The Epidemiology And Risk Factors Of Fungal Infection Following The Postoperative Period In Liver Transplantation

Since Starzl successfully operated the first human liver transplantation in the world in 1963, the liver transplantation has underwent nearly 50 years'development, and became the most effective treatment for patients of last stage liver diseases and the acute liver function failure. But fungal infection is still one of the most important causes of death following the post-operative period in the liver transplantation, The incidence of fungal infections following liver transplantation reaches as high as 15%-42%, and the mortality reaches 40%-80%, which are higher than that of acute rejection, kidney failure and virus infections. Fungal infection after liver transplantation often lack of typical clinical manifestations, which is difficult for correct clinical diagnosis; because of the specificity of surgery and medication for patients who received liver transplantation, fungal infection is difficult to controlled and is a serious complication. The epidemiological features and risk factors of fungal infection after liver transplantation has its uniqueness. As the the growing awareness of fungal infection, the researches of the epidemiology and risk factors for fungal infections after liver transplantation are also increasingly being concerned and become an important subject. We made a retrospective research for epidemic characteristics of the fungal infections within 118 cases who received liver transplantation in Nanfang hospital from August 2004 to January 2009, studied and identified the fungi and drug resistance; selected independent variables to analyzed by univariate analysis and logistic regression to screen out the risk factors. Thus we can provide a theoretical basis for effectively prevention and treatment of fungal infections following liver transplantation.Patr One Analysis of epidemiology and drug resistance of fungal infection during the early postoperative period in liver transplantation[OBJECTIVE] Fungal infection is still the most important complication affecting the success rate and postoperative survival rate during the early postoperative period in liver transplantation.With the introduction of new anti-fungal measures and preventive treatment in recent years. As reported at home and abroad the incidence of fungal infections is still rising, meanwhile the bacterial spectrum has undergone some changes and the fungal resistance rate is gradually increased. In the purpose of making more effective prevention and treatment of fungal infections, we make a retrospective analysis of fungal infection after liver transplantation in 118 cases from August 2004 to January 2009 in Nanfang hospital, to Identify fungi types and drug resistance pattern.[MATERIALS AND METHODS]1. Cases Source The 118 cases who received liver transplantion from August 2004 to January 2009 were included in the research. We test the (1,3)-β-D-glucan of serum and fungal smear specimens 2-3 times a week. The specimens contained: respiratory tract specimens (sputum, throat swab), gastrointestinal tract specimens (gastric juice, faeces), ascites, bile, midstream urine, blood. Of which the positive serum (1,3)-P-D-glucan and (or) positive smear test results,We collected the specimens repeated several times to the appropriate fungal culture and sensitivity test. The patients who were suspected of fungal infections, we collected specimens for culture and sensitivity test repeatedly regardless of the outcome of serum (1,3)-β-D-glucan and smear.2. Fungi identification and susceptibility test We selected chromogenic medium frome Zhengzhou Bossay Bioproducts Co. for fungal culture and identification, The antifungal of piromidic susceptibility test methods refer to M38-A program publiced by the National Committee for clinical trials Standardization (NCCLS) 2003, other drug use Danish Rosco Determination of fungal susceptibility disk diffusion method.3. Diagnostic Criteria①Patients with systemic or local infection in the clinical manifestations and can not be explained by other complications, while the broad-spectrum antibiotics and anti-viral treatment are ineffective.②Fungi Specimens isolated from a sterile site (blood, cleaning the middle of urine, bile, pleural effusion, peritoneal drainage fluids, catheters, etc.) one or more times.③Continuous culture for the kind of fungi two times or more from the same parts by funal culture or pathological examination,or isolated the same kinds of fungi from different parts.④Repeated smear microscopy found that a large number of fungal hyphae or spores and confirmed by fungal culture at least once.⑤Fungal colonization or fungal skin infections are not incorporated into statistical areas.4. Prophylactic treatment with antifungal drugs 58 cases in this group were given preventive use of antifungal agents since the first day after operation: intravenous fluconazole 150～200mg/d,2～3 weeks.5. Statistical analysis SPSS 13.0 statistical software were used to calculate the frequency and percentage.[RESULTS]1. The diagnose and clinical data of 26 cases of suspected fungal infections 26 cases were confirmed to be fungal infections, infection rate was 22.0%, of which 22 male and 4 female. The average age of 54.3 (32～74) years, the average hospital stay was 71.4 (33～193) d. The primary disease including posthepatitic cirrhosis in 12 cases (including 3 cases of acute liver failure),13 cases of primary liver cancer, severe hepatitis in 1 case.26 patients were given triple anti-rejection therapy routinely postoperation [Tacrolimus (FK506), mycophenolate mofetil, methylprednisolone; and changed to FK506, mycophenolate mofetil, prednisone 5 days later]. Plasma concentration of FK506 were maintained at 10-15ng/ml. All cases of postoperative antibiotics were combined, with an average course of 35.9 (20～50) d.2. The site of infection and fungal species Six kinds of fungi were isolated, totally 49 fungi,With the highest detection rate of Candida albicans, Totally of 49 fungi strains were isolated, of which mainly were Candida albicans(57.1%), following the aspergillus, smooth candida, Candida tropicalis, Candida parapsilosis, Candida krusei. Infection site is mainly in respiratory tract, followed by the gastrointestinal tract, abdomen, biliary tract, blood, urinary tract. In which a single system (or organs) fungal infection in 22 cases (84.6%), multiple systems (or organs) fungal infection in 4 cases (15.4%),5 patients with combined more than two kinds of fungal infection.3. Time distribution of fungal infection The average time for infection 13.6 (1～53) d, of which 93.8%occurred within 1 month after surgery. Time distribution of the fungal infection was found after 1 week analysis of detection rate (42.9%) the highest, with time extended, and the detection rate of decline.4. The results of susceptibility test The overall sensitivity of fluconazole was lowest (55.1%), itraconazole and voriconazole was the highest (90.0%, respectively, 92.0%). The resistance rate of Candida tropicalis and Candida were highest (both 42.9%). 5. Treatment and outcome 26 cases of fungal infection were treated with anti-fungal treatment, that is, intravenous fluconazole 150-400mg/d,8-31d, of which 4 cases because of resistance to fluconazole than changed to intravenous infusion of itraconazole 200～00mg/d for 10～25d.19 patients were cured and 7 deaths, the mortality was 26.9%; of which 5cases were directly related with the fungal infection, The direct cause of the other two cases of death is graft-versus-host reaction.[CONCLUSION]1. The pathogenic fungal infections after liver transplantation in the still mainly Candida, including Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida krusei, etc., of which the highest proportion of Candida albicans. Aspergillus with higher mortality (18.4%) of infection is also higher than other reports at home and abroad. Spectrum of fungal infections in recent years, prompted a change in bacteria.2. Infection site is mainly respiratory and gastrointestinal tract, accounting for 75.5%and 10.2%. Fungal infection mainly occurred in the postoperative 1 week (42.9%), with the time extened, the incidence of fungal infections showed a downward trend, suggesting that patients susceptible to liver transplantation period (within 1 month after operation, especially within 1 week) should strengthen the respiratory tract, gastrointestinal tract and other parts susceptible to fungal infection monitoring, and strive to early detection and timely treatment of fungal infections.3. Susceptibility test results of this study show that voriconazole, itraconazole against fungi have a higher sensitivity to amphotericin B, flucytosine, fluconazole and other drugs on fungi, the average sensitivity was relatively low. Various types of antifungal agents on the sensitivity of different species of fungi there are certain differences, itraconazole, voriconazole against Candida and Aspergillus sensitivity rates were generally higher, flucytosine, amphotericin B followed, while the fluconazole against Candida and Aspergillus sensitivity is generally low. As the antifungal agents are widely used in liver transplantation preventive and empirical therapy, and the continual emergence of drug-resistant strains, especially fluconazole-resistant strains increased gradually.4. Anti-fungal treatment should be integrated types of pathogens, drug resistance characteristics and so a reasonable choice of drugs, choice should be based on susceptibility-sensitive drugs, parallel enough, enough course of anti-fungal treatment, poor drug efficacy when used alone can also be changed to combined medication. Itraconazole, amphotericin derivatives, voriconazole with a minor dverse drug reactions which are more sentive to Candida and Aspergillus is a better choice alternative to fluconazole.5. Recent studies suggest that preventive anti-fungal therapy in reducing the liver transplantation the incidence of deep fungal infection has a positive effect. This study also found that preventive anti-fungal effective in preventing fungal infections.Patr Two Analysis and prophylaxis of the risk factors for fungal infection following liver transplantation[OBJECTIVE] Fungal infections are hospital-acquired infection, there are multiple risk factors in susceptible populations,As it's recognized, patients with severe underlying diseases, immune dysfunction, malnutrition, long-term use of antibiotics and acceptance of a variety of invasive diagnosis and treatment of patients are all the risk factors. Liver transplantion is intended primarily for patients with end-stage liver disease, such as primary liver cancer, hepatitis, cirrhosis, liver failure and so on, the receptor preoperative conditions and nutritional status are always poor, together with the long time and large traumatic of surgry, immunosuppressive therapy and anti-infection treatment-specific after surgry. Therefore, in view of perioperative and operation inherent specificity, it is necessary to find out the major risk factors from a variety of factors leading to fungal infections for perioperative prevention and provide a theoretical basis.[MATERIALS AND METHODS]1. Clinical data 118 cases of patients received liver transplantation in the Nanfang hospital of the South Medical University for liver transplant from.100 cases were male and 18 female, mean age of 47.2 (16～74) years, the average hospital stay was 62.9 (16～193) d, the average intensive care unit (ICU) observation with the time 3.8 (1～19) d. The primary disease, including hepatitis,42 patients with liver cirrhosis, primary liver cancer in 70 cases,4 cases of severe hepatitis, Budd-Chiari syndrome in 1 case, hepatic degeneration in 1 case.2. Surgery program and immunosuppressive regimen Classic orthotopic liver transplantation in 78 cases, piggyback liver transplantation in 40 cases. All patients were given triple anti-rejection therapy routinely postoperation[Tacrolimus (FK506), mycophenolate mofetil, methylprednisolone; and changed to FK506, mycophenolate mofetil, prednisone 5 days later]. Plasma concentration of FK506 were maintained at 10-15ng/ml. All cases of postoperative antibiotics were combined, with an average course of 35.9 (20～50) d.3. The choice of relevant factors we selected 44 related factors as follows for statistical analysis according to the experience in our center and reference literature.①preoperative factors:gender, age, weight, length of stay in hospital, smoking history, hepatopulmonary syndrome, other lung diseases (such as lung inflammation, chronic obstructive pulmonary disease, bronchial asthma, etc.), liver function classification, malignant tumor in liver, hypoalbuminemia, diabetes, ascites, preoperative serum total bilirubin 1d before operation [(TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT), serum creatinine (Cr), blood urea nitrogen (BUN)).②Intraoperative factors:liver warm ischemia time, cold ischemia time, operation time, anhepatic phase, blood loss, perioperative blood transfusion.③Postoperative factors:examine the (TBIL, ALB, ALT, AST, PT, Cr, BUN) 1d after operation, pleural effusion (including those which existed before surgery), intensive care unit (ICU) observation with time, there are invasive mechanical ventilation, parenteral nutrition (TPN) time, use of time and types of antibiotics, deep venous catheter indwelling time, catheter indwelling time, intra-abdominal drainage tube indwelling time, acute rejection, surgical complications (eg. postoperative abdominal bleeding, biliary fistula, biliary stricture, etc.), bacterial infections, continuous renal replacement therapy (CRRT), re-operation.4. Statistical analysis Cases consistent with the above-mentioned diagnostic criteria of cases classified as a fungal infection group, the remainder were classified as the control group. First, the major independent variables in perioperative period of the liver transplantion recipients were analyzed in univariate analysis (which count data compared with theχ2 test, measurement data used to compare the independent samples t test), compared with fungal infection group and the control group the difference between the initial search for out the risk factors associated with infection. In view of the existence of certain factors can interact, there will be statistically significant risk factors included in Logistic regression analysis to identify major risk factors. Using SPSS13.0 statistical software, according toα= 0.05 significance level, P<0.05 for the difference statistically significant.[RESULTS]1. Univariate analysis of the relevant factors 44 perioperative factors were analyzed in univariate analysis, found that preoperative hypoproteinemia, liver decompensation, hepatopulmonary syndrome, ICU observation with time, invasive mechanical ventilation, pleural effusion, the use of antibiotics time and type of deep venous catheter indwelling time, intra-abdominal drainage tube indwelling time etc, there are significant difference in the 9 related factors between the fungal infection group and control group statistically.2. Multivariate analysis of risk factors The nine factor which are statistical significance were include into Logistic regression analysis, than final selected five factors after liver transplantation was significantly related to risk factors. According to the risk (OR value) as followed:the use of antibiotics≥3 kinds and the time≥2 weeks, ICU observation with time≥5d, pleural effusion, invasive mechanical ventilation≥48h decompensated liver function.3. The connection between infection and risk factors 19 patients were cured and 7 deaths, mortality of 26.92%; of which are directly related with the fungal infection in 5 cases, mortality of 19.23%, in this 5 cases,preoperative liver failure in 2 cases, merger chest plot fluid in 3 cases, invasive mechanical ventilation were greater than 48h, observation more than five days in the ICU, the use of antibiotics≥3 kinds and the time≥2 weeks.[CONCLUSION]1. Preoperative hypoproteinemia, liver function decompensation, hepatopulmonary syndrome, Deep venous catheter indwelling time, intra-abdominal drainage tube indwelling time, pre-operative liver failure, duration of ventilator over 48 hours, pleural effusion, observation in ICU more than 5 days, the use of antibiotics more than 3 kinds and longer than 2 weeks are risk factors.And the last 5 are the most important risk factors2. We should take effective preventive and treatment measures In response to these risk factors, strengthen high-risk patients in monitoring in early postoperative,such as respiratory tract, gastrointestinal tract and other parts which susceptible to fungal infection. and strive to early detection and timely treatment of fungal infections. The above measures can help to reduce the incidence of postoperative fungal infections and improve the success rate of surgery.