R. Fernandez1, M. M. DeCamp1, D. D. Odell1, A. Bharat1 1Feinberg School Of Medicine – Northwestern University,Division Of Thoracic Surgery,Chicago, IL, USA
Introduction: Hyperammonemia is a fatal syndrome of unclear etiology following lung transplantation. It is postulated to result from an inborn error of Urea-cycle metabolism. We recently demonstrated that a Mollicute, Ureaplasma, causes this syndrome. Here, we further investigated the source of Ureaplasma infection and the incidence of hyperammonemia.
Methods: Consecutive lung transplant recipients were prospectively evaluated between July 2014 and May 2016. All recipients had pre-transplant urine and bronchoalveolar lavage fluid (BALF) tested for all Mollicutes (Ureaplasma and Mycoplasma species) by PCR and culture, and antimicrobial susceptibilities determined. Additionally, BALF from all donors was tested. Patients found positive for Mollicutes pre-transplant were successfully treated using antimicrobials based on the antimicrobial susceptibility. Ammonia was analyzed in all patients post-transplant. Ureaplasma isolates were grown in specialized culture media and titrated amounts were injected into immunocompetent C57BL6 mice to determine development of hyperammonemia, thereby testing Koch’s third postulate.
Results: Human Studies: Five of the 29(17%) recipients tested positive for Mollicutes (Ureaplasma=4, Mycoplasma=1) in urine pre-transplant and were successfully treated. Native lung BALF from all patients was negative for Mollicutes. BALF from four (14%) donors was positive for Ureaplasma, but not Mycoplasma. These donors were younger, 23.3 vs 38.3 years (p<0.001), tended to be male, sexually active, and all had aspiration. All recipients of Ureaplasma-positive, but not of Ureaplasma-negative, donor lungs developed hyperammonemia and demonstrated increased morbidity and mortality. One isolate revealed macrolide-resistance associated with a novel ribosomal mutation. All other isolates were pan-susceptible to macrolides, fluoroquinolones, and tetracycline. All recipients demonstrated a decrease in ammonia levels within 24-hours of antimicrobial therapy and normalization within 7 days. Murine Studies: Human isolates of Ureaplasma led to dose-dependent hyperammonemia in wild-type mice (Ammonia >3 times the baseline, p<0.001). Treatment with antibiotics to which the isolate was susceptible prevented hyperammonemia.
Conclusion: Ureaplasma infection in lung recipients is transmitted via donor lungs resulting in significant morbidity and mortality. The incidence of Ureaplasma infection is 14%, higher than previously reported, which may support the role of routine donor screening. Early recognition and treatment of Ureaplasma infection can improve lung transplant outcomes.