Characteristics of gas-forming pyogenic liver abscess caused by Klebsiella pneumoniae and Clostridi perfringens

Background: Gas-forming pyogenic liver abscess is a life-threatening disease with poor prognosis commonly caused by 2 bacteria, Klebsiella pneumoniae and Clostridium perfringens . Due to its low incidence and associated high mortality rate, it is important to study the biological characteristics of the disease. The aim of this study was to conduct a worldwide review of literature on gas-forming pyogenic liver abscess caused by K. pneumoniae and C. perfringens . Methods: We searched PubMed and Web of Science databases from January 2009 to March 2019, with published in English. All relevant articles were accessed in full text. The manual search included references of retrieved articles. Finally, 35 publications were selected for review. Results: The results showed that more cases of gas-forming pyogenic liver abscess in Asia were caused by K. pneumoniae than by C. perfringens (P=0.011). The prevalence of diabetes mellitus in patients with gas-forming pyogenic liver abscess caused by K. pneumoniae was higher than caused by C. perfringens (P=0.032). The survival rate of patients with gas-forming pyogenic liver abscess caused by K. pneumoniae who received surgical debridement or drainage was higher than caused by C. perfringens (P=0.002). Conclusions: The prevalence of diabetes mellitus was higher in patients with gas-forming pyogenic liver abscess caused by K. pneumoniae than in patients caused by C. perfringens .

In contrast, of the 24 patients with GFPLA-Cp, 11 (45.8%) were from Asia (6 from Japan, 1 from China, 2 from Hong Kong, and 2 from Australia), 9 (37.5%) were from Europe (2 from the UK, 2 from Spain, 2 from Germany, 2 from the Netherlands, and 1 from Belgium), and 4 (16.6%) were from the USA. With regard to the patients from Asia, the proportion of patients with GFPLA-Kp was greater than the proportion of patients with GFPLA-Cp (P=0.011).
Although Thng et al. reported that K. pneumoniae was the most common bacteria causing GFPLA, it is not clear what the most common bacteria causing GFPLA in patients with DM is [48]. Data showed that the most common underlying disease in patients with GFPLA-Kp was DM (83.3%). Of the 24 patients with GFPLA-Cp, 10 (41.6%) had DM, 6 (25%) had malignant tumors (1 patient with pancreatic cancer, 2 with gastric cancer, 2 with colon cancer, and 1 with HCC), 3 (12.5%) had cholangitis, 3 (12.5%) were previously in good health, 1 (4%) had undergone a hemi-hepatectomy for liver metastasis of a neuroendocrine tumor with an unknown primary site, and 1 (4.1%) had received a liver transplant for alcoholic cirrhosis. DM was more prevalent in patients with GFPLA-Kp than in patients with GFPLA-Cp (P=0.032). The results showed that DM is strongly associated with GFPLA-Kp. All but 3 patients (91.3%) presented with fever and 2 patients (8.3%) had no localizing signs.
Positive results of blood and pus cultures, blood culture, and pus culture were obtained in 6 patients (50%), 5 patients (41.6%), and 1 patient (8.3%) with GFPLA-Kp, respectively. With regard to laboratory investigations ( With regard to the underlying diseases in patients with these 2 categories of GFPLA, we found that DM was more prevalent in patients with GFPLA-Kp than in patients with GFPLA-Cp (P=0.032). This is similar to the results of studies by Chou et al. and Yang et al. [6,53]. The higher incidence of GFPLA in patients with DM is because poor glycemic control leads to compromised immunity, neutrophil dysfunction, and chemotaxis dysfunction.
These lead to poor microcirculation in the liver, with rapid growth and vigorous metabolism of bacteria in the affected areas, which may in turn lead to gas production [53]. Furthermore, poor glycemic control in patients with DM may provide gas-forming microorganisms with a more favorable environment for gas formation through mixed acid fermentation of glucose. Mixed acid fermentation within the abscess contributes to gas production resulting from carbon dioxide produced during glucose fermentation in liver tissues under anaerobic conditions. K. pneumoniae was reported to produce formic hydrogenlyase, an enzyme that is only produced in acidic environments when local pH reaches 6 or less by acid accumulation. Fermentation by formic hydrogenlyase is a key process that often leads to accumulation of acids, and formic acid accumulated within the abscess is converted to carbon dioxide and hydrogen gas by formic hydrogenlyase when the pH is 6 or less [2] . Poor glycemic control compromises the immune system and increases glucose metabolism via the polyol pathway. This depletes the nicotinamide adenine dinucleotide phosphate hydrogen necessary for superoxide production in neutrophil-mediated opsonophagocytosis [54], thereby providing a favorable microenvironment for the rapid growth and vigorous metabolism of the microorganisms and leads to gas formation [3] . However, an earlier study found that high glucose levels  [58]. However, the details need to be further explored. The above-stated actions of CPS facilitate gas formation in patients with PLA caused by K. pneumoniae who have DM.
There are 5 serotypes of C. perfringens (A, B, C, D, and E) based on the production of 4 different lethal toxins (alpha, beta, epsilon, and iota) [59]. All 5 serotypes of C.
perfringens produce alpha-toxin, which is a phospholipase C that hydrolyzes lecithin to form phosphorylcholine and diglyceride [60]. It has been suggested that poor glycemic control may inhibit the action of phospholipase C and limit the damage to alpha-toxin.
This may explain why DM is less prevalent in patients with GFPLA-Cp than in patients with GFPLA-Kp. However, the incidence of hemolysis in patients with GFPLA-Cp was higher than that in patients with GFPLA-Kp. Alpha-toxin is the main cause of hemolysis as it can hydrolyze the phospholipids in red blood cell membranes [60]. The N-terminal and Cterminal domains are structures of the alpha-toxin that form a loop. The former has phospholipase activity while the latter is hydrophobic and enters the cell membrane [60].
The loop formed by the C-and N-terminals contains GM1 ganglioside-binding motifs and specifically binds to GM1a. The alpha-toxin binding to GM1a triggers specific signaling events that lead to activation of tyrosine kinase A and the subsequent signaling cascade results in the release of TNF-α, which causes catastrophic hemolysis and inflammation [61].
For the early diagnosis of C. perfringens infection, gram staining of the blood sample is important because it is a gram-positive rod, while K. pneumoniae is gram-negative. That is why there were more positive blood culture results in patients with GFPLA-Cp than in patients with GFPLA-Kp (P=0.03). Therefore, for early diagnosis of GFPLA-Cp, blood culture tests should be considered at hospital admission. In contrast, early diagnosis of GFPLA-Kp usually involves physical and laboratory examinations and CT scans.