Ureaplasma-Induced Hyperammonemia Syndrome - an Acute Complication Post Allogeneic Stem Cell Transplant

Hyperammonemia syndrome is characterized by elevated serum ammonia levels and neurological dysfunction due to cerebral encephalopathy, andcauses lethargy, confusion, hyperventilation, seizures, death. In solid organ transplantation, hyperammonemia syndrome has been reported as a potentially fatal complication secondary to Ureaplasma infection ( Ureaplasma urealyticum or parvum). We present a patient with acute lymphoblastic leukemia (ALL) who underwent allogeneic stem cell transplant (HSCT) and developed hyperammonemia syndrome during systemic infection with Ureaplasma urealyticum.

A 32-year-old female with B-ALL received a haploidentical HSCT complicated by stage II acute GvHD of the gut and skin. During her hospital course, on Day +43, cellulitis of the right arm was diagnosed and treated empirically with amoxicillin-clavulanate on discharge. She presented back to the hospital on Day +53 with bilateral elbow pain and cellulitis. She had no focal neurological deficits initially but became increasing drowsy with dilated pupils. She had no episodes of sustained fever throughout her hospitalization. Empiric antimicrobial coverage with Meropenem and Vancomycin was given, and she was intubated and admitted to the ICU all on the same day. CT head was normal, and blood cultures and lumbar puncture were negative. She developed status epilepticus and her ammonia level increased to >1500 μmol/L on Day +57. Liver function, renal function and extended electrolytes remained within normal limits. MRI was consistent with hyperammonemic encephalopathy, prompting initiation of intermittent hemodialysis, lactulose, Rifaximin, and L-carnitine. EEG revealed no discernible rhythms, and intensive life support was discontinued on Day +61. PCR testing of preserved lung tissue confirmed Ureaplasma urealyticum as the likely cause.

Ureaplasma infections can be a serious complication of HSCT. The hydrolysis of urea by U reaplasma leads to elevated serum ammonia levels when systemic infections occur in immunocompromised patients. HSCT patients often have hypogammaglobulinemia due to conditioning and immunosuppressive therapies with a reduced ability to neutralize Ureaplasma. The role of neutrophil in controlling Ureaplasma is limited, as antibody-mediated defence is the sole mechanism of protection. Other contributing factors that can exacerbate hyperammonemia include Valproic acid, severe liver disease, and TPN.

Ureaplasma is challenging to diagnose due to limited growth on standard culture medium PCR testing is required for diagnosis and was the method of detection in our reported case. Numerous cases in non-HSCT immunocompromised populations have reported soft tissue infections involving Ureaplasma species, indicating a possible source for infection in the current case. Although there are no other reported cases of cellulitis and Ureaplasma infection in HSCT, a previous case with polyarthritic involvement may be mechanistically similar. A literature review was completed with results presented in Table 1 outlining details of reported cases with confirmed Ureaplasma infection post-HSCT. The cases were quite heterogenous although two of the cases were treated for Non-Hodgkin's Lymphoma where they were heavily pretreated with agents targeting B-Cells and immunoglobulin production.

Empirical doxycycline should be considered first line due to the Ureaplasma resistance to other agents such as Azathioprine. Beta-lactam antibiotics and vancomycin have limited efficacy as Ureaplasma's does not have a cell wall. Adjunct therapies to reduce ammonia production and increase elimination should also be considered.

Ureaplasma should be considered in immunocompromised patients in the context of fever of unknown origin and altered level of consciousness, especially if rising serum ammonia levels and soft tissue infections is present. The overall 50% mortality associated with the six cases presented demonstrates the significant risk associated with the infection.