Intratracheal Administration of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Patient with Acute Respiratory Distress Syndrome
A 59-yr-old man with a history of pulmonary tuberculosis (TB) and no significant family history was diagnosed with idiopathic thrombocytopenia in June 2008. The patient was treated with corticosteroid therapy. In October 2008, he developed a cough, sputum, and rhinorrhea and five days later displayed fever and dyspnea. He was subsequently admitted to hospital. His chest radiography and computed tomography (CT) scan showed multifocal patchy ground-glass opacities (GGOs) in both lungs with underlying emphysema with large bullae in the left lower lobe and focal irregular nodular lesions in the right upper lobe that were presumed to be TB sequelae. He was assessed as having atypical pneumonia. Considering his immunocompromised status, antibiotic therapy was commenced empirically.\nAfter five days, he was transferred to our hospital, a tertiary referral center, and admitted to the medical intensive care unit. At admission, he had tachypnea with a fever of 39℃. He had progressive bilateral diffuse infiltrations on his chest radiography. His initial SaO2 level was 75% and his PaO2/FiO2 (P/F) ratio was 166 mmHg. He was diagnosed with ARDS caused by atypical pneumonia. He then received mechanical ventilation (MV). We started a course of methylprednisolone at a dose of 40 mg twice a day to treat a possible Pneumocystis jiroveci pneumonia in conjunction with a continuing regimen of empirical antibiotics and an antiviral agent. However, no specific pathogen was identified in any specimen from this patient, including bronchoalveolar lavage, blood or sputum. Then, his chest radiography was stationary and his P/F ratio began to gradually improve.\nOn hospital day (HD) 7, he underwent tracheostomy to enable early weaning from MV. However, he then developed hospital-acquired pneumonia and hydropneumothorax due to a ruptured bullae with bronchopulmonary fistula (BPF). The repeated lung infections made him dependent on MV and weaning proved difficult. He was conscious during this time but he could not communicate with the medical team or even his family members. A psychiatrist diagnosed a hypoactive delirium due to his poor condition. On HD 87, he had a follow-up high-resolution CT, which showed aggravation of diffuse GGOs and interlobular septal thickening in both lungs. This indicated the progression of pulmonary fibrosis as a post-ARDS sequelae. After discussing the possibility of administering MSCs with his family, we commenced with a trial of this therapy.\nThe MSC trial was approved by the Institutional Review Board of Asan Medical Center. The umbilical cord blood (UCB)-derived MSCs (UCB-MSCs) were prepared as follows. UCB was obtained from a full-term delivery with informed maternal consent. UCB-MSCs were produced at the Good Manufacturing Practice facility of Medipost Co., Ltd., Seoul, Korea. Quality control and quality assurance for the production of these cells were performed according to the standards of the Korea Food and Drug Administration. Flow cytometry analysis of expressed surface antigens showed that these cells were uniformly positive for CD29, CD44, CD73, CD105, and CD166 and negative for the hematopoietic lineage markers CD34, CD45, CD14, and HLA-DR. The final UCB-MSCs preparations used in the infusion were harvested from cell culture passage 6 and suspended at a final density of 7.5×106/1.5 mL in normal saline.\nOn HD 114, the patient underwent the intratracheal administration of UCB-MSCs at a target dose of 1×106/kg. Before the procedure, the ventilator was set to the pressure-controlled ventilation (PCV) mode of 26 cmH2O of inspiratory pressure (IP) and 0.45 of FiO2. We evenly infused 5.5×107 MSCs into both bronchi by wedging each bronchus. There were no peri-procedural complications.\nThe next morning (16 hr later), he was able to communicate effectively with our medical team, which had not been possible in the previous few months. The IP was reduced to 24 cmH2O with 0.4 of FiO2. After 24 hr, we changed the PCV to a pressure support mode with 18 cmH2O of support pressure with 0.4 of FiO2. After 48 hr, PCV was applied again with 22 cmH2O with 0.35 of FiO2. The dynamic compliance of his lung improved from a pre-procedure value of 22.7 to 26.5, 27.3, and 27.9 mL/cmH2O after 24, 48, and 72 hr, respectively. His P/F ratio subsequently increased from pre-procedural 191 to 328 mmHg on day 1 after the procedure and to 334 mmHg on day 3 (). A follow-up chest radiography showed a slight decrease in bilateral lung infiltrates ().\nOn day 3, however, he suddenly experienced six generalized tonic-clonic seizures during the course of the day with a fever near to 39℃. He had no focal lateralizing signs. A brain CT was performed and showed no hemorrhage. His electroencephalogram showed no abnormal epileptiform discharge. We discussed the case with neurological specialists and determined that the current use of carbapenem was the most probable cause of his seizure. We discontinued it and started him on an anticonvulsant. Subsequently, he had no more seizures.\nThe weaning trial was restarted for our patient and the IP was reduced to 12 cmH2O with 0.3 of FiO2 during the following week. However, he could not be weaned because his repeated infection by multidrug-resistant pathogens was not controlled. Eventually, he suffered septic shock due to empyema and died on HD 231 or day 118 after MSC administration.