Is it heart failure or multilobar pneumonia?
An 82-year-old lady with hypertension and hyperlipidaemia presented with 2 weeks’ history of increasing breathing difficulty. She had flu-like illness 2 weeks ago with some residual dry cough. Physical examination showed low-grade fever of 37.8°C with mildly elevated jugular venous pressure and mild pedal oedema. There was no obvious murmur, and chest auscultation revealed bilateral basal crepitations. Her blood pressure was 130/80 mm Hg. She required oxygen 1 L/min to maintain blood oxygen saturation level (SpO2) of 94 percent.
Clinical and laboratory investigations
Blood tests showed white blood cell (WBC) count of 11,000/µL and C-reactive protein (CRP) level of 5.5 mg/L. Results of liver and renal function tests were normal. N-terminal pro-B type natriuretic peptide (NT-proBNP) was elevated to 711 pg/mL (acute heart failure possible at 300–1,800 pg/mL). Troponin I was normal, and ECG was unremarkable. Chest X-ray showed perihilar and some peripheral ground-glass opacities with increased cardiothoracic ratio. Mild blunting of costophrenic angles were noted, suggestive of mild pleural effusion. (Figure 1)
The patient was started on the angiotensin II receptor agonist furosemide, along with antibiotics including ertapenem and azithromycin, but her condition did not improve with treatment. Nasopharyngeal swab for respiratory panel was negative. Urine tests for Legionella and pneumococcal antigens were negative. Sputum was negative for bacterial culture and acid-fast bacilli (AFB) smear. Serial ECG and cardiac enzymes were unremarkable. Echocardiogram showed normal ejection fraction with moderate-to-severe aortic regurgitation. Autoimmune antibodies including antinuclear antibodies (ANA), rheumatoid factor (RF), antibodies to extractable nuclear antigens (anti-ENA) and antineutrophil cytoplasmic antibodies (ANCA) were negative.
The patient’s condition gradually deteriorated, requiring oxygen 2 L/min to maintain saturation while worsening respiratory rate and chest X-ray shadow were noted. Her WBC count had increased from 11,000/µL to 13,000/µL, while CRP had increased to 50 mg/L. NT-proBNP was around 1,000 pg/mL.
Low-dose CT thorax on day 4 showed multiple mixed ground glass opacities and peripheral consolidations. (Figure 2)
Bronchoscopy on day 5 showed essentially normal airways. Bronchoalveolar lavage (BAL) fluid was obtained at the right lower lobe, with normal saline 180 mL instilled in three aliquots. Around 70 mL of straw-coloured lavage fluid was returned. Increased lymphocyte count was noted (neutrophils, 6 percent; lymphocytes, 63 percent; macrophages, 23 percent; eosinophils, 5 percent; basophils, 2 percent). Lavage fluid for culture, Gram stain and polymerase chain reaction (PCR) tests for respiratory viruses and bacteria were negative. AFB smear and cytology were negative.
Transbronchial biopsy taken at the right lower lobe showed buds of granulation tissue occupying alveoli and bronchioles. There was no granuloma formation, interstitial inflammation or vasculitic changes.
The patient and her daughter declined surgical lung biopsy after considering the clinical features, BAL finding and biopsy finding. She was treated as having cryptogenic organizing pneumonia (COP) with prednisolone 40 mg every morning. Her dyspnoea and lung shadow showed gradual improvement after 2 weeks. (Figure 3)
The term COP was first used by Davison in 1983 to describe eight cases of idiopathic intra-alveolar organization treated successfully with steroid.1 It was almost identical to the pathological description of bronchiolitis interstitial pneumonia by Liebow and Carrington in 1969 and reports of obliterative bronchiolitis organizing pneumonia (BOOP) by Epler in 1985.2,3
The term COP is preferred over BOOP in a joint statement published by the American Thoracic Society and European Respiratory Society in 2013.4 Patients with COP typically present with subacute illness of relatively short duration (median, <3 months), with variable degrees of cough, dyspnoea or influenza-like illness. CT characteristically show patchy and often migratory consolidation in subpleural, peribronchial or band-like pattern, commonly associated with ground-glass opacity. Perilobular opacities and reversed halo sign may be helpful in diagnosis. However, COP could appear focal or interstitial or can be associated with effusion, making radiological diagnosis difficult.
BAL is commonly used for investigation of diffuse infiltrative lung disease with nondiagnostic CT. Increased mixed cellularity with lymphocyte count around 25–50 percent and lymphocytes more than eosinophils would be typical of COP.5 In contrast, increased eosinophil count of >25 percent is typical of eosinophilic pneumonia, and lymphocyte count of >50 percent is typical of drug reaction or hypersensitivity pneumonitis. However, BAL finding is highly variable and, as in our case, increased lymphocyte count of >50 percent suggested drug reaction, cellular nonspecific interstitial pneumonia or hypersensitivity pneumonitis. All these did not fit well with the patient’s clinical history, CT finding or biopsy result and subsequent clinical course.
Transbronchial biopsy may reveal a typical histology of COP. However, the finding can be misleading as the lung tissues obtained are usually small, and COP can be associated with other types of interstitial pneumonia. In case of doubt, surgical lung biopsy is preferred. Presence of alveolar buds of granulation tissue with or without extension to bronchioles is typical of COP. Presence of granuloma would suggest an alternative diagnosis of hypersensitivity pneumonitis. Marked interstitial inflammation, eosinophilic infiltrate or vasculitic changes should also prompt consideration of an alternative diagnosis instead of COP.
Our patient continued to improve with steroid after 6 months, with an episode of relapse during steroid weaning that responded to resumption of higher-dose steroid. She remained symptom-free with all opacities resolved on her latest follow-up.