Donor-To-Host Transmission of Bacterial and Fungal Infections in Lung Transplantation

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1 American Journal of Transplantation 2006; 6: Blackwell Munksgaard C 2005 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Donor-To-Host Transmission of Bacterial and Fungal Infections in Lung Transplantation I. Ruiz a,,j.gavaldà a,v.monforte b,o.len a, A. Román b,c.bravo b,a.ferrer c,l.tenorio d, F. Román e,j.maestre e,i.molina a,f.morell b and A. Pahissa a a Department of Infectious Diseases, b Department of Pulmonology, c Department of Microbiology, d Intensive Care Unit and e Thoracic Surgery Department, Lung Transplantation Program, Hospital General Vall d Hebron, Universitat Autònoma de Barcelona, Spain Corresponding author: Dr. Isabel Ruiz, iruiz@vhebron.net The purpose of this study was to evaluate the incidence and etiology of bacterial and fungal infection or contamination in lung allograft donors and to assess donor-to-host transmission of these infections. Recipients who survived more than 24 h and their respective donors were evaluated. The overall incidence of donor infection was 52% (103 out of 197 donors). Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Donor-to-host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients, 7.6% of lung transplants performed. Among these cases, 2 were due to donor bacteremia and 13 to colonization of the graft. Twenty-five percent of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Excluding the five cases without an effective prophylactic regimen, prophylaxis failure occurred in 11 out of 197 procedures (5.58%). Donor-to-host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with an appropriate prophylactic antibiotic regimen that must be modified according to the microorganisms isolated from cultures of samples obtained from donors, grafts, preservation fluids and recipients. Key words: Bacterial infection, donor infection, donorto-host transmission, fungal infection, graft colonization, lung transplantation Received 17 June 2005, revised 23 August 2005 and accepted for publication 12 September 2005 Introduction Lung transplantation is increasingly being performed for the treatment of several end-stage lung diseases. The relative scarcity of organ donors remains one of the most important factors limiting the number of transplantation procedures. Worldwide guidelines have been established to help in the selection of optimal donors, and there is emphasis on the importance of identifying potential donors with an underlying disease or condition that makes them unsuitable. One of the main problems in determining the suitability of organs for transplantation is the potential for donor-to-host transmission of a bacterial or fungal infection, due to infection or contamination of the allograft. Infection retrieved from donor organs has been well documented in several studies concerning solid-organ transplantation (1 5). The level of contamination and outcome have been examined in these studies, but donorrelated transmission is often not differentiated from iatrogenic contamination. The risk of transplanting a bacteriacontaminated kidney has been defined, but there is little information of this type regarding other transplanted organs (5 7). To date, there are no data on the rate and etiology of infection or contamination of the lung allograft and the role of these factors in donor-to-host transmission of bacterial and fungal infections in lung transplantation. The purpose of this study was to determine the incidence, etiology and types of bacterial and fungal infection or contamination in lung allograft donors and to assess donor-tohost transmission of these infections. Patients and Methods All patients who underwent lung transplantation at Vall d Hebron Hospital in Barcelona, Spain between August 1994 and December 2002 were included in this retrospective study. Patients were followed up for a period of 2 months following transplantation. Only recipients who survived more than 24 h and their respective donors were evaluated for the presence of donor bacterial or fungal infection or colonization and possible donor-to-host transmission. Quantitative culture for bacteria (aerobic and anaerobic), fungi and mycobacteria from the donor and recipient were performed at the moment of organ removal. Our protocol includes donor and the recipient blood cultures and culture of the preservation fluids. The explanted lungs were sent to the microbiology laboratory where sterile samples were obtained from respiratory secretions, or in their absence, protected tracheal-bronchial aspirates were performed. The explanted lungs were then sent to the pathology laboratory for analysis and culture of homogenized tissues. Selective and protected bronchial washing of the graft was done before its removal; both lungs were analyzed in the case of double-lung transplants. Samples were sent and processed immediately. Gram stain results were available within hours 178

2 Bacterial and Fungal Infections in Lung Transplantation and the preliminary results of cultures obtained at organ extraction were delivered less than 24 h later. Antibiotic prophylaxis included cefuroxime 1.5 g/8 h ( ) or amoxicillin-clavulanate 2 g/8 h plus aztreonam 1 g/8 h ( ) in recipients with a non-septic underlying disease. Prophylaxis was modified according to the microorganisms isolated from the last cultures performed in donors with a septic underlying disease. Two antibiotics with activity against Pseudomonas aeruginosa were used in these cases. The duration of antibiotic prophylaxis was contingent on the results of recipient and donor intraoperative cultures. Antiviral prophylaxis consisted of intravenous ganciclovir at 5 mg/kg/12 h during the first 15 days after the procedure for all patients, followed by a course of 5 mg/kg/day five times weekly for 90 days in CMV-seronegative patients and the same course for 45 days in CMVseropositive patients. The baseline immunosuppressive regimen began with an intravenous dose of 500 mg of methylprednisolone just before transplantation. Continuous intravenous cyclosporine A was administered as soon as the recipient attained hemodynamic stability. The maintenance treatment consisted of cyclosporine A at doses that maintained trough levels of lg/ml, methylprednisolone 0.5 mg/kg and azathioprine 1 3 mg/kg, adjusted to maintain the leukocyte count above cells/l. Rejection was documented by biopsy and treated with intravenous methylprednisolone at a dose of mg/kg/day for three consecutive days. Recycled oral corticosteroids were given in cases in which an initial response was followed by sluggish improvement. Antifungal prophylaxis consisted of nebulized amphotericin B at 6 mg/8 h during the first 4 months after the procedure and once daily thereafter. Donor and recipient baseline characteristics (age, gender, underlying disease, etc.) were recorded, as was the interval under which donors were on mechanical ventilation. Blood and respiratory secretions from the donor and preservation fluids were cultured at the moment of organ recovery. All positive cultures from these samples and all episodes of recipient infection that developed during the first month after transplantation were recorded. The diagnosis of donor infection was based on isolation of at least 10 3 cfu/ml of bacteria or of fungi from respiratory samples, or a positive culture of fungi or bacteria from blood or preservation fluid at the time of organ recovery. Donor infection was classified as bacteremia, graft colonization or isolated contamination of preservation fluids. Donor-to-host transmission of infection was defined as any infection in the recipient due to at least one microorganism also isolated from the donor during the first month of follow-up. We considered that the microorganism found in the recipient was the same as the microorganism in the donor when the antimicrobial susceptibility patterns were identical. A descriptive analysis was carried out on the type and etiology of donor and recipient infection, and the outcome. Results Over the study period, 210 lung transplantations were performed. Thirteen patients died within 24 h after the procedure, leaving 197 recipients for the final evaluation. Underlying diseases included idiopathic pulmonary fibrosis (n = 43), emphysema (n = 41), bronchiectasis (n = 13), cystic fibrosis (n = 26), lymphangioleiomyomatosis (n = 4), primary pulmonary hypertension (n = 4) and others (hemosiderosis, histiocytosis X, bronchiolitis obliterans and organizing pneumonitis secondary to ammonia inhalation and desquamative interstitial pneumonitis, one case each). The mean age of recipients was 46.2 years (range, 4 months to 67 years) and there were 121 men and 76 women. Singlelung transplantation was performed in 64 cases, doublelung transplantation in 139 cases and retransplantation in 2 cases. The 197 donors included 94 men and 103 women (mean age 32 years; range, 14 months to 55 years). Causes of death included head injury (n = 107), stroke (n = 83), suicide (n = 3) and meningioma (n = 4). One hundred fortyfour donors were mechanically ventilated for less than 48 h and 53 for more than 48 h. An episode of infection was recorded in 103 out of 197 donors. The overall incidence of donor infection was 52%. Thirty-four (33%) of these episodes were polymicrobial. Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Patients ventilated for more than 48 h presented a higher incidence of infection than those ventilated for less than 48 h: 48 infected donors out of 53 (90.5%) vs. 55 out of 144 (38.2%), respectively (p = ). There were no differences in the incidence of donor infection related to the cause of donor death. Twenty-eight donors with no other type of infection had contaminated fluid cultures. Cultures of preservation fluids from these patients were monomicrobial in 14 cases and polymicrobial in the other 14 cases. Gram-positive cocci were the most frequently isolated microorganisms (Staphylococcus epidermidis in 17 cases, Staphylococcus aureus in 6 cases and Streptococcus viridans in 3 cases). Gram-negative bacilli, the most common being Branhamella catarrhalis, Haemophilus influenzae and Klebsiella pneumoniae, accompanied gram-positive cocci in polymicrobial infections. Only one recipient of an organ from a donor with preservation fluid contamination by S. epidermidis presented bacteriemia and tracheobronchitis due to the same microorganism the first month after transplantation. Eight donors were bacteremic at the time of recovery. Four of them had polymicrobial bacteremia and concomitantly three out of four had positive preservation fluid cultures. Only one of the four donors with monomicrobial bacteremia had positive preservation fluid cultures. Donorto-host transmission occurred in two of the eight cases (25%). One recipient experienced purulent tracheobronchitis due to S. aureus and the other necrotizing pneumonia due to Klebsiella pneumoniae and Escherichia coli. The timing of the infection was 3 and 2 days following transplantation, respectively. Neither of the recipients of lung allografts from donors with bacteremia due to nonvirulent microorganisms such as S. epidermidis or viridans streptococci developed an infection in the first month American Journal of Transplantation 2006; 6:

3 Ruiz et al. Table 1: Description of infection episodes due to donor-to-host transmission Microorganism Type of donor infection Type of recipient infection Outcome Prophylaxis A. fumigatus Colonization Tracheobronchitis Cured A A A. fumigatus Colonization Tracheobronchitis Cured A A A. fumigatus Colonization Mediastinitis Died A A K. pneumoniae + E. coli Bacteremia Pneumonia Cured A A MRSA Colonization Pneumonia Died A A S. aureus Colonization Pnemonia Cured Cefuroxime S. maltophilia Colonization Tracheobronchitis Cured A A S. aureus Bacteremia Tracheobronchitis Cured A A P. aeruginosa Colonization Tracheobronchitis Cured Cefuroxime S. aureus Colonization Tracheobronchitis Cured Cefuroxime S. aureus Colonization Tracheobronchitis Cured A A S. aureus Colonization Cutaneous lesions Cured A A P. aeruginosa Colonization Tracheobronchitis Cured A A P. aeruginosa Colonization Tracheobronchitis Cured A A S. viridans Colonization Pneumonia Cured A A A A: Amoxicillin-clavulanate + aztreonam. after the procedure. Episodes of donor-to-host transmitted infections are recorded in Table 1. Sixty-five of the lung allografts (63.1%) had bacterial colonization at the moment of recovery and 28 out of 65 (43%) were polymicrobial. Gram-positive cocci were more frequently isolated than gram-negative rods, although there were no marked differences. S. aureus and H. influenzae were the microorganisms most frequently isolated. In 14 cases, donor cultures yielded fungi (5 Aspergillus fumigatus and 9 Candida albicans). It is noteworthy that only 11 donors were colonized by Pseudomonas aeruginosa. The etiology of respiratory colonization in donors is shown in Table 2. Colonization was found in 50 of the 107 (47%) grafts in donors who died of head injury compared to 42 out of the 83 (50.6%) who died of stroke (p = NS). With regard to etiology, S. aureus (n = 21) was the most frequently isolated gram-positive coccus in donors with head injury, whereas S. pneumoniae was more frequent in donors with stroke (n = 10); differences were not statistically significant. Donor-to-host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients (Table 1), that is, 7.61% of the total number of lung transplants performed in our center. Among these cases, two were due to donor Table 2: Etiology of graft colonization in donors Gram + cocci 46 Gram bacilli 34 Fungi 15 (48.3%) (35.8%) (15.8%) S. aureus 26 H. influenzae 14 C. albicans 10 S. pneumoniae 10 P. aeruginosa 11 A. fumigatus 5 S. viridans 8 K. pneumoniae 4 E. faecalis 2 E. coli 1 A. calcoaceticus 2 S. maltophilia 1 E. cloacae 1 bacteremia and 13 to colonization of the graft. In our experience, 25% of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Two patients died as a result of transmitted infection, one due to mediastinitis caused by A. fumigatus and one due to pneumonia by methicillin-resistant S. aureus (MRSA). Five cases of infection were caused by microorganisms for which it is extremely difficult to design effective prophylactic regimens: A. fumigatus, Stenotrophomonas maltophilia and MRSA. Excluding these cases, prophylaxis failure occurred in 11 of 197 procedures (5.58%). Discussion Bacteria or fungi can be transferred to the allograft by contamination during recovery, preservation or handling, or at transplantation. Contamination from donor infection is probably the most critical, since a large inoculum of microorganisms can be transmitted, thereby putting the recipient at higher risk for subsequent infection. Nevertheless, although donor infection may be a more serious source of infection in transplanted patients, it appears to be less common than contamination during preservation and handling. Donor-to-host transmission of bacterial infection has been documented in some case reports and large series investigating kidney transplantation (8,9). Most of these studies do not differentiate between donor-related transmission and iatrogenic contamination, and the incidence of donor-to-host infection varies widely from 2.1% to 23.4% (1 4,8,9). This wide range is attributed to differences in the preservation methods used, the antibiotic approaches for the preservation fluids and prophylaxis and the bacterial surveillance-culture protocols developed in the different studies. Transmission of fungal infection has received less attention. There are only a few case reports and no systematic studies on donor-to-host transmission of bacterial or fungal 180 American Journal of Transplantation 2006; 6:

4 Bacterial and Fungal Infections in Lung Transplantation infection in solid transplantation other than kidney (6,7,10 14). In lung transplantation, Low et al. found that 97% of donors were infected or colonized and that the same organism was isolated in 43% of recipients, although nearly 80% of them showed no invasive pulmonary infections. In another study, Weill et al. (11) reported that there was no relationship between positive donor gram stain and respiratory infection in recipients. In our cohort of lung recipients, we found a rate of donor-to-host transmission of bacterial or fungal infections of 6.59%. This figure is low compared to the infection rate observed in the donors (52%). Two of the eight (25%) patients that received a graft from a bacteriemic patient developed infection. This finding contrasts with published data (13), reporting no evidence of infection transmission in a large solid-organ transplantation series including lung transplantation. Nevertheless, the small number of bacteriemic patients in the present study does not allow for comparisons or interpretations. Although this is a retrospective study, with the inherent limitations associated with this type of design, the information was retrieved from a prospectively created database containing all the results from cultures performed in the peritransplant period. There is no consensus among authors about the effect on the recipient of transplanting an organ preserved in fluids found to be contaminated. Two series (15) showed a direct correlation between positive fluid culture and morbid infection after transplantation. However, in the majority of studies, the overall relationship between pre-transplant contamination and post-transplant infection is limited (14,15). According to various reports, infection transmitted by the contaminated graft was the cause of death in less than 1% of the population (7,15), and survival in recipients of organs from infected and non-infected donors was not significantly different (6,7,13). Certain bacteria cultured from the donor or preservation fluids seem to carry a special risk for morbid infection after transplantation and have correlated with graft loss or death in large series. Case reports have confirmed donor-to-host transmission of severe infection with these same organisms and have related several complications after transplantation. On the basis of this information, two groups of bacteria with a different associated risk for morbid infection after the procedure can be postulated: (1) commonly cultured gram-positive microorganisms such as S. epidermidis or diphtheroids (low risk) and (2) a series of microorganisms that are less frequently isolated, such as S. aureus, Enterobacteriaceae, P. aeruginosa and fungi (higher risk). In our experience, only three recipients of grafts from donors culture-positive to the first group of bacteria developed an infection by the same bacteria, and it was difficult to demonstrate whether the origin was the donor infection or catheter-related infection in the recipient. All the remaining episodes of donor-to-host transmitted infection in our patients were produced by uncommon, fastidious microorganisms belonging to the second group. This is partly the result of our antibiotic prophylaxis strategy and the fact that drug regimens were modified according to the microorganisms isolated from the last donor cultures performed. It is noteworthy that life-threatening recipient infections were exclusively related to graft colonization with highly virulent microorganisms (Aspergillus spp. and MRSA), for which there are no effective prophylactic regimens. These cases should be considered accidents associated with the act of transplantation. Accepting this observation, we believe that our aggressive prophylactic strategy is effective in preventing donor-to-host transmission of bacterial and fungal infections. In conclusion, donor-to-host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with appropriate prophylactic antibiotic regimens that should be modified according to the microorganisms isolated from cultures of samples obtained from the donors, grafts, preservation fluids and recipients. Acknowledgment This study was financed in part by RESITRA. References 1. Majeski JA, Alexander JW, First MR, Munda R, Fidler JP, Craycraft TK. Transplantation of microbially contaminated cadaver kidneys. Arch Surg 1982; 117: Anderson CB, Haid SD, Hruska KA, Etheredge EA. Significance of microbial contamination of stored cadaver kidneys. Arch Surg 1978; 113: Häyry P, Renkonen OV. Frequency and fate of human renal allografts contaminated prior to transplantation. Surgery 1979; 85: Spees EK, Light JA, Oakes DD, Reinmuth B. Experiences with cadaver renal allograft contamination before transplantation. Br J Surg 1982; 69: López-Navidad A, Domingo P, Caballero F, González C, Santiago C. 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