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When You Hear the Drumming of Hooves, Think Horses... (But Don't Forget Unicorn): Hyperammonemia Associated with Ureaplasma spp. Infection in Lung Transplant Recipients


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Claire Aguilar, MD
University Health Network
Toronto, Canada
Claire.Aguilar@uhn.ca



When I started my fellowship in Transplant Infectious Diseases in Toronto two years ago, I was expecting to order numerous tests to find unusual infections in those very immunocompromised patients.

As an example, the differential diagnosis for neurological symptoms in immunocompromised hosts includes various infectious etiologies. In fact, I quickly realized that after transplant, a lot of patients had delirium. My staff, Dr. Husain, asked me if I knew the proportion of cases due to infections. Less than 5% quite low. Think horses: medications, metabolic disorders, psychological stress post-transplant.

Few weeks after the beginning of my fellowship, Dr. Michael Ison from Chicago was an invited professor in Toronto and presented new data about hyperammonemia syndrome, a rare but very severe disease in lung transplant recipients. Firstly described in the 90's, hyperammonemia syndrome is characterized by increased ammonia levels in blood, usually in the early post-transplant phase, associated with neurological symptoms, and results in high mortality rates [1, 2].

Ison's team found evidence of infection with Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis in respiratory samples and blood from lung transplant recipients suffering from hyperammonemia syndrome [3]. Surprisingly, Ureaplasma sp. and Mycoplasma hominis are classically responsible for urogenital tract infections in immunocompetent patients, without neurological symptoms. Ureaplasma spp. and Mycoplasma spp. are urea splitting organisms. Recent experiments in mice models showed that inoculation of Ureaplasma urealyticum or Ureaplasma parvum in immunosuppressed mice resulted in high ammonia levels in blood compared to infected control mice [4,5].

This association also raises the question of the transmission mode. Fernandez et al. reported a case where the donor sample was positive for Ureaplasma urealyticum [6]. In a prospective study including 28 donors, Fernandez et al. found that 14% of respiratory samples from donor had a positive PCR for Ureaplasma spp. These positive donors were mostly young male patients who had an aspiration pneumonia [7].

This finding raises the question of screening systematically donor samples for those pathogens to administer appropriate antibiotics to the recipients, and consequently avoid the occurrence of hyperammonemia syndrome. Such screening test should be done by PCR to provide a quick result, as hyperammonemia tends to occur shortly after transplant.

Nowadays, in the Toronto Lung Transplant Program, all patients are monitored for ammonia levels during the first month post-transplant, and if ammonia is elevated, an empirical treatment with Moxifloxacin and Doxycycline is administrated, associated with the prompt initiation of dialysis to reduce ammonia levels. Recently, we retrospectively studied the samples from 8 patients who had hyperammonemia syndrome in the last 5 years, and found a positive PCR for Ureaplasma and/or Mycoplasma in donor or recipient samples in 6 cases. Interestingly, we also studied 2 recipients with cerebral edema without hyperammonemia, and Ureaplasma urealyticum was found in their respiratory samples.

This example highlights the difficulty of transplant infectious diseases, where we have to prioritize the diagnostic assumptions and think first to the most common etiologies, but at the same time keep in mind that unusual infections, with unexpected presentations, can require a quick and accurate diagnosis in order to appropriately treat our patients. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Lichtenstein GR, Kaiser LR, Tuchman M, Palevsky HI, Kotloff RM, O'Brien CB, et al. Fatal hyperammonemia following orthotopic lung transplantation. Gastroenterology. 1997 Jan;112(1):236-40.
  2. al KD et. Idiopathic hyperammonemia after solid organ transplantation: Primarily a lung problem? A single-center experience and systematic review. - PubMed - NCBI [Internet]. [cited 2017 Nov 24]. Available from: https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/?term=Krutsinger+hyperammonemia
  3. Bharat A, Cunningham SA, Scott Budinger GR, Kreisel D, DeWet CJ, Gelman AE, et al. Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med. 2015 Apr 22;7(284):284re3.
  4. Wang X, Karau MJ, Greenwood-Quaintance KE, Block DR, Mandrekar JN, Cunningham SA, et al. Ureaplasma urealyticum Causes Hyperammonemia in an Experimental Immunocompromised Murine Model. PloS One. 2016;11(8):e0161214.
  5. Wang X, Greenwood-Quaintance KE, Karau MJ, Block DR, Mandrekar JN, Cunningham SA, et al. Ureaplasma parvum causes hyperammonemia in a pharmacologically immunocompromised murine model. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2017 Mar;36(3):517-22.
  6. Fernandez R, Ratliff A, Crabb D, Waites KB, Bharat A. Ureaplasma Transmitted From Donor Lungs Is Pathogenic After Lung Transplantation. Ann Thorac Surg. 2017 Feb;103(2):670-1.
  7. Fernandez R, Chi M, Ison MG, Waites KB, Crabb DM, Ratliff AE, et al. Sequelae of Donor-derived Mollicutes Transmission in Lung Recipients. Am J Respir Crit Care Med. 2017 Mar 1;195(5):687-9.



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