Prophylactic Ureaplasma-directed Antimicrobials in Lung Donors Can Prevent Fatal Hyperammonemia

Letter to the Editor

Hyperammonemia syndrome (HS) is a fatal complication, refractory to medical treatment,^1,2 which can affect over 5% of lung transplant as well as other solid organ recipients. The pathogenesis of hyperammonemia was previously hypothesized to be related to unmasking of an inborn error of metabolism induced by the introduction of calcineurin inhibitors, such as tacrolimus or cyclosporine, following transplantation.³ However, we recently discovered that a Mollicute, Ureaplasma spp, leads to the development of HS.⁴ Subsequently, in a prospective study, we found a high incidence of Ureaplasma in the donor lungs which was associated with serious posttransplant complications.⁵ Independently, other investigators demonstrated that both species of Ureaplasma, namely Ureasplasma urealyticum and Ureaplasma parvum, are causally linked to the pathogenesis of hyperammonemia in rodent models.^6,7 Based on these data, we implemented universal screening of all donor lungs using both polymerase chain reaction (PCR) and microbial cultures, as previously described.³ However, given the limited availability of testing for Ureaplasma spp, it required the test result to be sent out to a reference lab. The delay of 3–5 days resulted in the development of HS and permanent neurological injury in 1 of our recipients. Given the high incidence of Ureaplasma in the donor lungs and inability to perform in-house donor testing at our hospital or in our donor service area, we initiated universal donor prophylaxis using a dual antimicrobial agent with a fluoroquinolone (levofloxacin 500mg q12h) and azithromycin (500mg IV q24h) since single agents can result in the development of antimicrobial resistance in Ureaplasma.⁴ These antimicrobials were also administered to the recipient following transplantation until the Ureaplasma PCR and cultures were resulted. A positive PCR or culture necessitated continuation of the dual antimicrobials for 2 weeks following which a repeat bronchoalveolar lavage fluid testing was performed to confirm elimination of the Mollicute. While 2 patients died of HS prior to the initiation of Ureaplasma prophylaxis, there were no new cases of HS in 92 consecutive patients (6.8% vs 0% respectively, p=0.01) subsequently (Table 1). Additionally, following initiation of Ureaplasma prophylaxis, the incidence of Ureaplasma infection in donor lungs reduced from 27.5% to 9.7% (p=0.01). The median duration of antimicrobial therapy in the donors was 1.7 days. Following transplantation, mild QTc prolongation was observed in only 1 recipient on posttransplant day 2 which resolved following the replacement of levofloxacin and azithromycin with doxycycline. There were no differences in the incidence of acute rejection episodes, development of antimicrobial resistant microbes, or immunosuppressive drug dosing in the historic and current cohort.

Table 1.

Chatracteristics of Study Cohort

Variable	Overall (n=121)	No Prophylaxis (n=29)	Prophylaxis received (n=92)	P value
Recipient profile
Age, years	56.8 ±12.0	55.2 ± 12.0	57.3 ± 12.0	0.43
Female	58	11	47	0.21
BMI, kg/m2	25.6 ± 4.2	25.8 ± 4.4	25.6 ± 4.1	0.83
Smoking history	59	14	45	0.95
Hypertension	67	19	48	0.21
Diabetes	52	14	38	0.51
PVD	3	1	2	0.70
CKD	25	8	17	0.29
Laboratory
Hemoglobin, g/dL	10.7 ± 2.6	10.9 ± 2.7	10.7 ± 2.5	0.62
WBC, 1,000/mm3	11.2 ± 4.8	11.4 ± 5.9	11.1 ± 4.4	0.75
Platelets, 1,000/mm3	224.8±101.5	207.7±68.9	230.2±109.3	0.30
Creatinine, mg/dL	0.7 ± 0.1	0.8 ± 0.1	0.7 ± 0.1	0.14
BUN, mg/dL	16.3 ± 6.2	16.1 ± 5.5	16.3 ± 6.3	0.83
AST, U/L	27.6 ±45.7	33.8 ± 45.2	25.7 ± 45.7	0.41
ALT, U/L	52.2±122.4	76.2±202.9	44.9 ± 81.6	0.23
Total bilirubin, mg/dL	0.9 ± 0.8	0.9 ± 0.7	0.8 ± 0.8	0.68
Albumin, g/dL	4.0 ± 3.9	3.5 ± 0.5	4.1 ± 4.4	0.49
INR	1.2 ± 0.42	1.2 ± 0.2	1.2 ± 0.4	0.99
PT	13.6 ± 4.8	13.1 ± 2.5	13.8 ± 5.3	0.52
PTT	30.9 ± 12.2	29.1 ± 4.2	31.5 ± 13.7	0.37
Donor profile
Age, years	34.3 ± 12.7	36.9 ± 14.4	32.7 ± 11.7	0.01
Female	47	8	39	0.15
Cause of death
Anoxia	34	4	30	0.08
Head trauma	53	13	40	0.89
Stroke	27	12	15	0.01
Brain tumor	3	0	3	0.32
Others	4	0	4	0.25
Donor Ureaplasma testing
Ureaplasma positive	17 (14%)	8 (27.5%)	9 (9.7%)	0.01
Posttransplant HS	2 (1.6%)	2 (6.8%)	0	0.01

Continuous data are shown as median ± SD. Categorical variables are presented as number and percentage. BMI, body mass index; PVD, peripheral vascular disease; CKD, chronic kidney disease; WBC, white blood cell; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, Alanine aminotransferase; INR, international normalized ratio; PT, prothrombin time; PTT partial thromboplastin time; HS, Hyperammonemia Syndrome

Recent reports have causally linked Ureaplasma to the pathogenesis of hyperammonemia by fulfilling Koch’s postulates for disease causation. Since the rates of Ureaplasma infection in untreated donor lungs can approach 30% (Table 1) and the morbidity and mortality associated with Ureaplasma in the recipients is high, we propose that donor lungs be screened prior to implantation. However, when that is not feasible, a short duration of Ureaplasma prophylaxis may be a safe and highly effective alternative to prevent the fatal hyperammonemia syndrome.

Abbreviations

HS

Hyperammonemia Syndrome

PCR

Polymerase Chain Reaction