IPF exacerbations unless extensive honeycombing is noted on CT scans at initial presentation that indicates underlying UIP.

Acute IPF exacerbations remain unpredictable occurrences in patients with IPF that cause significant morbidity and mortality. Unlike COPD exacerbations that are easily recognized even in patients without previously diagnosed COPD, exacerbations of interstitial disease remain difficult diagnostic and management problems. A high index of suspicion is necessary to make a diagnosis in elderly patients without known IPF who present with diffuse air-space disease that does not improve with therapies directed at infectious pneumonia or other specific etiologies.

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Conflicts of interest 

The authors report no conflict of interest with companies/organizations whose products or services may be discussed in this article.

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Acknowledgments 

The authors are grateful to Dr. Kevin Leslie, Professor of Pathology, Mayo Clinic, Scottsdale, Arizona, for his review and preparation of the pathology slides and comments on the manuscript.

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References 

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PII: S1755-0017(07)00010-3

doi:10.1016/j.rmedc.2007.11.004

Respiratory Medicine CME
Volume 1, Issue 1 , Pages 43-47, 2008

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