2007 NDH - "What Lies Beneath?"
Dr. CM Wong, Dr. WK Lam, Dr. Choo Kah Lin and Dr. Wong Kwan Keung
Department of Medicine, North District Hospital
Case History
Mr. Liu is an 82-year-old gentleman who presented to our unit in June 2006. He was an ex-smoker and retired soldier. The patient had a spinal cord infarct in 1993 resulting in bilateral spastic paraparesis and neurogenic bladder. He also had hypertension, duodenitis, reflux oesophagitis, hiatus hernia, urethral stricture and history of appendicectomy. He was on long term methyldopa, famotidine, baclofen and gabapentin (the listed medications have no known association with drug-induced interstitial pneumonia) for his medical conditions.
He was admitted to our unit on 17th June 2006 and presented with shortness of breath for few days. There was no history of cough, sputum or fever. He also did not have chest pain, orthopnoea or ankle oedema. There was no history of malar rash, discoid rash, photosensitivity, oral ulcer, arthralgia, myalgia, dysphagia or Raynaud’s phenomenon. He had no occupational exposure to silica or asbestos. He did not keep birds or pets. There was no recent travel history or poultry contact.
On admission, the blood pressure was 160/70 mmHg and pulse rate was 65 beats per minute. Oxygen saturation was 93 % while the patient was breathing 100 % oxygen via the non-rebreathing mask. The body temperature was 36.5 degree Celsius. On examination, there was bilateral fine basal crepitations on auscultation. There was no cardiac murmur or lower limb oedema. Jugular venous pressure was not elevated. There was no finger clubbing, joint swelling/ deformity, sclerodactyly or skin rash. Other parts of physical examination were unremarkable. Urine dipstix was trace for protein and negative for blood. Baseline blood test results on admission:
Haematology results
WCC: 10 (Neu 7.7) x 109/l ↓Hb: 12.5 g/dl (NcNc) PLT: 342 x 109/l
PT: 11.2 s APTT 35.4 s INR 1.0
Biochemical results
ABG: ↑pH 7.47, pCO2 4.85 kPa, pO2 13.09 kPa, BE 2.2 mmol/l, HCO3 25.8 mmol/l, SaO2 98 % (FiO2 1.0), ↓PaO2: FiO2 ratio: 98.4 mmHg
RFT: Na 129, K 4.3, Urea 5.0 mmol/l, Cr 55 µmol/l
LFT: Bil 8 ↓Alb 31, Globulin 41 g/dl, ALP 111, ALT 20 U/ml
CK 28, ↑LDH 321 U/ml
Spot glucose 5.3 mmol/l
Chest radiography (CXR) on admission showed bilateral diffuse ground glass opacity and reticulonodular shadowing bilaterally (Fig. 1). Electrocardiogram was normal. Echocardiogram demonstrated normal left ventricular ejection fraction 76.8 % and normal left ventricular size. No other abnormalities were identified.
He was initially managed as severe community acquired pneumonia and given amoxicillin/clavulanate and azithromycin intravenously. Amoxicillin/clavulanate was changed to cefotaxime on day 2 of admission. Patient however remained apyrexic during hospital stay. Sputum grew oral commensals only. The acid fast bacilli smear and culture were negative for three times. Blood culture did not yield any organism.
Old chest radiographs in 1999, 2002 and 2004 were traced, showing progressively increased bilateral lower zone reticular shadowing. High resolution computerized tomography (HRCT) of thorax on day 2 of admission showed subpleural fibrosis with honeycombing at bilateral lung bases which was associated traction bronchiectasis. There were ground glass opacities in both lungs and which was predominant in upper zones. There was mild bilateral pleural effusion (Fig. 2).
Further blood tests:
RF –ve
ANA +ve Titre 640
Anti-ENA –ve (Sm –ve , RNP –ve , La –ve , Ro –ve , Jo-1 –ve , Scl-70 –ve )
ANCA +ve, Anti-PR3 normal, Anti-MPO normal
VDRL: -ve
Histological diagnosis was not made as the patient refused bronchoscopy and surgical lung biopsy. In view of progressive bilateral lower zone reticular shadowing over the past few years, ground glass opacities with underlying usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis on HRCT thorax, and absence of evidence suggesting infections and connective tissue diseases, the clinical diagnosis at that juncture was acute exacerbation of idiopathic pulmonary fibrosis (IPF). The patient was given methylprednisolone 1 g intravenously for 3 consecutive days since day 4 of admission which was then followed by prednisolone 60 mg daily.
The patient improved both clinically and radiologically and was transferred to convalescence hospital for rehabilitation on day 10 of admission. Oxygen was eventually weaned off. He was followed up in our outpatient respiratory clinic and prednisolone was tailed down to 10 mg daily together with addition of azathioprine 25 mg daily. Physical examination on follow-up showed the normal power of the upper limbs with no proximal muscle weakness. HRCT thorax at 3 months showed that the ground glass opacities had already resolved with residual subpleural fibrosis and traction bronchiectasis (Fig. 3).
Discussion
Idiopathic pulmonary fibrosis is clearly defined as one of the most common form of idiopathic interstitial pneumonia by international guidelines. It is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lung with histological pattern of UIP. (2)
The clinical course of IPF is traditionally believed to be chronic and slowly progressive. However, rapid deterioration during the course of illness can sometimes be observed. Martinez and colleagues demonstrated in IPF patients the change of physiological (forced vital capacity, diffusion capacity for carbon monoxide, alveolar-arterial gradient) and functional parameters (Transition Dyspnoea Score and Shortness of Breath Questionnaire) were minimal over a median period of 76 weeks. However, twenty-three percent of them required hospitalization for acute respiratory disorder and 21 % died. Idiopathic pulmonary fibrosis was the major cause of death in 89 % of patients who died, and acute exacerbation of the illness preceded death in 47 % of these patients. (3) Therefore, the disease may be less gradual decline and more a step-like process, with periods of relative stability punctuated by periods of acute decompensation. The disease carried high mortality with median survival from 2 to 4 years.
Kondoh et al has proposed the diagnostic criteria for acute exacerbation of IPF. It included aggravation of dyspnoea within 1 month, hypoxaemia with arterial oxygen tension to inspired oxygen tension ratio of less than 225 mmHg, newly developing pulmonary infiltrates on chest radiography and absence of apparent infection or heart disease. (4) Kim and colleagues showed that the 2-year frequency of acute exacerbation of IPF was 9.6 %. Most of the cases were idiopathic and no significant risk factor was identified. (5) The clinical features included rapidly progressive dyspnoea, cough, scanty sputum, fever, inspiratory crackles and clubbing. (4-6) Laboratory findings were characterized by hypoxaemia (PaO2/FiO2 70-144 mmHg), elevated inflammatory markers (white cell count, erythrocyte sedimentation rate, C-reactive protein), lactate dehydrogenase, fibrinogen, cancer antigen 19-9 and thrombocytopenia. (4-6) High resolution CT thorax may show one of three radiological patterns that included diffuse, multifocal and peripheral pattern. The peripheral pattern was associated with a better prognosis. (5) When bronchoscopy was performed in patient with acute exacerbation of IPF, bronchoalveolar lavage was characterized by marked neutrophilia (11-90 %), raised albumin (139-357 µg/ml) and type II reactive cells. (4, 6) Histology may show various combination of typical UIP and diffuse alveolar damage (DAD) area (DAD:UIP area ratio 3:1-1:1.5) and some of them may have hyaline membranes as well. Other histological features included type II pneumocyte hyperplasia, fibroblastic foci, organizing pneumonia and haemorrhage with capillaritis. (4-6) Acute interstitial pneumonia (Hamman-Rich syndrome) was the one of the important differential diagnosis in this disease entity. It was the most common form of rapidly progressive diffuse interstitial lung disease characterized by DAD on lung biopsy. Distinguishing acute exacerbation of IPF from acute interstitial pneumonia hinges on recognition of underlying UIP in the former.
While histology can facilitate the diagnosis of various forms of interstitial lung disease, the safety of surgical lung biopsy has been debated. In Kim’s study, two of the 11 patients with acute exacerbation developed the exacerbation shortly after surgical lung biopsy. (5) The short-term mortality rate (16.7 %) after surgical lung biopsy was higher in patients with IPF, compared with the mortality rate of 1.7 % in 771 unselected patients undergoing surgical lung biopsy at the same institution. (7) Kondoh and colleagues investigated 236 consecutive patients with interstitial pneumonia who underwent surgical lung biopsy. There were 5 patients (2.1 %) (IPF 3; non-specific interstitial pneumonia 1; cryptogenic organizing pneumonia 1) who developed acute exacerbations 1-18 days after surgical lung biopsy. (8) Lettieri and his colleagues had conflicting results concerning the safety of surgical lung biopsy. They found that among patients with IPF, death following surgical lung biopsy was rare and did not differ statistically from the mortality observed in patients with non-IPF interstitial lung disease. (9)
Bronchoalveolar lavage (BAL) had been reported to cause acute exacerbation of IPF. Hiwatari investigated 124 IPF who underwent BAL, three patients (2.4 %) developed acute exacerbation of IPF immediately after the procedure. In contrast, no deteriorations after BAL observed in 282 patients with other pulmonary diseases in the same period. Therefore, BAL sometimes induced a progressive deterioration in IPF patients. (10)
There was no treatment guideline for acute exacerbation of IPF. Most of the studies included high dose corticosteroids and broad-spectrum antibiotics as the mainstay of treatment though it was not effective most of the time. In Kim’s study, all patients were treated with broad-spectrum antibiotics and high dose corticosteroids. The mortality rate was 81.8 %. (5) Ambrosini et al reviewed 5 patients with acute exacerbation of IPF who all treated with high dose methylprednisolone 500-1000 mg daily for three days and cyclophosphamide. They yielded a similar mortality rate of 80 %. (6)
In view of limited effectiveness of corticosteroids and cyclophosphamide, other immunosuppressive agents were investigated. Inase and colleagues examined the effect of cyclosporin A on acute exacerbation of IPF. In their study, all 13 patients received pulse-therapy with methylprednisolone (1000 mg/day for 3 days), followed by oral prednisolone (40-60 mg/day). Seven patients were given additional cyclosporine A (1-2 mg/day). Those treated with cyclosporin A had a trend of better survival rate. (11) Homma et al reported a significantly better survival for those patients with acute exacerbation of IPF received cyclosporin A when compared to historical cohort. (12) In a 3-year prospective and controlled study, Kubo and colleagues investigated the role of anticoagulation on clinical course and mortality of IPF. Treatment group received prednisolone plus warfarin as outpatient. Warfarin was replaced by low-molecular weight heparin if they were hospitalized. Control group received prednisolone alone. Although rate of readmission due to acute exacerbation was similar, treatment group had significantly decreased mortality associated with acute exacerbation (18 %) when compared to control group (71 %). (13) Azuma et al performed a randomized, double-blinded, placebo-controlled study on the use of antifibrotic agent pirfenidone in IPF. Acute exacerbations occurred in 5 (14 %) out of 35 patients in placebo group but in none of the 72 patients receiving pirfenidone during follow-up. The trial was aborted early at 6 months by the data safety and monitoring board because of this finding despite this is only a secondary end-point of the study. (14) Therefore the promise of an effective therapy for IPF exacerbations may holds in preventing their occurrence rather than treatment of acute episodes.
Although IPF is considered to be a chronic and progressive disease, it must be noted that some patients with IPF experienced acute exacerbation during their clinical course, and our case was not exceptional. Further studies are required to answer the underlying pathogenesis as well as the effective therapeutic approach for this disease entity.
References:
- Lim MK, Im JG, Ahn JM, et al. Idiopathic pulmonary fibrosis vs. pulmonary involvement of collagen vascular disease: HRCT findings. J Korean Med Sci 1997; 12:492-498
- American Thoracic Society, European Thoracic Society. American Thoracic Society/ European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165:277-304
- Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142:963-967
- Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993; 103:1808-1812
- Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006; 27:143-150
- Ambrosini V, Cancellieri A, Chilosi M, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 2003; 22:821-826
- Allen MS, Deschamps C, Jones DM, et al. Video-assisted thoracic surgical procedures: the Mayo experience. Mayo Clin Proc 1996; 71:351-359
- Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006; 100:1753-1759
- Lettieri CJ, Veerappan GR, Helman DL, et al. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005; 127:1600-1605
- Hiwatari N, Shimura S, Takishima T, et al. Bronchoalveolar lavage as a possible cause of acute exacerbation in idiopathic pulmonary fibrosis patients. Tohoku J Exp Med. 1994; 174:379-386
- Inase N, Sawada M, Ohtani Y, et al. Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid. Intern Med 2003; 42:565-70
- Homma S, Sakamoto S, Kawabata M, et al. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med 2005; 44:1144-50
- Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128:1475-1482
- Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171:1040-1047
