Use of Novel Diagnostic Approaches to Identify Disseminated Ureaplasma urealyticum Infection Causing Hyperammonemia Syndrome After Heart-Kidney Transplant.

Hyperammonemia syndrome (HS) is a potentially fatal condition characterized by elevated blood ammonia (NH3) levels and progressive confusion, obtundation, cerebral edema, seizure, and coma.1Bharat A. Cunningham S.A. Scott Budinger G.R. et al.Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.Sci Transl Med. 2015; 7: 284re283Crossref Scopus (105) Google Scholar The syndrome is well described in immunocompromised patients after hematopoietic stem cell and solid organ transplant, with predilection for lung transplant recipients.2Moffatt-Bruce S.D. Pesavento T. Von Viger J. et al.Successful management of immunosuppression in a patient with severe hyperammonemia after lung transplantation.J Heart Lung Transplant. 2008; 27: 801-803Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Ureaplasma urealyticum and Ureaplasma parvum, commensal organisms that colonize human urogenital flora, have been causally linked to HS, with clinical resolution of hyperammonemia with antimicrobial therapy targeting Ureaplasma spp.1Bharat A. Cunningham S.A. Scott Budinger G.R. et al.Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.Sci Transl Med. 2015; 7: 284re283Crossref Scopus (105) Google Scholar,3Tantengco O.A. De Jesus 2nd, F.C. Gampoy E.F. Ornos E.D. Vidal Jr., M.S. Abad C.L. Hyperammonemia syndrome associated with Ureaplasma spp. infections in immunocompromised patients and transplant recipients: a systematic review and meta-analysis.Clin Transplant. 2021; 35e14334Crossref PubMed Scopus (7) Google Scholar We present the case of a 45-year-old woman with history of nonischemic cardiomyopathy secondary to mantle radiation for Hodgkin lymphoma, mechanical mitral valve replacement, and renal cell carcinoma with partial right nephrectomy who underwent orthotopic heart and kidney transplant. She received peritransplant prophylaxis including fluconazole, trimethoprim-sulfamethoxazole, and valganciclovir. Four weeks after transplant, confusion, acute kidney injury (creatinine concentration, 2.88 mg/dL [to convert to μmol/L, multiply by 88.4]; blood urea nitrogen level,73 mg/dL [to convert to mmol/L, multiply by 0.357]), fever, and leukocytosis (white blood cell count, 29.5 × 109 cells/L) developed. Computed tomography scans of the head and of the chest, abdomen, and pelvis were unremarkable. Metabolic studies demonstrated worsening hyperammonemia (peak, 94 mcmol/L; Figure) but normal liver function test results. Blood, urine, and sputum cultures were negative. Serum and urine specimens were sent for Ureaplasma/Mycoplasma polymerase chain reaction (PCR) analysis and microbial cell-free DNA (mcfDNA)–next-generation sequencing (NGS) assay (Karius test), and empirical doxycycline was initiated. Serum testing returned negative results, whereas urine PCR and subsequent Karius test results returned positive for Ureaplasma urealyticum. Her hyperammonemia and encephalopathy improved within 72 hours of doxycycline initiation (Figure). Because of persistent positive response on urine PCR, she received an extended 8-week course of doxycycline without further complications noted at 3-month follow-up. Although the source of infection, whether donor or recipient derived, was unclear, recipients of liver and second kidney from the same deceased donor had no infectious complications or encephalopathy reported. Hyperammonemia syndrome secondary to Ureaplasma infection has been noted in up to 4% of lung transplant recipients.1Bharat A. Cunningham S.A. Scott Budinger G.R. et al.Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.Sci Transl Med. 2015; 7: 284re283Crossref Scopus (105) Google Scholar,3Tantengco O.A. De Jesus 2nd, F.C. Gampoy E.F. Ornos E.D. Vidal Jr., M.S. Abad C.L. Hyperammonemia syndrome associated with Ureaplasma spp. infections in immunocompromised patients and transplant recipients: a systematic review and meta-analysis.Clin Transplant. 2021; 35e14334Crossref PubMed Scopus (7) Google Scholar However, HS as a cause of encephalopathy is rare in heart-kidney transplant.3Tantengco O.A. De Jesus 2nd, F.C. Gampoy E.F. Ornos E.D. Vidal Jr., M.S. Abad C.L. Hyperammonemia syndrome associated with Ureaplasma spp. infections in immunocompromised patients and transplant recipients: a systematic review and meta-analysis.Clin Transplant. 2021; 35e14334Crossref PubMed Scopus (7) Google Scholar Whereas donor-derived infection is a common mechanism of transmission, recipient-derived infection should be considered in women of childbearing age, as Mycoplasma/Ureaplasma can colonize the urogenital flora.4Roberts S.C. Bharat A. Kurihara C. Tomic R. Ison M.G. Impact of screening and treatment of Ureaplasma species on hyperammonemia syndrome in lung transplant recipients: a single center experience.Clin Infect Dis. 2021; 73: e2531-e2537Crossref PubMed Scopus (12) Google Scholar Notably, the underlying acute kidney injury may have predisposed our patient to development of hyperammonemia as Ureaplasma spp have been demonstrated to produce higher concentrations of ammonia under uremic conditions.5Fleming D. Cunningham S.A. Patel R. Contribution of uremia to Ureaplasma-induced hyperammonemia.Microbiol Spectr. 2022; 10e0194221Crossref Scopus (4) Google Scholar The diagnosis of disseminated Ureaplasma/Mycoplasma infections can be challenging.1Bharat A. Cunningham S.A. Scott Budinger G.R. et al.Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.Sci Transl Med. 2015; 7: 284re283Crossref Scopus (105) Google Scholar Ureaplasma PCR from urine and urogenital swabs has a high sensitivity (96.5%), but the sensitivity of serum PCR is unknown.6Cunningham S.A. Mandrekar J.N. Rosenblatt J.E. Patel R. Rapid PCR detection of Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum.Int J Bacteriol. 2013; 2013168742Crossref PubMed Google Scholar As demonstrated in this case, mcfDNA-NGS may represent a novel tool to augment the diagnosis of disseminated Ureaplasma infection. Accurate diagnosis is critical as mortality can range from 25% to 40%.3Tantengco O.A. De Jesus 2nd, F.C. Gampoy E.F. Ornos E.D. Vidal Jr., M.S. Abad C.L. Hyperammonemia syndrome associated with Ureaplasma spp. infections in immunocompromised patients and transplant recipients: a systematic review and meta-analysis.Clin Transplant. 2021; 35e14334Crossref PubMed Scopus (7) Google Scholar Therefore, future studies should aim to investigate novel strategies like mcfDNA-NGS to accurately diagnose disseminated Ureaplasma infection. The authors report no competing interests. Download .pdf (.17 MB) Help with pdf files Application