Klebsiella pneumoniae liver abscess (KPLA) has been reported with increasing frequency in East Asian countries in the past 3 decades, especially in Taiwan and Korea 1 2 3 4 5 6 7 . K. pneumoniae is the dominant cause of pyogenic liver abscesses in Taiwan and has contributed to the endemic feature of the disease in Taiwan 8 9 10 . Since 1986, many researchers in Taiwan and several other areas have noted the distinctive syndrome of KPLA, complicated by bacteremia, sepsis, and metastatic infection of brain, eyes, lungs and other organs, especially in patients with diabetes 2 5 6 11 12 13 14 15 . The mortality rate of KPLA has decreased in recent years in Taiwan 6 8 ; nevertheless, despite aggressive therapy, the outcomes of these patients frequently involve catastrophic disability. Our recent study also has indicated that catastrophic disability due to ocular or neurological complications from KPLA could lead to poor long-term prognosis 10 .

Patients with diabetes are at increased risk for common infection due to impaired host defense mechanisms 16 . Diabetes is a well-known risk factor for pyogenic liver abscess 17 and highly associated with KPLA 5 18 19 . One animal study of KPLA has suggested that diabetes might provide a specialized environment that allows K. pneumoniae strains to disseminate from the intestines into the blood 20 . In addition, diabetes is the most common underlying disease among patients with septic metastatic complications from KPLA 12 13 19 21 , and predisposes patients with KPLA to develop septic metastasis 22 . Compared with the monomicrobial cryptogenic noninvasive KPLA, cryptogenic KPLA with septic metastasis is characterized by an ~20-fold increased association with diabetes 23 .

Previous studies have compared the characteristics of liver abscess patients with and without diabetes 17 18 24 . The influence of diabetes on KPLA has also been described 1 . However, no research is available on the impact of glycemic control on the characteristics of KPLA in diabetic patients. To monitor glycemic control, hemoglobin A1c (HbA_1c) gives an estimate of average blood glucose during the preceding 3 months, and is widely accepted as the primary indicator of the level of glycemic control for optimal management of diabetes 25 .

Therefore, we conducted this study to investigate whether glycemic control assessed by HbA_1c affected the clinical characteristics of diabetic patients with KPLA.

It is believed that several aspects of immunity are altered in patients with diabetes. For example, polymorphonuclear leukocyte function is depressed; leukocyte adherence, chemotaxis and phagocytosis may be affected; and antioxidant systems involved in bactericidal activity may also be impaired. Although these in vitro findings have not yet been fully confirmed in clinical studies, there is evidence that improving glycemic control in patients improves immune function 27 . Kornum et al. found that an elevated HbA_1c predicted increased risk for all-cause community-acquired pneumonia among patients with diabetes 28 . In diabetic patients with sepsis, one study has demonstrated that HbA_1c is an independent prognostic factor for hospital mortality and length of stay 29 . Regarding the issue of glycemic control and KPLA, only one case series from Taiwan analyzing 6 cases of recurrent KPLA has been reported in the literature. Five of the six patients had diabetes with poor glycemic control, and four had HbA_1c >; 9% (range: 9.2–17.5%) 30 . The current study is, to the best of our knowledge, the first to investigate the effect of glycemic control on characteristics of KPLA in diabetic patients.

In our study, we found that patients with uncontrolled glycemia tended to be younger, and had the trend to have a higher rate of cryptogenic liver abscess, gas-forming liver abscess, and metastatic infection than those with controlled glycemia, although these differences did not reach significance. Young age, newly diagnosed diabetes, cryptogenic liver abscess and metastatic infection were more common in the poor glycemic control group (HbA_1c value >; 10%). Cryptogenic invasive KPLA is frequently associated with diabetes 23 ; therefore, we further established that it was highly linked to diabetic patients with high level of HbA_1c. The finding that younger patients with KPLA are prone to have uncontrolled glycemia has never been reported, in part due to the small sample sizes of studies reported in the literature 6 13 .

Lin et al. have analyzed the effect of glycemic control of type 2 diabetes on neutrophil phagocytosis of serotype K1/K2 K. pneumoniae isolates. This in vitro study suggests that strict metabolic control may improve the neutrophil phagocytosis of K1/K2 K. pneumoniae in patients with type 2 diabetes 31 . In the current study focusing on diabetic patients, we not only found that the rate of metastatic infection was more common in patients with poor glycemic control, but also that HbA_1c level was an independent risk factor for metastatic infection. It is also notable that there was no mortality, metastatic infection or gas-forming abscess in the group with controlled glycemia. The previous in vitro study by Lin et al. may support our clinical findings, and we suggest that HbA_1c level is detrimental in KPLA, and controlled glycemia may prevent the development of serious metastatic complications.

Previous case reports have demonstrated that diagnosis of diabetes may come to light because of KPLA 32 33 . It is notable that around 25% of cases were newly recognized diabetes in the current study despite improvement in diagnosis and awareness in recent years, and the existence of a comprehensive national health insurance program in Taiwan that optimizes access to medical care. Due to unrecognized diabetes complicated with infection, extreme hyperglycemia, even hyperglycemic hyperosmolar state or diabetic ketoacidosis, may occur. Physicians should not ignore the underlying diabetes in patients with KPLA in clinical practice. One particularly interesting finding in our study was that liver abscess < 5 cm in diabetic patients was independently associated with metastatic infection, which has not been reported in the literature. It suggested that we should not overlook the risk of complication from small sized liver abscess in diabetic patients.

We acknowledge some limitations in our study that deserve mention. First, the data were collected retrospectively from medical records. Second, participants were recruited from a medical center in Northern Taiwan, and therefore we could not evaluate possible regional variations. Further analyses should be conducted in other regions and countries to confirm our findings. Thirdly, our results were also limited by the incomplete collection of HbA_1c data. Finally, the isolates were not collected for further analysis, such as virulence factors or clonal types, in the current study. Despite these limitations, our study is believed to be the first to discuss the characteristics of KPLA due to the different level of glycemic control, which sheds further light on the association between diabetes and KPLA, and our results may partly elucidate the role of host factors in the pathogenesis of KPLA.

Patients with uncontrolled glycemia were significantly younger than those with controlled glycemia. Patients with uncontrolled glycemia had the trend to have a higher rate of gas-forming liver abscess, cryptogenic liver abscess and metastatic infection than those with controlled glycemia. Cryptogenic liver abscess and metastatic infection were more common in the poor glycemic control group (HbA_1c value >; 10%). HbA_1c level and abscess < 5 cm were independent risk factors for metastatic complications from KPLA. Therefore, glycemic control in diabetic patients plays an essential role in the clinical features of KPLA, especially in metastatic complications from KPLA.

KPLA: Klebsiella pneumoniae liver abscess; 95% CI: 95% confidence interval; OR: Odds ratio; HbA_1c: Hemoglobin A1c.

All authors declare that they have no conflict of interest.

YTL conceived of the study, and participated in its design and coordination. YTL, FDW, PFW and CPF performed the laboratory experiments, reviewed and collected the data. YTL analyzed and interpreted the data. YTL and PFW drafted the manuscript. FDW and CPF reviewed the manuscript. All authors read and approved the final manuscript.