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Volume: 15 Issue: 5 October 2017

FULL TEXT

ARTICLE
Early-Onset Pneumonia After Liver Transplant: Microbial Causes, Risk Factors, and Outcomes, Mansoura University, Egypt, Experience

Objectives: Pneumonia has a negative effect on the outcome of liver transplant. Our aim was to analyze early-onset pneumonia that developed within the first month after transplant.

Materials and Methods: This prospective single-center study included 56 adult living-donor liver transplant recipients; those who developed early-onset pneumonia based on clinical and radiologic criteria were investigated as to causative pathogens and then followed up and compared with other recipients without pneumonia to illustrate risk factors, outcomes, and related mortality of posttransplant pneumonia.

Results: Twelve patients (21.4%) developed early-onset pneumonia with mortality rate of 75% (9 of 12). Sixteen pathogens were isolated; extended spectrum beta-lactamase producing Enterobacteriaceae were the most common (31.2%) followed by carbapenem-producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus (18.8%). Fungi were isolated in 3 cases that were also coinfected with bacteria. Diabetes mellitus (P = .042), liberal postoperative fluid therapy (P = .028), prolonged posttransplant intensive care unit stay (P = .01), atelectasis grade ≥ 2 (P ≤ .001), and calcineurin inhibitor-induced neurotoxicity (P = .04) were risk factors for early posttransplant pneumonia.

Conclusions: Pneumonia is the leading cause of early mortality after liver transplant. The emergence of multidrug-resistant bacteria is major issue associated with a high rate of treatment failure.


Key words : Mortality, Multidrug-resistant bacteria, Pneumonia

Introduction

Liver transplant is the preferred available treatment for patients with end-stage liver disease. The 1-, 5-, and 10-year survival rates are significantly improved up to 85%, 71%, and 62% with transplant.1 However, liver transplant is a costly procedure and has questionable economic benefit, given that transplant recipients may not regain adequate health-related quality of life and/or rejoin the workforce.2 Many studies have investigated pneumonia risk factors to apply prophylactic strategies to decrease the negative effects of posttransplant pneumonia on clinical outcomes and health care costs.3-5 However, such data are lacking for our liver transplant center. The aim of this study was to evaluate early-onset pneumonia with regard to incidence, microbial causes, and risk factors and its effect on survival of liver transplant recipients.

Materials and Methods

Patients
This prospective descriptive study included 56 consecutive patients who underwent living-donor liver transplant (LDLT) between June 2012 and August 2013. All operations were performed at the Gastroenterology Surgical Center, Mansoura University, Egypt, after written informed consents were obtained from the patients and after approval from the liver transplant committee of Mansoura University. The study protocol complies with the 1975 Declaration of Helsinki and was approved by the Institutional Research Board of the Faculty of Medicine, Mansoura University, Egypt. Written informed consents were obtained from patients or their relatives. According to our protocol, 2 patients were excluded: 1 patient with liver retransplant and 1 patient who was younger than 18 years old.

Preoperative data collection
The following data were recorded: age, sex, primary indication for liver transplant, comorbidities including diabetes mellitus, Child-Pugh score,6 and Model for End-Stage Liver Disease score, which was calculated as described by Wiesner and associates.7

Postoperative treatment
Patients were immediately transferred to the intensive care unit (ICU) after surgery. Extubation was done within 2 hours when the patient reached appropriate neurologic status, had stable cardio-vascular function, and maintained an adequate gas exchange on spontaneous breathing according to Alía and Esteban.8 During the first 72 hours, fluid balance was closely adjusted to maintain core perfusion to ensure graft survival. The target points were urine output > 0.5 mL/kg/h according to Barri and associates9 and a central venous pressure up to 8 cmH2O according to Mark and Slaughter.10 Oral fluids were initiated 24 hours after liver transplant. Urinary catheter and nasogastric tube were removed on day 4 with start of oral solid intake. Routine postoperative laboratory investigations and chest radiographic scans were done for all patients immediately after transplant and then daily throughout ICU stay. In accordance with Golfieri and associates,11 atelectasis was radiologically classified into 3 grades. Grade 1 atelectasis referred to involvement of 1 subsegment or discoid atelectasis, grade 2 atelectasis represented 2 subsegments affected, and grade 3 represented ≥ 3 subsegments affected.

Immunosuppressive therapy
Intravenous methylprednisolone and basiliximab with mycophenolate mofetil through the nasogastric tube were given during transplant, and then intravenous basiliximab was introduced at day 4 posttransplant. Maintenance therapy of tacrolimus and mycophenolate mofetil started at day 1 posttransplant. In cases of renal impairment and in cases of calcineurin inhibitor (CNI)-induced neurotoxicity, the tacrolimus dose was reduced to its lower therapeutic range, with cyclosporine given if no improvement occurred. In severe refractory cases of neurotoxicity or renal failure despite reduction of cyclosporine dose by 25% to 50%, CNI administration was discontinued and replaced by everolimus. Cellular rejection was diagnosed based on histologic confirmation by targeted liver biopsy and was managed by addition of intravenous methylprednisolone for 3 successive days, which was then replaced with oral prednisolone and gradual tapering of the dose.

Perioperative antimicrobial prophylaxis
All patients received intraoperative and then postoperative antibiotic prophylaxis according to pretransplant culture surveillance, which then changed according to the results of posttransplant culture surveillance, especially if associated with symptoms and signs of infection. Postoperatively, all patients received sulfamethoxazole/trimethoprim for prophylaxis against Pneumocystis jiroveci, fluconazole for prophylaxis against fungal infection, and intravenous gancyclovir and then oral valacyclovir for prophylaxis against Cytomegalovirus (CMV) according to the protocol of our center.

Pneumonia diagnosis
Early posttransplant pneumonia was considered when the pneumonia episode occurred within the first month after liver transplant. Chest radiography was done for any patient who developed cough and dyspnea accompanied by at least 2 of 3 features (fever > 38ºC, leukocytosis or leukopenia, and purulent secretions), along with inspiratory crackles or bronchial breathing on auscultation. Criteria that were suggestive of pneumonia were new infiltrate on lung imaging plus clinical features according to the American Thoracic Society and Infectious Diseases Society of America.12 Chest computed tomography was a valuable adjunct in cases of inconclusive results on chest films despite respiratory symptoms. Thoracic ultrasonography was used to assess, to follow-up parapneumonic effusion, and to guide sample aspiration and catheter drainage of effusion.

For patients who received mechanical ventilation, a microbiologic diagnosis was obtained by tracheal aspirate culture in patients with contraindications for fiberoptic bronchoscopy, including hemodynamic instability, uncorrectable severe hypoxemia, international normalized ratio > 2, or platelet count < 50 000/mm3. Bronchoalveolar lavage (BAL) culture was performed in other mechanically ventilated patients. Tracheal aspirate was taken by sterile suction catheter through the endotracheal tube. Bronchoalveolar lavage procedure through fiberoptic bronchoscopy (Olympus BF-1T20D, Tokyo, Japan) was performed with adjustment of mechanical ventilation settings according to the standardized guidelines from the affected lobe according to chest radiography; if pneumonia was bilateral, BAL was done from the lingua or the middle lobe according to Tai.13 Sputum culture was performed only in patients who were spontaneously breathing. For associated parapneumonic effusion, culture of pleural fluid sample aspirated under complete aseptic precautions was done.

Respiratory samples were subjected to aerobic semiquantitative bacterial culture and drug sensi-tivity, fungal culture on Sabouraud dextrose agar, and tuberculosis assessment by Ziehl-Neelsen staining. Bronchoalveolar lavage and tracheal aspirate samples were investigated by additional tests, including tuberculosis nucleic acid amplification by polymerase chain reaction, tuberculosis culture on Lowenstein Jensen medium, staining for Pneumocystis jiroveci with Giemsa stain, and influenza virus assessment using reverse transcription polymerase chain reaction assays (in addition to nasopharyngeal swabs and nasal swabs).

Blood samples were taken from all patients for aerobic bacterial and fungal culture according to the standard method of microbiology, CMV assessment by the enzyme-linked immunosorbent assay for detection of CMV immunoglobulins G and M, and molecular amplification by COBAS Amplicor test (Roche Diagnostics, Branchburg, NJ, USA). Serum samples were sent for serologic profile of influenza viruses (hemagglutinin and neuraminidase anti-bodies).

Respiratory failure was defined by a partial pressure of oxygen in arterial blood of less than 55 mm Hg when fraction of inspired oxygen was 0.60 or greater (oxygenation failure) with or without ventilatory failure defined as an arterial carbon dioxide tension greater than 45 mm Hg with resultant acidemia.14 Patients were considered as having acute respiratory distress syndrome according to the Berlin definition.15

Diagnosis of severe sepsis
Severe sepsis was diagnosed when any of the following developed as sequelae to pneumonia or extrapulmonary infections16: (1) hypotension (systolic blood pressure < 90 mm Hg, mean arterial pressure < 70 mm Hg, or decrease in systolic blood pressure > 40 mm Hg), (2) urine output < 0.5 mL/kg/h for more than 2 hours despite adequate fluid resuscitation, (3) creatinine > 2.0 mg/dL, (4) bilirubin > 2 mg/dL, (5) platelet count < 100 000/mm3, and (6) international normalized ratio > 1.5.

Postoperative data collection
The following data were recorded: (1) the length of posttransplant ICU stay, (2) daily fluid balance for the first 3 postoperative days, and (3) the length of ICU readmission and mechanical ventilation duration for pneumonia and other complications.

Statistical analyses
Data were analyzed with SPSS software (SPSS: An IBM Company, version 16, IBM Corporation, Armonk, NY, USA) and Epi Info version 7 (Centers for Disease Control and Prevention, Atlanta, GA, USA). The 2 groups (patients with and without early pneumonia posttransplant) were compared with Mann-Whitney test for nonparametric data and chi-square test or Fisher exact test for categorical variables as appropriate. The relative risk (RR) and its 95% confidence intervals (CI) were calculated to identify risk factors for pneumonia. Cumulative survival rates were analyzed using the Kaplan-Meier method. P values ≤ .05 were considered statistically significant.

Results

Characteristics of the recipients
Fifty-six patients who underwent LDLT between June 2012 and August 2013 were included in this prospective study. Of these patients, 50 were males (89.3%) and 6 were females (10.7%); the mean age of patients was 49.7 ± 7.42 years (range, 26-62 y). The primary indications for liver transplant are shown in Table 1.

Posttransplant early-onset pneumonia and causative pathogens
Twelve liver transplant recipients (21.4%) developed early-onset pneumonia; 9 patients had associated parapneumonic effusion. Microbiologic cultures isolated 16 pathogens. Four of the pneumonia cases were polymicrobial. The gram-negative bacilli (GNB), gram-positive bacteria (GPB), and fungi represented 50%, 31.2%, and 18.8% of the pathogens. Among GNB, extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most common bacterial pathogens (31.2%) followed by carbapenem-producing Enterobacteriaceae (18.8%). Among GPB, methicillin-resistant Staphylococcus aureus (MRSA) was the most common pathogen (18.8%), followed by Streptococcus pneumoniae and methicillin-sensitive Staphylococcus aureus. Candida albicans was isolated in 2 cases (12.5%) followed by Aspergillus fumigates in 1 case (6.3%) (Table 2).

Posttransplant pneumonia-associated outcomes
Severe sepsis complicated the course of pneumonia in 6 patients (50%). Nine patients with pneumonia (75%) developed respiratory failure, necessitating mechanical ventilation, with 7 of these patients (58.3%) developing acute respiratory distress syndrome (Table 3). For patients with posttransplant pneumonia, the length of ICU stay and the duration of mechanical ventilation were significantly longer than in patients without pneumonia (P ≤ .001). The frequency of severe sepsis was higher in patients with pneumonia (P = .013). Patients who developed pneumonia had a significantly higher mortality than those patients without pneumonia (P ≤ .001) (Table 4). Figure 1 shows the cumulative survival of patients with and without early-onset pneumonia. The 3-month survival rate of the studied 56 liver transplant recipients was 76.8%. Regarding pneumonia-related mortality, 2 patients died at 1 month after liver transplant and 7 patients died at 2 months after transplant. For patients without pneumonia; 2 patients died at month 1 after liver transplant, 1 patient died at month 2, and 1 patient died at month 3.

Risk factors for early pneumonia after living-donor liver transplant
We compared patients with and without post-transplant early pneumonia (Table 5). Our analyses showed that the presence of diabetes mellitus (RR = 2.87, 95% CI, 0.98-8.41; P = .042), daily fluid balance > 500 mL for ≥ 2 days of the first 3 days after transplant (RR = 3.09, 95% CI, 1.06-9.05; P = .028), prolonged posttransplant ICU stay (P = .01), atelectasis grade ≥ 2 (RR = 8.2, 95% CI, 2.56-26.29; P ≤ .001), and CNI-induced neurotoxicity (RR = 2.73, 95% CI, 1.04-7.17; P = .04) were significant risk factors for posttransplant early-onset pneumonia.

Discussion

Patients treated with liver transplant have a generally poor preoperative clinical condition and are subjected to lengthy extensive surgical pro-cedures in addition to posttransplant use of immunosuppressive agents, such as cyclosporine and tacrolimus, to avoid graft rejection. Thus, liver transplant recipients are liable to considerable risks of morbidity and mortality from surgery com-plications (intra- or postoperative hemorrhage, vascular or biliary complications), graft dysfunction or rejection, and infections, especially during the first month after liver transplant, which is considered to be the most critical period.11,17,18 Although post-transplant pneumonia occurs less frequently than other infections, such as intra-abdominal, biliary tract, and urinary tract infections, they can cause more morbidity and mortality due to rapid progression to diffuse lung injury and multisystem organ failure.18,19

In this study, we followed patients who received LDLT at the Gastroenterology Center, Mansoura University, Egypt, to monitor and evaluate all pulmonary infectious complications that may affect those patients within the first month after transplant. Our aim was to identify an effective management strategy.

Our study showed early-onset pneumonia in 12 of 56 patients (21.4%); multidrug-resistant (MDR) GNB including carbapenems-producing Enterobacteriaceae and extended-spectrum beta-lactamase-producing Enterobacteriaceae (50%) and MRSA (18.8%) were the most common isolated causative pathogens. Similarly, Ikegami and associates4 in a retrospective analysis reported pneumonia in 14.5% of patients (50 of 346) during the first 3 months after LDLT and reported that GNB represented 84.0% of the causative pathogens. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were reported as the most common isolated bacteria, whereas GPB (mainly MRSA) accounted for 16% of the isolated organisms. Santoro-Lopes and de Gouvêa20 stated that the prevalence of MDR GNB and GPB isolated from transplant patients increases due to pretransplant colonization with MDR bacteria, which may be due to frequent hospital admissions and antibiotic use in patients with high pretransplant clinical severity.

In this study, the reported pneumonia-related mortality rate was 75% (9 of 12 patients). Ikegami and associates4 reported a 42% mortality rate (21 of 50 patients). The higher mortality rate in our study can be explained by a high prevalence of MDR GNB, coinfection with invasive fungal infections in 3 patients, high frequency of severe sepsis, acute respiratory distress syndrome, and respiratory failure, which complicated the course of pneumonia. However, Weiss and associates21 reported mortality rate of only 13% (3 of 23 patients). The explanation of this low mortality rate may be the relatively low rate of MDR pathogens with high response to empirical antibiotic regimens using broad-spectrum β-lactams plus aminoglycosides. Kim19 stated that posttransplant infections with MDR GNB and MRSA are associated with higher rates of allograft failure and mortality due to high therapeutic failure rates. In addition, the mortality associated with invasive fungal infections can reach 100%, especially in cases of invasive aspergillosis according to Liu and associates.22

Our study revealed that daily fluid balance > 500 mL for ≥ 2 days during the first postoperative 3 days was a risk factor for posttransplant early pneumonia (RR = 3.09, 95% CI, 1.06-9.05; P = .028), and this was in agreement with a meta-analysis conducted by Corcoran and associates,23 in which they found that patients who receive liberal fluid therapy had a higher risk of pneumonia (RR =2.2, 95% CI, 1.0-4.5; P = 0.04) than those in the restrictive fluid strategy group. According to Holte and associates,24 the liberal perioperative intravenous fluid administration may contribute to an exaggerated fluid shifting into the interstitial space, which in turn could potentially increase several problems after surgery, including prolonged postoperative ileus, impaired anastomotic healing, and pneumonia through fluid accumulation in the lungs. The resulting inhibition in gastro-intestinal motility may predispose to sepsis through bacterial translocation from the gut.

Our study reported that patients with diabetes mellitus had higher risk of posttransplant early pneumonia (RR = 2.87, 95% CI, 0.98-8.41; P = 0.042). Consistent with our results, Ikegami and associates4 reported that the presence of diabetes mellitus was a significant risk factor for posttransplant bacterial pneumonia (odds ratio = 2.8, 95% CI, 1.4-5.6; P < .01). Casqueiro and associates25 explained the underlying mechanisms of increased incidence of infections with diabetes mellitus as a result of increased virulence of pathogens with hyperglycemia, defect in the production of interleukins in response to infection, decreased expression of class I major histocompatibility complex on the surface of myeloid cells, reduced chemotaxis and phagocytic activity, reduced response of T cells, and defective humoral immunity (deficiency of the C4 complement component and biologic dysfunction of antibodies).

Golfieri and associates11 reported that persistent pleural effusion and atelectasis were major independent predictors of posttransplant pneumonia (odds ratio = 3.95; 95% CI, 2.16-7.25; P ≤ .001). Imai and associates26 showed that the incidence of pneumonia was significantly higher in liver transplant recipients with grade ≥ 2 postoperative atelectasis than without (18.4% versus 1.6%; P = .002). Similarly, our study reported that patients with atelectasis grade ≥ 2 had higher risk of posttransplant early pneumonia (RR = 8.2, 95% CI, 2.56-26.29; P ≤ .001).

In agreement with our results that showed that CNI-induced neurotoxicity was associated with increased risk of posttransplant early pneumonia (RR = 2.73, 95% CI, 1.04-7.17; P = .04), Balderramo and associates27 reported that CNI-induced neurotoxicity was associated with significantly higher rate of infections such as bacterial (P = .001), fungal (P = .002), and CMV (P = .009) than shown in the control group. Bechstein28 described the neurologic adverse effects of CNI, which include tremor, altered mental functioning, seizures, cerebellar syndrome, extrapyramidal syndrome, pyramidal weakness, and peripheral neuropathy, and reported that many of these symptoms may persist even after CNI dose reduction or CNI conversion. These neurologic complications may result in prolonged ICU stay and immobilization. Imai and associates26 showed that performance status ≥ 3 was a risk factor for postoperative pulmonary complications (odds ratio = 7.1, 95% CI, 2.0-28.0; P = .003). According to the Eastern Cooperative Oncology Group scale of performance status, a performance status ≥ 3 indicates that a patient is bedridden for greater than 50% of the day.29

There were limitations to our study. First, our sample size (56 patients) was somewhat small because the primary focus of our study was to prospectively evaluate consecutive liver transplant recipients who underwent LDLT within 1 year. Second, our study was performed at a single hospital; therefore, the results might not be applicable to other health care facilities. Further prospective and multicenter studies are thus needed to validate these finding.

In conclusion, pneumonia is the most serious infection after LDLT due to its association with a high mortality rate, the significant increase in the duration of mechanical ventilation, and prolonged ICU stay. The emergence of MDR bacteria is associated with a high rate of treatment failure. Risk factors for early pneumonia after liver transplant include diabetes, liberal postoperative fluid therapy, atelectasis grade ≥ 2, prolonged ICU stay, and CNI-induced neuro-toxicity.


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Volume : 15
Issue : 5
Pages : 547 - 553
DOI : 10.6002/ect.2016.0176


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From the 1Department of Chest Medicine, Mansoura Universty Hospitals, 2Department of Anesthesia and Intensive Care, the Gastrointestinal Surgical Center, and the 3Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Egypt
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Rehab Ahmad Elmorsey, Daqahlia, Mansoura University, Egypt 35516
Phone: +201063884630
E-mail: rehabahmad435@yahoo.com