Bacterial and Miscellaneous Infections of the Liver

Epidemiology

Liver abscesses are generally divided into two categories, those pyogenic in nature and the others due to amebic infections. Pyogenic liver abscess (PLA) has been recognized since the time of Hippocrates and was associated with a high mortality until the advent of antibiotic therapy, improved imaging modalities, percutaneous and minimally invasive procedures, and surgical drainage. Subphrenic abscesses share the same pathogenesis as PLA including intraperitoneal processes, appendicitis, diverticulitis, perforated duodenal ulcers, anastomic leaks, or as a postprocedural complication.

In the United States the incidence of hospitalization for PLA was reported at 3.6 per 100,000 population, with a case-fatality rate of 5.6%, and a 4.1% annual average percent increase from 1994 to 2005. In comparison, population-based studies in Canada observed an annual incidence of PLA of 2.3 per 100,000 population. In Denmark, the incidence rate was reported to have been 11.8 and 9.7 per 1,000,000 for men and women, respectively, from 1977 to 2002. In Taiwan, the annual incidence of pyogenic liver abscesses increased from 11.15 per 100,000 to 17.59 per 100,000 between 1996 and 2004. These occurred in the setting of diabetes, malignancy, and renal disease. PLA is generally present in individuals in their fifth and sixth decades of life without significant racial or ethnic differences. The elderly have a higher mortality along with those with cirrhosis, malignancy, and chronic kidney disease. In contrast to the preantibiotic era where the most common cause of PLA was appendicitis and diverticulitis, today it is most commonly associated with biliary disease or is cryptogenic in nature.

Etiology, Pathogenesis, and Pathophysiology

Although a distinct pathophysiologic process has not been reported with PLA, using a mouse model, Chung et al. were able to elucidate the role of T-lymphocytes in the development of liver abscess caused by Bacteroides fragilis . The researchers described the likely mechanisms behind the formation of liver abscess through activation of Kupffer cells after bacterial exposure resulting in cytokine and chemokine production, which in turn activates T cells and natural killer cells. Encapsulation then occurs by fibrosis through cytokine release and the employment of circulating inflammatory cells. Development of PLA is usually due to bacterial invasion through the portal vein or direct extension from a contiguous neoplasm, suppurative processes or infection involving the biliary tract. Penetrating and nonpenetrating traumas and bacteremia via the hepatic artery have also been well documented in earlier literature ( Figs. 40-1 and 40-2 ). The abscess is located most often in the right lobe (71.5% of cases) due to its size and significant portal blood flow, followed by the left lobe (15%), and caudate lobe (0.8%). Bilobar involvement may occur in 12.6% of cases with abscess size ranging from less than 5 cm (40.3%), 5 cm to 10 cm (50.6%), and greater than 10 cm (9.1%). The majority of patients (67.6%) have a solitary abscess versus 32.4% with multiple abscesses and 9.5% with accompanying gas formation. Studies in the 1970s documented changes in the presentation of PLA including increasing age in patients, greater association with malignancy, and a decrease in amoebic infections in the United States. Additionally, the ingestion of foreign bodies leading to perforation and the development of liver abscesses has been well documented. A systematic review of 59 cases identified the most common foreign bodies including fish bones, toothpicks, chicken bones, and, to a lesser degree, metallic foreign bodies.

Chronic pancreatitis leading to pylephlebitis, also referred to as portal pyemia or septic portal vein thrombosis , has been implicated as a cause of PLA. The development of PLA has been reported from pylephlebitis. This was most commonly seen in the setting of diverticulitis and appendicitis and to a lesser extent, cholecystitis, cholangitis, and inflammatory bowel disease. Bile duct procedures such as biliary enteric anastomosis, biliary stenting, and wide sphincterotomy performed on patients with biliary cysts and liver metastases have been associated with the development of liver abscesses especially after hepatic radiofrequency ablation or chemoembolization. A study of Pseudomonas aeruginosa –associated liver abscesses indicated that a large proportion of patients with hepatobiliary comorbidity were diagnosed immediately following an intraabdominal surgical or endoscopic procedure, or those with a history of intraabdominal procedures. However, a third of the patients in the study had not undergone any invasive procedure and did not have predisposing risk factors for P. aeruginosa infections. Patients with autosomal dominant polycystic kidney disease (ADPKD) can experience infection of hepatic cysts, which can then become complicated by abscess formation.

Studies have indicated a distinct presentation of PLA when associated with hepatic neoplasms. In a study of 318 patients diagnosed with PLA between 2000 and 2009, 29 hepatopancreatobiliary cases were identified, including cholangiocarcinoma, gallbladder cancer, and pancreatic cancer. Patients tended to have similar mean age and comorbid conditions; however, in comparison with patients without malignancy, patients with malignancy and PLA had more hyperbilirubinemia, hepatomegaly, thicker wall abscess, septal lobulation, gas formation, portal thrombophlebitis, aerobilia, polymicrobial infection, and overall greater mortality. In a retrospective analysis of patients admitted for PLA from 2004 to 2008, 12 out of 211 cases of liver abscess were found to be associated with colorectal neoplasia and as such the authors recommended that in patients without known underlying disease, a screening colonoscopy be performed.

Microbiology

Numerous bacteria have been implicated in PLA and case reports of rare organisms are abundant in the literature. Early studies of bacterial causes were mostly associated with infections due to Escherichia coli and other Enterobacteriaceae, aerobic streptococci, and Staphylococcus aureus . Later studies indicated the contribution of anaerobes, including microaerophilic streptococci, Bacteroides, Fusobacterium, and Actinomyces , to PLA and highlighted the fact that 22% to 52% of the cases reported in the literature were due to mixed infections. Brook and Frazier reported a total of 116 isolates from 48 abscesses and found aerobic bacteria in 25% of the cases, anaerobic bacteria in 17%, mixed aerobic and anaerobic bacteria in 58% of cases, and polymicrobial infection in 79% of cases. The main aerobic and facultative isolates were Escherichia coli, Streptococcus , Klebsiella pneumonia, Staphylococcus aureus, and the majority of anaerobes included Peptostreptococcus , Bacteroides , Fusobacterium , Clostridium , and Prevotella species. In Taiwan during the 1990s Streptococcus species (29.5%) and Escherichia coli (18.1%) constituted most of these infections.

In 1981 the first reported cases of Klebsiella pneumoniae PLA associated with septic endophthalmitis, with distinct phenotypic and genotypic features were emerging in Taiwan. Elderly patients were reported to have had lower incidence of gram-positive bacteria and, in contrast to Western nations, polymicrobial infections with K. pneumoniae and E. coli were more common. The authors speculated that this was due to the lower prevalence of inflammatory bowel disease among Asian populations in comparison with Caucasians. Mortality associated with K. pneumoniae PLA is usually in the setting of septic shock and other complications such as spontaneous abscess rupture. This occurs more commonly among diabetics who tend to have larger size abscesses, associated gas formation, and left hepatic lobe involvement. The increased mortality is also seen in the setting of embolic events leading to meningitis, endophthalmitis, and abscesses involving the central nervous system, lungs, muscles, spleen, skin and soft tissues, spine, and long bones. Rare complications reported in the literature include abscess rupture resulting in pyopericardium, subdiaphragmatic abscess, and bilateral endophthalmitis.

In 1994, the first report of K. pneumoniae liver abscess was reported in the United States. This was followed by reports of other cases in Western Europe also in patients who were not of Asian descent. The distinctive pattern of K. pneumoniae strains associated with liver abscesses represents the invasive and metastatic nature of these infections, which have commonly been described in patients with diabetes mellitus. These infections are associated with serotypes K1/K2, with associated virulence factors, including mucoviscosity-associated gene A ( mag A), regulator of mucoid phenotype A gene ( rmp A), and aerobactin. This hypermucoviscous phenotype allows the bacteria to resist phagocytosis and intracellular killing. Almost all cases of PLA complicated by bacteremia and extrahepatic infections are due to infections with K. pneumoniae serotypes K1 or K2, but not all infections with K1 or K2 serotypes result in PLA with extrahepatic manifestations. Fulfillment of both the clinical and microbiologic definitions of the invasive syndrome portends a poor prognosis and warrants immediate and aggressive treatment. In a large retrospective cohort study of patients with PLA, those with K. pneumoniae had a significantly higher incidence of other infections during a 1-year follow-up period. In comparison with the non– K. pneumoniae cohort, these patients suffered significantly more lung abscesses, empyemas, renal and perinephric abscesses, spinal epidural abscesses, and splenic abscesses. In a study comparing the characteristics of patients with Streptococcus milleri (SM) to patients with K. pneumoniae– associated PLAs, those with SM had a higher incidence of active malignancy, were more distinctly symptomatic (fever, chills, right upper quadrant pain), and had greater duration of symptoms and incidence of hepatomegaly. Those with K. pneumoniae suffered greater complications, including bacteremia, septic shock with organ failure, and metastatic infections. The most common cause of infection for both groups was underlying biliary disease.

MRSA-associated PLAs have been described in patients with human immunodeficiency virus (HIV) and other immunodeficiency states. Staphylococcus aureus is implicated less commonly and has been reported in 7% to 10 % of liver abscesses. A retrospective review from 2004 to 2009 of 117 patients revealed that the most common etiology included biliary disease and recent abdominal surgery in MRSA-associated PLA. Community-acquired MRSA PLA has been reported among young patients without predisposing factors, which are often associated with hematogenous spread from complicated skin and soft tissue infections, injection drug use, or catheter/device-related infections.

In contrast to the common bacterial causes of PLA, Pseudomonas aeruginosa infections are reported infrequently in the literature but have been associated with a mortality rate of 20% when compared with 5.3% among patients with nonpseudomonal PLAs. Other causes of PLA reported in the literature include actinomyces, Nocardia species , Yersinia pseudotuberculosis and Y. enterocolitica, Listeria monocytogenes, Campylobacter jejuni, Legionella pneumophila, Mycobacterium tuberculosis, S. typhi or S. paratyphi, and Bartonella henselae. Microorganisms leading to PLA may be assisted by host factors such as diabetes, cirrhosis, malignancy, and acquired immunosuppression including HIV and inherited diseases such as chronic granulomatous disease, Crohn disease, sickle-cell disease, and hemochromatosis.

Clinical Manifestations, Diagnosis, and Management

The classic triad of fever, jaundice, and right upper quadrant tenderness is only present in a minority of patients with PLA. Other symptoms include malaise, fatigue, anorexia, and weight loss, although this can vary based on bacterial and host factors. A large retrospective review of adults with PLA indicated that patients were more likely to be over the age of 50 and diabetic. These older diabetic patients often present with jaundice, pulmonary findings, multiple abscesses, and lower albumin levels in comparison to the younger patients with amoebic infections. PLA has a more atypical presentation among elderly patients where infection is more commonly present with acute respiratory symptoms, septal lobulation, and pneumobilia. The elderly often require longer courses of antibiotic therapy; have greater local recurrence, and mortality. Studies of prognostic factors in PLA have identified findings such as gas-forming abscesses, MDR isolates, anaerobic bacteria, elevated levels of blood urea nitrogen (BUN), and high APACHE II (Acute Physiologic Assessment and Chronic Health Evaluation II) scores at the time of admission.

The diagnosis of PLA may be challenging due the fact that many patients do not present with specific symptoms. Although elevations in alkaline phosphatase levels may alert clinicians to the presence of PLA, normal levels do not exclude the condition. In addition, blood cultures may be positive in only 50% of cases. Gram stains and cultures need to be collected from drained fluid while insuring timely transport of anaerobic samples under appropriate conditions. Due to its lower cost, lack of radiation exposure, greater availability, and noninvasiveness, many experts recommend ultrasound (US) as the initial imaging test for the diagnosis of PLA. US also has a sensitivity of 70% to 90% in making the diagnosis of PLA. However, the role of ultrasound imaging has been questioned for specific situations. In a review of cases admitted via the emergency department, patients with abscesses located in Segment 8 of the liver presented more often with septic shock and experienced a delay in diagnosis. As such, computed tomography (CT) imaging is recommended if there is a high index of suspicion for PLA even in the setting of a negative ultrasound. In addition, contrast-enhanced CT scanning has a sensitivity of 95% and it can assist with interventional drainage procedures. CT images may also provide clues to the etiology and type of organism involved. A study comparing CT image findings in K. pneumoniae –associated liver abscesses to liver abscesses associated with other bacterial pathogens indicated that the presence of a thin abscess wall, necrotic debris, metastatic infection, and the absence of biliary disease could predict K. pneumoniae– associated abscesses with a specificity of 98.6% when at least three of the four criteria were present. Triphasic enhanced multislice CT has also shown greater sensitivity in comparison with sonography. The CT imaging may be visualized in two phases including a presuppurative and suppurative phase where images become delineated and indicate the presence of a capsule. Magnetic resonance imaging (MRI) is an additional imaging tool that can assist with the detection of biliary obstruction as the underlying cause of PLA ( Figs. 40-3 and 40-4 ). Other diagnostic tools reported in the literature include 18-F-fluorodeoxyglucose (FDG) positron emission tomography (PET). PET has been studied in the diagnosis of infected hepatic cysts in patients with ADPKD and has been found to be useful. This is because conventional imaging may not be able to distinguish hemorrhage from infection.

Once the microbiologic diagnosis has been made, general recommendations for the treatment of PLA include 2 to 3 weeks of intravenous antibiotic therapy followed by conversion to oral therapy for a 4 to 6 week course, although shorter durations have been recommended in the literature. Documentation of clearance of infection is recommended and may be confirmed by close clinical and imaging follow-up. In a study of 107 patients with PLAs of less than 3 cm, a success rate of 100% was achieved when patients were treated with antibiotics alone. Additional studies have reported similar success rates but may have been subjected to selection bias. Several experts have recommended that antibiotic therapy alone should be reserved for those with small abscesses that cannot be appropriately drained or in those who the expected rate of complication is high, until better patient selection guidelines become available. The topic of MDR organisms will be addressed in the transplant section of this chapter. However, in 2006, the first patient without comorbid conditions or previous hospitalization was diagnosed with CTX-M-15 ESBL-producing K. pneumonia– associated liver abscess, raising the possibility of future increases in community-acquired liver abscess.

Whereas antibiotic therapy is the mainstay in the treatment of PLA, drainage of abscesses greater than or equal to 5 cm result in faster and more successful resolution. Drainage can occur via nonsurgical methods, such as percutaneous needle aspiration (PNA) or percutaneous catheter drainage (PCD). However, a surgical approach, including open surgery (OS) and laparoscopic drainage (LD), may be required in the setting of a ruptured abscess, associated biliary disease, intraabdominal disease, or uncontrolled sepsis. A meta-analysis of five randomized controlled trials (RCTs) from 1998 through 2013, covering 306 patients, indicated that PCD was superior to PNA with regard to clinical improvement and time required to obtain a 50% reduction in cavity size. The rates of complications were reported to have been similar and the advantage in PCD was apparent in abscesses with large cavities that required frequent drainage. Studies investigating the role of laparoscopic surgery (LS) versus OS in the treatment of PLA due to biliary disease have indicated that LS may be efficacious in select patients and has similar outcome to OS. In this report, no significant differences were found with regard to operation time, intraoperative blood loss and transfusion, postoperative complication rate, abscess recurrence, or overall mortality between these two modalities, whereas hospital stay was shorter with LS. Finally, complete surgical resection may be indicated in the setting of rupture, multiloculation, and associated biliary or intraabdominal disease. Recent studies have evaluated the use of inflammatory markers because there are few prognostic tools available to assess the resolution of infection after completion of drainage and antimicrobial therapy. One study identified C-reactive protein (CRP) as an independent factor in the determination of successful antibiotic therapy for postpercutaneous drainage of PLA.

Miscellaneous Bacterial Infections

Other infections involving the liver include nontuberculosis mycobacteria, clostridia, actinomyces, meliodosis, shigellosis, legionellosis, ehrlichiosis, borreliosis, and staphylococcal and streptococcal toxic shock syndromes.

Conclusions

Bacterial infections in patients with end-stage liver disease contribute to significant morbidity and mortality. Continued efforts are needed to elucidate the underlying role of the immune system in these infections and eliminate factors that increase risk of infection. PLA and disseminated bacterial infections of the liver continue to be present due to the aging of the population and changing environmental and host factors. The increasing frequency of MDR organisms will make the management of these patients increasingly difficult. Preventative measures, rapid diagnostic tools, and new therapeutic modalities are needed to address these challenges.