Incidence and Timing of Infections After Liver Transplant in Italy

Incidence and Timing of Infections After Liver Transplant in Italy P. Piselli, C. Zanfi, V. Corazza, S. Ferretti, M. Scuderi, M. Gabriel Arana, S. Barzoni Secchia, A. Lauro, A. Dazzi, A. Pinna, G.M. Ettorre, G. Vennarecci, R. Santoro, G. Ferretti, N. Gusman, P.B. Berloco, P. Grossi, C. Angeletti, S. Bellelli, A. Nanni Costa, G. Ippolito, E. Girardi, and D. Serraino ABSTRACT Background. Infections are one of the main complications that cause high morbidity and mortality in transplant recipients. This study sought to estimate the incidence of infections and their main determinants in liver transplant recipients in the first year after transplantation. Patients and methods. A prospective study was conducted on 103 consecutive patients (72% men) who underwent liver transplantation in three centers in Northern (Bologna) and Central (Rome) Italy in 2005. Person-years (PY) at risk, incidence rates (IR), IR ratios and 95% confidence intervals were computed for viral, fungal, and bacterial infections. Results. The 103 patients (median age 55 years) contributed a total of 78.2 PYs, with a median follow-up of 286 days (interquartile range: 194 to 365 days). Fifty-eight patients (56.3%) experienced one or more infections, namely, 151 events (IR ⫽ 193.2 infections/100 PYs). IR for bacterial, fungal, and viral infections were 110.0, 56.3, and 26.9 infections/100 Pys, respectively. Within the first 30 days after transplantation, 37.9% patients (39/103) developed one or more events. Bacterial infections represented the most frequent event (86/151, 57.0%). Risk factors significantly associated with increased IR were gender (female), age (⬎50 years), prolonged intensive care stay, volume of blood transfused during surgery and posttransplant, and need for retransplantation. Conclusions. These preliminary results showed the relevance of infectious events after liver transplantation especially those of bacterial etiology, and identified factors mainly associated with their occurrence.

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N THE LAST DECADES substantial improvements have been made in surgical techniques and immunosuppressive regimens. However, as a consequence of immunosuppression and exposure to community acquired and nosocomial pathogens, infections continue to be a major problem, representing one of the leading causes of morbidity and mortality among liver transplant recipients.1,2 It has been estimated that more than two-thirds of liver transplant recipients experience an infectious episode in the first year after transplantation. In these patients, infection is the leading cause of death.3 Moreover, infections may contribute to other indirect complications, including allograft injury, opportunistic superinfection, and malignancies.4 This investigation was designed to better characterize the infections that occurred in the first 12 months following liver transplantation. In particular, the aim was to estimate

incidence rates and timing of infections, as well as to identify factors associated with their occurrence, in this

From the INMI “L. Spallanzani” IRCCS (P.P., M.S., M.G.A., S.B.S., C.A., S.B., G.I., E.G.), Rome; Policlinico “S. OrsolaMalpighi” (C.Z., A.L., A.D., A.P.), Bologna; Ins:tuto “Regina Elena” IRCCS (V.C., R.S., G.M.E., G.V.), Rome; Policlinico Universitario “Umberto I” (S.F., G.F., N.G., P.B.B.), Rome; Università Insubria (P.G.), Varese; Centro Nazionale Trapianti (CNT) (A.N.C.), Roma; and Centro di Riferimento Oncologico (CRO) IRCCS (D.S.), Aviano (PN), Italy. This work was funded by the Italian Ministry of Health (project COBM.F5). Address reprint requests to Dr Pierluca Piselli, Dipartimento di Epidemiologia, INMI “L. Spallanzani” IRCCS, Via Portuense, 292-00149 Rome, Italy. E-mail: [email protected]

0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.05.056

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Transplantation Proceedings, 39, 1950 –1952 (2007)

POSTTRANSPLANT INFECTIONS IN ITALY

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Table 1. Frequencies, Timing, and Incidence Rate for Infectious Events According to the Causative Agent in 103 Liver Transplant Patients Infectious Events Type of Infection

All Bacterial All Gram⫹ Gram⫺ Viral All New infections Reactivations Fungal/yeast

No. of Affected Patients (%)

n

Occurred Within 30 Days from Transplantation (%)

IR/100 PYs (95% CI)

58 (56.3%)

151

91 (60.3%)

193.2 (162.4–224)

35 (34.0%) 19 (18.4%) 26 (25.2%)

86 39 42

59 (68.6%) 32 (82.1%) 26 (61.9%)

110.0 (86.8–133.3) 49.9 (34.2–65.6) 53.7 (37.5–70.0)

37 (35.9%) 16 (15.5%) 23 (22.3%) 14 (13.6%)

44 18 26 21

21 (44.4%) 12 (66.7%) 9 (34.6%) 11 (52.4%)

56.3 (39.7–72.9) 23.0 (12.4–33.7) 33.3 (20.5–46.1) 26.9 (15.4–38.4)

paper we will illustrate the preliminary results of this ongoing epidemiological project. PATIENTS AND METHODS The study group included 103 patients, namely 72% men, of overall median age 55.3 years who underwent liver transplantation between January and December 2005 in three centers in Northern (“S. Orsola Malpighi Hospital,” Bologna) and Central (“Regina Elena Cancer Institute” and “Policlinico Umberto,” Rome) Italy. Four of 103 patients were transplanted with multiple organs: two kidney plus liver and two multivisceral plus liver. We analyzed data regarding the transplant, the clinical interventions during and after transplant—transfusions, prophylaxis and invasive procedures, intensive care unit (ICU) stay and posttransplant diagnostic findings and complications. We considered all documented infectious events of bacterial, viral (new infections or reactivation of preexistent infections), or yeast/fungal origin. These infections were classified on the basis of the type of infectious agent and site of infection.5,6 Multiple infectious events that recurred within 7 days were counted as a single event.5 Persons-year (PYs) (ie, time of total follow-up) was calculated starting from the date of transplant to the date of last follow-up or death, with a maximum follow-up of 12 months after transplantation. Infectious events were assessed using incidence rates (IR) for 100/PYs and incidence rates ratio (IRR) with their 95% confidence intervals (CI). Statistical analyses were performed using SPSS version 14 and STATA version 9 statistical software packages.

RESULTS

The 103 patients included in this study contributed to a total of 78.1 PYs, with a median follow-up of 286 days (interquartile range: 194 to 365 days). Twelve deaths were registered, an overall mortality rate of 15.4 deaths/100 PYs (95% CI: 6.7 to 24). Fifty-eight patients (56.3%, 95% CI: 46.7% to 65.9%) experienced at least one infectious event, with a total number of 151 events (IR ⫽ 193.2 infections/100 PYs). Overall incidence rates for bacterial, viral, and fungal infections were 110.0, 56.3, and 26.9 events/PYs respectively. Table 1 shows the frequency and incidence of all infectious events. Causative agents more frequently observed for gram⫺

bacterial infections, were: Pseudomonas spp (15 events, 13 caused by Psuedomonas aeruginosa) and Klebsiella spp (eight events). For gram⫹ they were Enterococcus spp (17 events, eight Enterococcus faecalis and seven Enterococcus faecium) and Staphylococcus aureus (eight events each). Cytomegalovirus was documented in 19 events, of which eight were reactivations of latent infections); hepatitis virus C in 16 events, of which 15 were reactivations of latent infections. These were the most frequent viral agents diagnosed. Candida spp (16 events) and Aspergillus spp (five) were the most represented agents for fungal/yeast infection. Within 30 days from transplant, 91/151 infectious events (60.3%) were recorded, with a cumulative incidence of infections of 37.9% (39/103, 95% CI: 28.5% to 47.2%). After stratification according to the causative agents in the same period, 32/39 (82.1%) of all gram⫹ infections were reported; among viral infections during the same period, 66.7% of all new infections were reported compared to 34.6% of all viral reactivations (Table 1). With regard to potential risk factors assessed in an univariate analysis (see Table 2), those significantly associated with an increased risk of developing all types of infection were: being female (IRR ⫽ 1.4), age more than 50 years (IRR ⫽ 1.6), being transfused with more than 1000 mL during operation (IRR ⫽ 3.6), residence in the ICU for more than 6 days (IRR ⫽ 3.2), and posttransplant transfusion (IRR ⫽ 2.5). The same factors were associated with a higher IRR (with an increased risk) of developing bacterial or fungal infections, while none of them was associated with an increased risk for viral infections (Table 2). Moreover, retransplantation, which was experienced by five patients, turned out to be significantly associated with bacterial infection only. DISCUSSION

The incidence of infections in this group of liver transplanted patients was high especially in the early postoperative period: 39/103 patients (37.9%) patients experienced at least one infectious event within 30 days and 58/103

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PISELLI, ZANFI, CORAZZA ET AL Table 2. Incidence Rate Ratio for Potential Risk Factors, According to the Type of Infection Incidence Rate Ratio (95% confidence intervals) All Kinds

Sex M F Age at transplant (y) ⬍50 ⱖ50 Red blood cell volume transfused during operation (in mL) ⬍1000 ⱖ1000 Postoperative intensive care unit stay (d) ⬍6 ⱖ6 Posttransplant transfusions No Yes Retransplantation No Yes

Bacterial

Viral

Fungal

1 1.4 (1.0–2.0)

1 1.7 (1.1–2.7)

1 0.6 (0.2–1.3)

1 2.9 (1.1–7.5)

1 1.6 (1.0–2.4)

1 1.8 (1.0–3.3)

1 1.1 (0.5–2.3)

1 2.4 (0.7–12.9)

1 3.6 (2.4–5.5)

1 7.0 (3.6–15.3)

1 1.2 (0.6–2.3)

1 8.8 (2.1–77.8)

1 3.2 (2.3–4.6)

1 4.8 (2.9–8.3)

1 1.2 (0.6–2.3)

1 6.6 (2.2–27.0)

1 2.5 (1.5–4.2)

1 4.3 (2.0–11.1)

1 1.0 (0.5–2.2)

1 6.6 (1.0–276.6)

1 1.7 (0.9–3.0)

1 2.4 (1.1–4.7)

1 0.9 (0.1–3.4)

1 0.9 (0.0–5.7)

(56.3%) within 1 year from transplantation. Bacterial infections were not only the most frequent infectious events (56.9% of all infections), but also those with a premature debut since they represented two thirds of all infections observed in the early postoperative period (ie, 30 days since transplant). Moreover, in the same time period, more than 80% of all gram⫹ infections (n ⫽ 39) were diagnosed. Risk factors significantly associated with increased IR were female gender, age above 50 years, prolonged ICU stay, volume of blood transfusion during surgery and posttransplant transfusions, and retransplantation. The same factors were significantly associated with an even higher IRR with an increased risk of developing bacterial or fungal infections, while none of them was associated with an increased risk for viral infections. Retransplantation, even if experienced by only five patients, turned out to be significantly associated with bacterial infection only. Even if these results are preliminary and need further analysis, frequency and distribution of infections as well as the etiologic agents were similar to those described by other centers in similar settings.7,8 The strong association of infection risk (especially bacterial and fungal etiology) with factors linked to the surgical

procedures or hospitalization address the need for further studies devoted to characterize risk factors and implement infective surveillance and clinical management of transplanted patients. REFERENCES 1. Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 338:1741, 1998 2. Winston DJ, Emmanouilides C, Busuttil RW: Infections in liver transplant recipients. Clin Infect Dis 21:1077, 1995 3. Snydman DR: Infection in solid organ transplantation. Transpl Infect Dis 1:21, 1999 4. Rubin RH: The direct and indirect effects of infection in liver transplantation: pathogenesis, impact, and clinical management. Curr Clin Top Infect Dis 22:125, 2002 5. Guaraldi G, Cocchi S, Codeluppi M, et al: Outcome, incidence, and timing of infectious complications in small bowel and multivisceral organ transplantation patients. Transplantation 80: 1742, 2005 6. Garner JS, Jarvis WR, Emori TG, et al: CDC definitions for nosocomial infections, 1998. Am J Infect Control 16:128, 1988 7. Blair JE, Kusne S: Bacterial, mycobacterial, and protozoal infections after liver transplantation—part I. Liver Transpl 11: 1452, 2005 8. Kusne S, Blair JE: Viral and fungal infections after liver transplantation-part II. Liver Transpl 12:2, 2006