A previously healthy 2-year-old boy presented with a 1-month history of cough and dyspnea. He had had a mild cough for 1 week before a sudden deterioration in his condition. The dyspnea increased despite treatment, and he was transferred to the Department of Pediatrics at the Asan Medical Center for further management. On arrival, he was apyrexial and tachypneic (respiratory rate, 66/min). Mild subcostal retraction was observed, and coarse breath sounds without crackles were noted on auscultation. Arterial blood gas analysis (ABGA) showed mild hypoxemia. His white blood cell (WBC) count was 14,300/µL, with 55.8% neutrophils and 36.3% lymphocytes. Radiography and computed tomography (CT) of the chest revealed the presence of fine peribronchial ground-glass opacities in both lungs (Fig. 1A and 1B). Blood, bronchoalveolar lavage (BAL) fluid, and sputum cultures were negative for bacteria, viruses, and fungi. A lung biopsy performed on day 3 of admission showed the organizing phase of DAD distributed mainly in the centrilobular area, with destruction and obliteration of bronchioles by fibroblasts (Fig. 1E). The patient was administered intravenous corticosteroids (2 mg/kg/day), followed by oral prednisolone (which was gradually tapered), hydroxychloroquine, and oral cyclophosphamide. His condition gradually improved, although exercise intolerance persisted. At the 1-year follow-up, a repeat CT scan of the chest revealed a decrease in the extent of ground-glass opacities in the affected areas of both lungs (Fig. 1C and 1D).

A previously healthy 47-year-old non-smoking male patient presented with a 2-day history of cough, mucoid sputum, and chills. His son was hospitalized with the same symptoms at the same time. On physical examination, he was apyrexial, tachycardic, and tachypneic, and rales were audible over the left lung field on auscultation. Chest radiography showed diffuse hazy patches in the left lung, and a chest CT scan revealed the presence of multifocal consolidation and diffuse centrinodular ground-glass opacities in both lungs. Laboratory findings included a normal WBC count, an elevated erythrocyte sedimentation rate (ESR) of 42 mm/hr, an elevated C-reactive protein (CRP) level of 5.19 mg/dL, and a normal ABGA. Laboratory tests for collagen disease and vasculitis were negative. Blood, sputum, and BAL fluid cultures were negative for bacteria, viruses, and fungi. Lung biopsy, performed on day 11 of admission, showed histological features of fibroproliferative DAD with diffuse interstitial fibrosis and relative sparing of the peripheral lobular air spaces. The patient required mechanical ventilation for a total of 36 days. He was administered broad-spectrum antibiotics and high-dose corticosteroids. On discharge, he still experienced dyspnea on exertion and required intermittent oxygen at night and on exertion. At the 1-year follow-up, radiography and a CT scan revealed a decrease in the degree of bronchial dilatation and peribronchial consolidation; the patient still complained of dyspnea on exertion.

A previously healthy 35-month-old girl was referred to our medical center for severe dyspnea. Four weeks prior to admission, she had developed a mild cough, and her oral intake had become poor. Four days prior to admission, she had developed sudden onset dyspnea and subcutaneous emphysema. On admission, she presented with marked tachypnea (respiratory rate, 80/min) and chest retraction, and rales were audible in both lungs on auscultation. Radiography and a CT scan of the chest showed an extensive pneumomediastinum, a pneumothorax in the right hemithorax, and diffuse ground-glass opacities with consolidation in both lungs (Fig. 2A and 2B). Her total leukocyte count was 9,300/µL, with 66% neutrophils and 27% lymphocytes. Blood, sputum, and BAL cultures for bacteria and fungi were negative. Multiplex RT-PCR of nasopharyngeal aspirates revealed the presence of respiratory syncytial virus (RSV). She was admitted to the intensive care unit and treated with steroids, cyclophosphamide, hydroxychloroquine, and broad-spectrum antibiotics. Her response to treatment was poor, and her condition deteriorated rapidly. On the third day of admission, mechanical ventilation was required for impending respiratory failure. Repeated chest radiography revealed the presence of increased opacities in both lungs (Fig. 2C). She then developed refractory hypoxemic and hypercarbic respiratory failure with subsequent multiorgan dysfunction. Despite the administration of antifibrotics and supportive therapy, she died 70 days after admission. A postmortem lung biopsy revealed the features of the fibrotic phase of DAD with occasional hyaline membrane and type II pneumocyte hyperplasia (Fig. 2D).

A 30-year-old non-smoking woman, who was the mother of Cases 3 and 5, was admitted to the Department of Internal Medicine at the Asan Medical Center with a 1-month history of cough and a 10-day history of dyspnea on exertion. On physical examination, she was apyrexial and tachypneic (respiratory rate, 44/min), and crackles were audible over the right lung on auscultation. No hypoxemia was detected by ABGA. Her leukocyte count was 14,000/µL, with 72% neutrophils and 20% lymphocytes. The ESR was 38 mm/hr; and the CRP was 1.92 mg/dL. Laboratory tests for collagen vascular disease and vasculitis were negative. Blood, sputum, and BAL fluid cultures were negative for bacteria, viruses, and fungi. Pulmonary function tests showed a mild restrictive defect. Radiography and a CT scan of the chest revealed the presence of multifocal patchy consolidation with ground-glass opacities and tiny nodular lesions in both lungs. The patient was treated with steroid pulse therapy, followed by oral steroids, azathioprine, and antibiotics. The dyspnea gradually decreased, and she was discharged after 2 weeks of treatment. A repeat CT scan of the chest 12 days post-discharge showed an increase in the extent of ground-glass opacities and tiny nodules in both lungs. She was readmitted 14 days post-discharge with increased dyspnea. Cyclosporine was added to her existing treatment regimen of steroids and azathioprine. Transbronchial biopsy showed a nonspecific subacute lung injury pattern, including focal-organizing pneumonia and mild interstitial chronic inflammation. A follow-up chest CT scan 4 weeks after readmission revealed mild resolution of the abnormalities in both lungs. After discharge, her daily activities were limited by dyspnea, and she continued to experience dyspnea at rest.

A 17-month-old girl presented to the out-patient clinic at our medical center with a 30-day history of worsening cough. Her older sister (Case 3) had been admitted to the intensive care unit at the Asan Medical Center with respiratory failure 1 month previously, and her mother (Case 4) had had similar symptoms during the previous 45 days. On physical examination, the patient was apyrexial, tachycardic, and tachypneic (respiratory rate, 40/min). Her WBC count was 21,900/µL, with 48% neutrophils and 43% lymphocytes. Blood, sputum, and BAL fluid cultures were negative for bacteria, viruses and fungi. However, multiplex RT-PCR of nasopharyngeal aspirates revealed the presence of rhinovirus. Radiography and a CT scan of the chest showed the presence of centrilobular ground-glass opacities and septal thickening in both lungs. She was treated with steroids, cyclophosphamide, and hydroxychloroquine for 2 weeks. She showed significant clinical improvement, and repeat chest radiography 2 weeks after the initiation of treatment revealed that the ground-glass opacities, septal thickening, and consolidation had decreased. After discharge, she did not require oxygen, and her daily activities were not restricted, although she continued to experience dyspnea on exertion.