The fourth reported case of donor-derived syphilis transmission was in a lung transplant recipient whose donor, a 38-year-old woman who died of subarachnoid bleeding, returned serology test results indicating past syphilis infection 1 day after transplantation had occurred. The recipient received penicillin G intravenously 3 times per day for 10 days, starting on day 1 posttransplant. Although immunoblot testing detected T. pallidum-specific newly synthesized IgG antibodies on day 29 posttransplant, the patient developed no clinical signs of syphilis infection, and by 3 months posttransplant, the T. pallidum hemagglutination titer had returned to negative. The recipient recovered well over long-term follow-up and graft function was normal.
In addition to these cases, there have been 4 cases of organ transplantation involving a syphilis-positive donor that did not result in transmission to the recipient after appropriate therapy. Transplanted organs included kidney, heart, lung, and liver, and in each case, there was no evidence of infection in the recipients, who had all received treatment with benzathine penicillin G. In the most recent of these cases, the EIA results showing that the donor was seropositive for syphilis were available only after transplantation had occurred. Based on negative results on TP-PA and VDRL confirmatory testing, it was not possible to differentiate between treated syphilis and late syphilis, and the decision was made to treat the recipient. Three doses of benzathine penicillin 2.4 MU were administered intramuscularly weekly for 3 weeks, and repeated serology at regular intervals posttransplant showed that the recipient remained free of syphilis infection at 3 months posttransplant.
These case reports suggest that, where the donor is found to have latent syphilis, clinical manifestations of T. pallidum can be successfully prevented with treatment of the recipient. However, a donor with secondary syphilis may be bacteremic with the involvement of many organs; hence, caution should be taken if clinical manifestations of secondary syphilis are present. The treatment regime of the recipient should be discussed with an infectious diseases physician and may include use of benzathine or IV penicillin (P Boan, personal communication).
There is substantial evidence that organs from bacteremic donors and donors with proven bacterial meningitis can be safely used for transplantation provided that the bacteria are confirmed to be susceptible to antibiotics and the donor and recipient receive appropriate treatment pretransplantation and posttransplantation. However, it is not uncommon for bacteremia in the donor to be unrecognized until after transplantation has occurred: in 1 study, 60% of bacteremic donors were afebrile in the 24 hours before organ procurement.
A retrospective study of organ donors in Spain found that 5% of liver and heart donors had bacteremia at the time of organ donation (including recognized and unrecognized infections). The most common microorganisms isolated from donors with bacteremia in were S. aureus, E. faecalis, A. baumanni, and S. viridans. There were no documented incidents of transmission of the isolated bacteria to recipients in this study nor was there evidence of any negative clinical impact on the outcomes of transplantation. The authors note, however, that bacteremic donors may not be safe in all circumstances, and their findings may in part be attributable to a degree of selection bias, whereby patients with positive blood cultures and evident sepsis were never considered as potential donors. It should also be noted that the risk of transmission varies according to the type of bacteria causing the infection:for example, Gram-negative bacilli (eg, E. coli) pose a greater risk than Gram-positive bacteria. Given the high rates of graft loss, morbidity and mortality associated with transmission of bacteremia:especially in the case of infection caused by Gram-negative bacilli:susceptibility testing in the donor is important.
Numerous other studies have demonstrated that transplant outcomes in recipients of organs from bacteremic donors are equivalent to outcomes from nonbacteremic donors, provided that the donor is treated with appropriate antibiotic therapy for at least 24 to 48 hours and shows some degree of clinical response (eg, improved white cell blood count, improved hemodynamics, defervescence), and tailored antibiotic treatment is initiated in the recipient in a timely manner. Recipients should be treated with tailored antibiotic therapy for at least 7 days posttransplant, or longer if the organism is difficult to treat (eg, S. aureus) or if there is the potential for infection to disrupt an anastomosis or seed an endovascular source. Based on existing evidence, no particular organ from a bacteremic donor is more likely to transmit infection to the recipient than another.
There are also numerous published studies describing successful transplantation using organs from donors who died from microbiologically proven bacterial meningitis caused by N. meningitidis, S. pneumoniae, Haemophilus influenzae, and E. coli. A contributing factor to the low rate of transmission of infection from donors with bacterial meningitis is that the most common meningeal organisms do not survive at the low temperatures maintained during cold perfusion and storage before transplantation. Before organ acceptance, meningitis should be confirmed as the sole site of infection, and the donor should ideally receive 48 hours of appropriate treatment with evidence of clinical improvement before organ retrieval, although successful outcomes have been reported after only 24 hours of antibiotic therapy where blood cultures were negative on the day of donation. Tailored antibiotic therapy in the recipient is recommended for at least 7 days posttransplant.
Exceptions exist; however, for example, meningitis caused by Listeria species may cause disseminated infection that is difficult to treat in the immunosuppressed patient, with a high risk of relapse. Similarly, meningitis caused by disseminated M. tuberculosis infection may be transmitted to the recipient with fatal consequences and is a contraindication to transplantation. Other organisms that are rare causes of meningitis but are notable for establishing metastatic infection, adherence to endothelial surfaces, or for having other markers of virulence:for example, S. aureus, P. aeruginosa, Salmonella spp.:are contraindications to organ donation. Lastly, the time course of infection is relevant: persistent bacteremia caused by any organism increases the risk of metastatic infection, and in such cases, organ transplantation may carry a higher risk of disease transmission.
European guidelines recommend that, in general, organs from donors with bacteremia or bacterial meningitis should only be considered for use after 48 hours of targeted and effective antibiotic therapy and with clinical evidence that the infection has been cleared. Utilization of donors with ongoing sepsis and positive blood cultures is not recommended, especially if effective therapy cannot be confirmed. If the results of blood cultures are not available before transplantation but clinical data indicate that antibiotic treatment has been effective, then it is recommended that a transplant infectious disease specialist be consulted before organs are discarded. Any meningitis caused by an unknown pathogen is an absolute contraindication for organ donation. A brain abscess is not a contraindication per se; however, the potential causes of the brain abscess should be evaluated before accepting the organs. Extreme precaution should be used for donors with presumed bacterial meningitis with negative cultures, especially when no pathogen can be identified by culture or PCR:in this case, organs should not be used for transplantation. In the case of a nonreactive culture but where the bacteria are confirmed by PCR as the pathogen causing the meningitis, it can be assumed that after 48 hours of antibiotic treatment, infection will not be transmitted.
UK guidelines state that where an organ donor has been diagnosed with bacteremia in the 5 days preceding the donation but there is no visible damage or local infection in the organ at retrieval, donation of an organ is acceptable with appropriate recipient antibiotic prophylaxis. Similarly, if bacterial meningitis has been confirmed, but there is no visible damage or local infection in the organ or tissues required at retrieval, the donation of the organs, tissues, and cells are acceptable. Appropriated antibiotic prophylaxis covering any organism from the donor should be considered for identifiable recipients, especially in the case of organs. However, organs from meningitis cases from whom no organism is cultured should not be used.
Summarizing these international guidelines, organs from bacteremic donors may be used provided the organism is readily treatable (not MDR), the donor has received at least 24 hours effective antibiotic therapy with some improvement, and a treatment course is administered to the recipient. Organs may be used from donors with bacterial meningitis with a treatment course given to the recipient, although caution is advised where the pathogen has not been confirmed.
Bacterial colonization of donor lungs is common as (1) the lungs are in constant contact with the external environment and the airways are normally colonized with multiple organisms; (2) most donors require emergency intubation, which may result in aspiration and pneumonia; and (3) the rate of bronchopulmonary infections increases in proportion to the length of time spent in the ICU (as does the rate of infection with antibiotic-resistant organisms). Before donation, aspiration and consequent pneumonia must, therefore, be ruled out/treated. In particular, the potential transmission of any MDR pathogens must be ruled out. European guidelines state that, in the case of pneumonia without bacteremia, all other organs can be used safely. After at least 48 hours of effective antibiotic treatment and unimpaired pulmonary function, lungs may be considered for donation. In cases where bacterial infection in the donor lungs is not detected before transplantation, lung recipients should not suffer complications due to donor-derived bacteria as long as the transmitted pathogens are not MDR and provided appropriate prophylaxis is given.
A recent significant discovery has been the role of disseminated Ureaplasma infection in hyperammonemia syndrome after lung transplantation. Hyperammonemia syndrome is a fatal complication of immunosuppressed patients in which serum ammonia levels progressively increase, leading to cerebral edema and death. It has been described in bone marrow, lung, heart-lung, kidney, liver, intestinal, and islet cell transplant recipients; however, it has most frequently been reported in lung transplant recipients. A large retrospective case series performed at Barnes-Jewish Hospital in St. Louis, Missouri, between 2000 and 2013 found an incidence of hyperammonemia syndrome after lung transplantation of 1% (n = 8/807), with a mortality rate of 75%. A smaller retrospective cohort study of 145 lung transplant recipients found an incidence of hyperammonemia syndrome of 4%.
Hyperammonemia syndrome was first described in 1991 in a recipient of a bone marrow transplant. The cause of the syndrome remained unknown, however, until 2015 when Bharat et al published preliminary evidence that the syndrome may be caused by donor-derived infection with Ureaplasma species. Ureaplasma species are mollicutes that depend on urea hydrolysis to ammonia and carbon for energy production, and are part of the normal microbiome of the urogenital tract. Although the hydrolysis of urea and the generation of ammonia in the urine do not cause harm, disseminated ureaplasma infection might pose a severe threat by releasing free ammonia into the circulation. The released ammonia is then converted back into urea in the liver, which provides more substrate to Ureaplasma, and thus a cycle of urea hydrolysis and hepatic urea production is established.
In their initial study, Bharat et al performed microbiologic examination (PCR, specialized culture, and molecular resistance profiling) of specimens taken from 6 lung transplant recipients who developed hyperammonemia syndrome posttransplantation. They found evidence of systemic infection with U. urealyticum or U. parvum in all 6 cases, but they found no evidence of infection in 20 control lung transplant recipients with normal ammonia concentrations.
Ureaplasma is not known to colonize normal healthy lungs, and why hyperammonemia is reported more frequently in lung transplant recipients than recipients of other solid organ transplants is not known. One theory relates to aspiration at the time of injury causing death. Ureaplasma is able to colonize the oral cavity, with possible routes of transmission, including sexual transmission from the genitourinary tract of a partner. An aspiration event at the time of injury could then cause the organism to be drawn down into the lungs, and given that Ureaplasma does not grow in routinely performed bacteriological cultures, it would not be detected on standard BAL culture.
NAT is the fastest detection method if Ureaplasma is suspected, and culture is also available. Bharat et al reported that Ureaplasma species are susceptible to macrolides, fluoroquinolones, and tetracyclines; however, they also observed the emergence of resistance in their case series of 6 patients. At this time, routine donor testing for Ureaplasma is not suggested.
Urinary tract infections (UTIs) and pyelonephritis are common among potential donors due to bacteria ascending along the urethral catheter. Any suspected UTIs in potential donors should be confirmed by urine culture, and potential kidney donors with UTI should be investigated to rule out upper tract infection. In case of a UTI restricted to the lower urinary tract, kidneys may be used as they are not infected. All other organs can be safely used for transplantation.
Before organ retrieval, the donor should be treated with antibiotics for 24 to 48 hours or until there is documented resolution of the infection. The final decision about organ utilization should be made at the time of organ recovery. Posttransplant treatment of the recipient may reduce the risk of donor-derived infection. In general, however, there is no need to treat the recipient of a nonkidney organ from a deceased donor with nonbacteremic, localized infection that does not involve the transplanted organ (excluding meningitis cases).
European guidelines state that in the case of UTI without bacteremia, all nonkidney organs can be used safely for transplant, and that uncomplicated UTI/bacteruria is in most cases not a contraindication for the utilization of kidneys, provided adequate antibiotic treatment is given to the donor and recipient.
Toxoplasma gondii is a protozoan (coccidian) parasite of mammals, which reproduces in cat species but has a wide intermediate host range. It is one of the most common parasitic infections of humans and other warm-blooded animals. Exposure is extremely common in all regions of the world, although there is substantial geographical variation in rates of T. gondii (see Table 33). It is estimated that 16% to 40% of the populations of the United States and United Kingdom are infected, whereas in Central and South America and parts of Europe, infection rates are as high as 80%. A study of pregnant women in Australia found 35% had IgG antibodies to T. gondii. Transmission can occur due to:
ingestion of undercooked meat containing Toxoplasma cysts;
ingestion of contaminated soil (eg, via unwashed fruit or vegetables) containing cat feces;
ingestion of cat feces via cleaning a cat's litter box, gardening, contact with sandpits, and so on;
transplacental transfer from mother to fetus.
It is believed that the majority of infections that occur globally are due to ingestion of cysts in infected meat, or oocysts in food or water contaminated with cat feces. Geographical variation in T. gondii infection is hypothesized to be due to (i) the relative level of contamination in the environment with oocysts, and (ii) local culinary traditions with respect to meat preparation (eg, a preference for raw or undercooked meat). When ingested, bradyzoites from tissue cysts or sporozoites from fecal oocysts transform into tachyzoites and penetrate intestinal epithelial cells and divide rapidly in the intestine. T. gondii is then spread to organs and tissues by invasion of the lymphatics and blood, and is able to multiply in almost any cell in the body. In immunocompetent hosts, symptoms are usually either absent or mild, such as swollen lymph nodes, headache, fever, and fatigue.
The immune response to T. gondii infection involves both humoral and cellular factors; however, immunity does not eradicate infection as cysts can persist for years after acute infection. After proliferating, tachyzoites transform into bradyzoites, which are less susceptible to proteolytic enzymes and form latent intracellular cysts mainly in muscle tissues and the brain (although visceral organs including lungs, liver, and kidneys may also be affected). Intact cysts may persist for the life of the host, and can, therefore, be transmitted directly by solid organ transplantation. Intact cysts are unlikely to cause harm in immunocompetent persons; however, in immunocompromised persons, the rupture of a tissue cyst may result in bradyzoites being transformed into tachyzoites, followed by renewed replication. Alternatively, if the donor has an acute T. gondii infection at the time of donation, then tachyzoites transmitted to the recipient may persist and continue proliferating, resulting in severe symptoms, complications, and death.
Organs which contain tissue cysts infected with T. gondii carry the risk of primary infection in a naive and immunosuppressed recipient. Hearts are at higher risk of containing T. gondii cysts compared with other organs, and serological tests for toxoplasma are usually included among standard screening tests for heart donors in most jurisdictions. Although a positive serological test for T. gondii is not a contraindication to donation, it may inform the need for prophylaxis in heart recipients.
Numerous serological tests exist for the detection of T. gondii antibodies, including both IgM and IgG. IgM antibodies appear sooner after infection than IgG, and disappear faster after recovery. NAT can be used to diagnose active infection; however, given that active infection is rare and the goal of donor screening is primarily to detect latent toxoplasma in the heart and other organs resulting from past infection, international guidelines recommend serological testing only for pretransplant screening of potential organ donors. Donor and recipient toxoplasma IgG are generally recommended as routine for cardiac transplant recipients, with donor testing for acute toxoplasma (IgM, NAT) used only in an appropriate clinical context (ie, where there is clinical suspicion of acute toxoplasmosis).
Toxoplasma gondii transmission by organ transplantation has been reported multiple times in the literature, most commonly by heart transplantation, followed by kidney and liver transplantation. Cases of toxoplasmosis after bowel and pancreas transplantation have also been reported. Presenting symptoms typically are nonspecific, including fever, respiratory distress, neurological manifestations, and bone marrow suppression. Cerebral toxoplasmosis, although a well-known complication in HIV patients, is extremely rare in transplant recipients. The majority of cases are diagnosed within 90 days of transplantation, although the median time to onset of symptoms in cases of donor-acquired primary toxoplasmosis is shorter:approximately 15 to 25 days posttransplant:than for reactivation of latent infection. Primary toxoplasmosis is also significantly more lethal: a review of published cases of primary toxoplasmosis after kidney transplantation found a mortality rate of 50%, with fatal outcomes confined to those patients who developed clinical evidence of toxoplasmosis less than 90 days posttransplant.
Mortality from toxoplasmosis posttransplantation is highest in those patients with disseminated disease, or where there is a delay in diagnosis and targeted treatment. In 1 such case of fatal disseminated toxoplasmosis after liver transplantation from a seropositive donor to a seronegative recipient, the recipient developed symptoms 12 days posttransplant and was initially treated for MRSA and then for CMV after this was detected on BAL performed on day 26 posttransplant. The patient's condition did not improve, and on day 40, she developed acute respiratory failure with shock. On admission to the ICU, a second BAL was performed and direct microscopy revealed T. gondii tachyzoites, at which point, therapy with pyrimethamine and sulfadiazine was initiated. The patient, however, died 5 days later. The recipients of the other organs from the same donor (heart, lungs, kidneys and cornea) showed no evidence of T. gondii infection more than 9 months posttransplant: all of these recipients were seropositive for toxoplasmosis before transplantation.