Maximal diameter of liver abscess independently predicts prolonged hospitalization and poor prognosis in patients with pyogenic liver abscess.

BACKGROUND/AIMS: This study aimed to investigate the factors associated with prolonged hospital stay and in-hospital mortality in patients with pyogenic liver abscess. METHODS: We retrospectively reviewed data from patients with pyogenic liver abscess who were admitted between 2005 and 2018 at three tertiary hospitals in Jeonbuk province, South Korea. Prolonged hospital stay was defined as a duration of hospital admission of more than 21 days. RESULTS: A total of 648 patients (406 men and 242 women) diagnosed with pyogenic liver abscess were enrolled in the study. The mean maximal diameter of the liver abscess was 5.4 ± 2.6 cm, and 74.9% of the lesions were single. The three groups were divided according to the maximal diameter of the abscess. Laboratory parameters indicated a more severe inflammatory state and higher incidence of complications and extrahepatic manifestations with increasing abscess size. Rates of percutaneous catheter drainage (PCD) insertion, multiple PCD drainage, and salvage procedures as well as duration of drainage were also higher in the large liver abscess group. Of note, the duration of hospitalization and in-hospital mortality were significantly higher in the large hepatic abscess group. A multivariate analysis revealed that underlying diabetes mellitus, hypoalbuminemia, high baseline high-sensitivity C-reactive protein (hs-CRP) and procalcitonin levels, and large maximal abscess diameter were independent factors associated with prolonged hospital stay. Regarding in-hospital mortality, acute kidney injury at admission and maximal diameter of the abscess were independent factors associated with in-hospital mortality. CONCLUSIONS: A large maximal diameter of the liver abscess at admission indicated prolonged hospitalization and poor prognosis. More aggressive treatment strategies with careful monitoring are warranted in patients with large liver abscesses.

Percutaneous fine-needle aspiration for pyogenic liver abscess (3-6 cm): a two-center retrospective study.

BACKGROUND: The role of ultrasonography-guided percutaneous fine-needle aspiration (PNA) for pyogenic liver abscess (PLA) remains without consensus, especially in abscesses 3 to 6 cm in diameter. The objective of this study was to evaluate the comparative effectiveness and safety of PNA combined with antibiotics. METHODS: This was a retrospective study of patients with PLA that were from 3 to 6 cm in diameter who treated at two medical centers in Shanghai, China, from January 2014 to March 2019. Patients were divided into groups treated by PNA plus antibiotics or antibiotics alone. Patients demographics and clinical data related diagnosis, antibiotic treatment, and patient outcomes were analyzed. RESULTS: Out of a total of 94 PLA patients, 42 (44.7%) patients received PNA combined with antibiotics, and 52 (55.3%) received antibiotics alone. There were no complications related to PNA. In the PNA group, 13 (31.7%) patients with negative blood culture and 8 (19.5%) patients without blood culture were microbiologically confirmed via aspiration. The time for temperature normalization (P < 0.001) and the reduction rate of C-reactive protein within the first week (P = 0.031) were significantly lower in the PNA group. In the multivariate analysis, treatment with PNA was more likely to result in clinical improvement of PLA (odds ratio = 0.33, 95% confidence intervals (CI): 0.11-0.96, P = 0.043). CONCLUSIONS: PNA combined with antibiotics appears to be a safe, effective, and promising treatment for PLA of 3-6 cm in size. Furthermore, the technique allows for direct microbial sample, which can improve the selection of antibiotics.

Clinical and computed tomography features of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae liver abscess.

BACKGROUND: Klebsiella pneumoniae (KP) is the primary pathogen associated with pyogenic liver abscesses (PLAs). Moreover, there has been an increase in the proportion of extended-spectrum beta-lactamase (ESBL)-producing KP. However, the clinical and computed tomography (CT) features of liver abscesses caused by ESBL-producing KP have not been separately described. We aimed to compare the clinical and CT features present in patients with ESBL-producing and non-ESBL-producing KP as well as to determine the risk factors for ESBL-producing KP liver abscesses (KPLAs). METHODS: We performed a retrospective analysis of data obtained from the medical records of patients with a first episode of KPLA admitted to Shengjing Hospital of China Medical University between May 2015 and May 2019. We compared the clinical and CT features between patients with ESBL-producing and non-ESBL-producing KPLA. RESULTS: We enrolled 100 patients with KPLA (14 and 86 in the ESBL-producing and non-ESBL-producing groups, respectively). There was no significant between-group difference in the proportion of patients with comorbid diabetes (71.43% vs. 66.2%, p = 0.086). The ESBL-producing KPLA group had a greater proportion of patients with a history of biliary disease (78.57% vs. 26.74%, p < 0.001) and gastrointestinal malignancy (50% vs. 6.98%, p < 0.001). Multivariate regression analysis showed that a history of biliary disease was an independent risk factor for ESBL-producing KPLA. Compared with the non-ESBL-producing KPLA group, the ESBL-producing KPLA group had a significantly higher intensive care unit (ICU) admission rate (28.57% vs. 2.33%, p < 0.001). All ESBL-producing KP isolates were susceptible to carbapenems and amikacin. Only the presence of multiloculation on CT was found to be significantly different between the groups (50% vs. 82.56%, p = 0.012). CONCLUSIONS: The presence of biliary disease was an independent risk factor for ESBL-producing KPLA. Patients with ESBL-producing KPLA had a higher ICU admission rate, with only half of patients having evidence of multiloculation on CT.

Morphological characteristics of liver abscesses according its etiology / Características morfológicas de los abscesos hepáticos según su etiología

Although infrequent in the diagnostics areas, liver abscesses are of significant relevance, which is related to the high morbidity and mortality figures they can cause if they are not detected and treated in time. Although multiple operational classifications are described, the one most recognized for its usefulness is that related to its causative agent (pyogenic or bacterial infection, hydatid origin or secondary to infected hydatidosis, and amoebic or by invasive amebiasis). The objective of this article was to generate a study report regarding the morphological characteristics of liver abscesses, characterizing them according to their etiology, as well as describing their study and the latest recommended treatments.

Los abscesos hepáticos son entidades nosológicas de baja frecuencia, pero de significativa relevancia, la que se relacionada con las elevadas cifras de morbilidad y mortalidad que pueden causar si no son detectados y tratados a tiempo. Si bien se describen múltiples clasificaciones operacionales, aquella más reconocida por su utilidad es la relacionada a su agente causal (piógenos o bacterianos, hidatídicos o secundarios a hidatidosis infectada, y amebianos o por amebiasis invasora). El objetivo de este artículo fue generar un documento de estudio respecto de las características morfológicas de los abscesos hepáticos, caracterizándolos de acuerdo con su etiología, así como describir su estudio y tratamiento recomendado de acuerdo con el estado del arte.

The increased recurrence rate of liver abscess caused by extended-spectrum ß-lactamase-producing Klebsiella pneumoniae.

The pathogenic bacterium Klebsiella pneumoniae (KP) is the major causative agent of pyogenic liver abscess (PLA). But reports about the prognosis of KP-caused PLA (KPLA) are rare. This study aimed to ascertain the recurrence rate of KPLA after initial treatment and its contributing factors. A total of 110 patients who had first-time episodes of KPLA were included into the study. The average follow-up time was 3.65 ± 2.18 years. Twenty (18.18%) KPLA patients experienced recurrence. Those in the recurrence group had a significantly greater incidence of extended-spectrum ß-lactamase (ESBL) production compared with the non-recurrence group (30.0% vs 8.89%, P = 0.018). Diabetes, biliary tract disease, and history of malignancy were not associated with recurrence (all P > 0.05). No difference in the CT characteristics of KPLA (including abscess size, location, whether multilocular, gas production of KPLA, and thrombophlebitis) was found between the two groups. Multivariate regression analysis showed that ESBL production (OR, 6.3; 95% CI, 1.02-38.59; P = 0.04) was an independent risk factor for the recurrence of KPLA. Our findings emphasize that KPLA has a high recurrence rate and ESBL production is an independent risk factor for recurrent KPLA.

Diagnosis efficacy of CEUS for hepatic inflammatory lesions.

PURPOSE: In this study, the efficacy of US/CEUS and clinicopathologic parameters in differential diagnosis of hepatic inflammatory lesions were evaluated. METHODS: This was a retrospective study in which CEUS imaging was performed on 182 patients. Among these patients, 44 patients had hepatic inflammatory lesions and 138 patients had malignant lesions. The ultrasound (US), CEUS, and clinicopathologic parameters with respect to differential diagnosis of hepatic inflammatory lesions were analyzed. RESULTS: Irregular lesion shape and unclear margin were commonly seen in hepatic inflammatory lesions by US/CEUS examination. Hypoenhancement in arterial phase (AP) and portal venous phase (PVP), and isoenhancement in delayed phase (DP) were more commonly found in inflammatory lesions rather than malignant lesions [9% (4/44), 68% (30/44), and 16% (7/44) vs 2% (3/138), 11% (15/138), 1% (1/138), respectively; P < .05]. The enhancement coverage was also a significant indicator for the differentiation of inflammatory lesions and malignant lesions (P < .05). History of hepatitis or cirrhosis, and higher serum alpha-fetoprotein (AFP) level were indicators for malignant lesions, while liver parasites and higher body temperature were indicators for inflammatory lesions. When the US/CEUS findings were combined with clinicopathologic parameters, the diagnostic accuracy of inflammatory lesions could reach 93.3%, with sensitivity, specificity, positive predictive value, and negative predictive value of 63.64%, 96.03%, 84.85%, and 88.32%, respectively. CONCLUSION: The US/CEUS findings combined with clinical characteristics can accurately differentiate hepatic inflammatory lesions and malignant lesions. The results of study will improve the diagnostic confidence for hepatic inflammatory lesions.

Evaluation of clinical risk factors for developing pleural empyema secondary to liver abscess.

BACKGROUND: The aim of this study was to investigate the clinical manifestation and predictive risk factors of pleural empyema developing during treatment of the pyogenic liver abscess. METHODS: Medical records of patients with the liver abscess in our institution were reviewed retrospectively. Enrolled patients were classified into four groups; Group 1: patients without pleural effusion, Group 2: patients with pleural effusion and who were treated noninvasively, Group 3: patient with pleural effusion and who were treated with thoracentesis, and Group 4: patients with pleural effusion that developed into empyema. Patient characteristics, clinical manifestation, and possible risk factors in development of empyema were analyzed. RESULTS: A total of 234 patients was enrolled in this study. The incidence rate of empyema was 4.27% (10 patients). The mean interval for developing pleural effusion was 5.6 ± 6.35 days. In multivariate analysis, risk factors for developing pleural effusion included the location of the liver abscess near the right diaphragm (segment 7 and 8, OR = 2.30, p = 0.048), and larger diameter of the liver abscess (OR = 1.02, p = 0.042). Among patients who developed pleural effusions, presences of mixed microorganisms from culture of liver aspirates (OR = 10.62, p = 0.044), bilateral pleural effusion (OR = 46.72, p = 0.012) and combined biliary tract inflammation (OR = 21.05, p = 0.040) were significantly associated with the need for invasive intervention including surgery on effusion. CONCLUSION: The location of the liver abscess as well as pleural effusion, elevated inflammatory markers, and combined biliary tract inflammation may be important markers of developing pleural complication in patients with pyogenic liver abscess.

​Treating pyogenic liver abscesses secondary to diverticulitis in a patient using immunosuppressants for Crohn's disease by performing a sigmoid colectomy.

Pyogenic liver abscess (PLA) formation is a rare complication of Crohn's disease (CD). As symptoms often mimic a CD exacerbation, diagnosis can be delayed leading to severe disease. The current case report describes a case of a patient with a history of CD that was admitted with multiple PLAs, which persisted despite percutaneous drainage combined with antibiotics. After a sigmoid resection, the liver abscesses diminished rapidly.

Population genomics of hypervirulent Klebsiella pneumoniae clonal-group 23 reveals early emergence and rapid global dissemination.

Severe liver abscess infections caused by hypervirulent clonal-group CG23 Klebsiella pneumoniae have been increasingly reported since the mid-1980s. Strains typically possess several virulence factors including an integrative, conjugative element ICEKp encoding the siderophore yersiniabactin and genotoxin colibactin. Here we investigate CG23's evolutionary history, showing several deep-branching sublineages associated with distinct ICEKp acquisitions. Over 80% of liver abscess isolates belong to sublineage CG23-I, which emerged in ~1928 following acquisition of ICEKp10 (encoding yersiniabactin and colibactin), and then disseminated globally within the human population. CG23-I's distinguishing feature is the colibactin synthesis locus, which reportedly promotes gut colonisation and metastatic infection in murine models. These data show circulation of CG23 K. pneumoniae decades before the liver abscess epidemic was first recognised, and provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To support such studies we present an open access, completely sequenced CG23-I human liver abscess isolate, SGH10.

Hepatogastric fistula as a rare complication of pyogenic liver abscess.

Hepatogastric fistula following a pyogenic liver abscess is extremely rare, and only a handful of cases have been reported. An 88-year-old female presented with generalized weakness, fever and chills. An abdominal computed tomography scan revealed a 5cm-sized hypodense lesion with internal septa in the left lateral section of the liver. Due to initial suspicion of early liver abscess, she was treated with empirical intravenous antibiotics. Initially, aspiration or drainage of the liver abscess was not performed due to immature lesion characteristics. An ultrasonography-guided percutaneous drainage of the liver abscess was performed 17 days after hospitalization due to a more mature lesion appearance on follow-up imaging. On tubography, contrast media leakage through the fistulous tract was visualized. Surgical management was performed, and she was discharged 2 weeks after surgery.

Percutaneous drainage for giant pyogenic liver abscess--is it safe and sufficient?

BACKGROUND: Large size is a predictor of failure of percutaneous drainage (PD) for pyogenic liver abscess (PLA). This article serves to establish the safety and sufficiency of PD in giant PLA (GPLA). METHODS: A retrospective review of all GPLA patients treated at a tertiary care academic hospital from 2001 to 2011 was performed. A GPLA is defined as an abscess greater than or equal to 10 cm size based on imaging. RESULTS: Forty patients (24 men, 60%) were treated for GPLA. All but 1 patient (98%) was managed with PD and the mean duration of drainage was 9 days (range 1 to 23 days). One patient underwent operative drainage. Three patients (7.7%) needed secondary procedures after the initial PD. One patient (2.6%) failed PD and subsequently underwent operative drainage. Among the patients who underwent PD, the overall morbidity was 25%; the median length of hospital stay was 13 days (range 5 to 31 days) and 1 (2.6%) mortality. CONCLUSIONS: Large size itself is not a contraindication for PD. PD is safe and sufficient even in GPLA patients.

Clinical Characteristics and Outcomes of Pyogenic Liver Abscess in Elderly Korean Patients.

BACKGROUND/AIMS: Incidence of pyogenic liver abscess (PLA) has been increasing worldwide, especially in the elderly population. Therefore, the aim of this study is to elucidate the clinical features and outcomes of PLA in elderly patients. METHODS: A total of 602 patients diagnosed with PLA from January 2003 to January 2013 were analyzed retrospectively. The patients were divided according to two age groups;≥ 65 years (n=296) and <65 years (n=306). RESULTS: The mean age was 73.59 ± 5.98 (range, 65-93) years in the elderly group. Significantly higher incidence of females (52.4% vs. 29.1%, p<0.001), hepatobiliary disease (41.2% vs. 24.8%, p<0.001), hepatobiliary procedure (29.4% vs. 13.7%, p<0.001), underlying malignancy (18.2% vs. 4.6%, p<0.001), culture positivity of resistant organism (20.6% vs. 14.4%, p=0.047), occurrence of complication (19.6% vs. 12.8%, p=0.026), and higher white blood cell (13.44 ± 6.56 vs. 12.26 ± 5.89, p=0.021), but lower rates of right lobe abscess (67.2% vs. 80.4%, p<0.001), fever (68.6% vs. 79.3%, p=0.003), and lower CRP (16.79 ± 9.67 vs. 18.80 ± 9.86, p=0.012) was observed in elderly PLA patients, compared to younger patients. Regarding complications, elderly patients had higher incidence of septic shock (8.1% vs. 2.3%, p=0.001) and cardiovascular disease (2% vs. 0%, p=0.014). CONCLUSIONS: More atypical presentations and complications tend to occur in elderly PLA patients compared with younger patients. Clinicians should be aware of these age-related differences in PLA and devise management strategies accordingly.

Pyogenic liver abscess among children in a medical center in Central Taiwan.

BACKGROUND: Pediatric pyogenic liver abscess is uncommon. This study aimed to investigate the clinical characteristics, radiologic features, pathogens, duration of hospitalization, and management of pediatric pyogenic liver abscess. METHODS: Pediatric patients with pyogenic liver abscess admitted to the China Medical University Hospital from 1995 to 2011 were reviewed. Their clinical characteristics, radiological features, laboratory data, clinical management, and outcomes were analyzed. Those with liver abscess due to the complication of oncologic disease were excluded. RESULTS: Fifteen patients were diagnosed with pyogenic liver abscess. Their most common symptoms were fever and abdominal pain. Eight (53.0%) had leukocytosis (>15000/µL) and elevated C-reactive protein (CRP) level (>10 mg/dL). The main imaging presentation was a single abscess in right lobe of the liver (13/15, 86.7%). Blood culture were mainly negative (12/15, 80.0%). Pathogenic microorganisms cultured from pus revealed Klebsiella pneumoniae (6/15, 40.0%) and Streptococcus spp. (6/15, 40.0%) as the two most common pathogens. Percutaneous abscess drainage followed by adequate parenteral antibiotics were effective interventions. Hospitalization of at least 2 weeks was needed in most cases. There were no mortalities. CONCLUSION: Pyogenic liver abscess should be considered in children presenting with fever, abdominal pain, and leukocytosis with a high CRP level. Most cases involve a single lesion on right lobe of the liver. K. pneumoniae and Streptococcus spp. are the two most common pathogens. Drainage with adequate antibiotics has significantly good response.

Comparison of pyogenic liver abscesses caused by hypermucoviscous Klebsiella pneumoniae and non-Klebsiella pneumoniae pathogens in Beijing: a retrospective analysis.

OBJECTIVE: To perform a retrospective comparison of the clinical and radiological features of Klebsiella pneumoniae (KP)-associated and non-KP-associated pyogenic liver abscesses (PLA) in Chinese patients. METHODS: Patients with confirmed diagnoses of bacterial liver abscess at three Beijing hospitals were enrolled. Clinical isolates from liver abscesses were used to determine serology and expression of hypermucoviscosity genes. Basic clinical, ultrasonographic (US) and computed tomography (CT) data were recorded and compared between patients with KP- and non-KP-associated PLA. RESULTS: A total of 101 (77.10%) and 30 (22.90%) cases were due to KP and non-KP pathogens, respectively. Compared with the non-KP cohort, the KP cohort demonstrated a significantly higher incidence of underlying diabetes mellitus, and more gas-forming abscesses, as demonstrated by US and CT examinations. Prior abdominal surgery or chemoradiation therapy was significantly associated with non-KP cases. The non-KP group had a higher chance of a clear edge, compared with the KP group, on pre-contrast CT images. CONCLUSION: KP and non-KP-associated PLA have distinctive risk factors and unique US and CT features, in Chinese patients.

Is there any difference in pyogenic liver abscess caused by Streptococcus milleri and Klebsiella spp?: retrospective analysis over a 10-year period in a regional hospital.

BACKGROUND/PURPOSE: To compare the clinical characteristics of patients with Streptococcus milleri (SM) and Klebsiella spp. associated pyogenic liver abscess (PLA). METHODS: A retrospective study of patients with PLA due to SM and Klebsiella spp. was conducted. Clinical characteristics, laboratory and radiological features, management and outcomes were analyzed. RESULTS: From 2000 to 2009 inclusive, 21 and 140 patients had SM and Klebsiella spp. associated monomicrobial infected PLA, respectively. A higher incidence of active malignancy occurred in the SM group (14.3% vs. 3.6%, p < 0.03). The common clinical features of the patients were fever, chill and right upper quadrant pain. A longer duration (6.3 vs. 4.4 day, p = 0.04) of symptoms and a higher incidence of hepatomegaly (14.3% vs. 2.9%, p < 0.01) occurred in the SM group. Common laboratory and imaging abnormalities included: anemia, leukocytosis, high erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, elevated total bilirubin and alanine aminotransferase, right hepatic lobe involvement, hypoechoic in ultrasonograpghy, rim enhancement and septal lobulation in computed tomography. The biliary tract disorder was the most common cause of the disease in the two groups. Patients with Klebsiella spp. associated PLA tended to have more complications: bacteremia (61.6% vs. 31.6%, p < 0.01) septic shock (33.6% vs. 19%, p = 0.11), disseminated intravascular coagulation (20.7% vs. 4.8%, p = 0.04), metastatic infections (10.7% vs. 0%, p = 0.06), acute renal and respiratory failure (5% vs. 0%, p = 0.14). However, both were effectively managed by the combination of antibiotics and image-guided aspiration with/without drainage, and their mortality rates were comparable to each other. Those patients with metastatic infection might need a longer duration (6.07 vs. 5.32 week, p = 0.144) of antibiotic therapy, which was due to the longer mean duration (3.85 vs. 2.86, p < 0.04) of an intravenous counterpart. CONCLUSION: SM associated PLA tends to have a distinct clinical syndrome as compared with that of Klebsiella spp. with regard to risk factors, clinical manifestations and complications. However, both can be effectively treated with a combination of antibiotics and image-guided aspiration with/without drainage.

Pyogenic liver abscess and colorectal neoplasia: a case series.

BACKGROUND: Colorectal neoplasia is occasionally associated with hepatic abscess. To identify cases, we retrospectively analyzed the medical records of all patients admitted to our hospital for liver abscess from 2004 to 2008. METHODS: Underlying disease was actively sought for all patients. Cases with obvious causes, such as biliary tract obstruction and immunocompromising conditions, were excluded. RESULTS: Out of 211 cases of liver abscess included, 12 were found to be associated with colorectal neoplasia. None of these 12 cases had gastrointestinal symptoms. The stool occult blood test was positive in only 3 cases. There were 3 cases of focal adenocarcinoma in tubulovillous adenoma and the remaining 9 cases all had adenomatous polyps. Complete cure was achieved in all cases. CONCLUSIONS: When managing patients with liver abscess, colorectal neoplasia should be considered as a possible associated underlying condition.

Is hepatic neoplasm-related pyogenic liver abscess a distinct clinical entity?

AIM: To compare the clinical characteristics of pyogenic liver abscess (PLA) in patients with and without hepatic neoplasm (HN). METHODS: Authors performed a retrospective analysis involving patients with PLA. The demographic, clinical features, laboratory and imaging findings, management and outcome of patients with and without HN were studied. RESULTS: From January 2000 to December 2009 inclusive, 318 patients (35 with HN) had PLA, and mean age and comorbidity were comparable between the two groups. More patients with HN experienced right upper quadrant pain (68.6% vs. 52.7%, P < 0.04), developed jaundice (14.3% vs. 5.7%, P < 0.03) and hepatomegaly (17.1% vs. 3.9%, P < 0.01), and had higher serum total bilirubin level (43.3 µmol/L vs. 30.0 µmol/L, P = 0.05). Most patients in both groups had PLAs in the right hepatic lobe, and biliary tract disorder was the most common underlying cause (71.4% and 61.8%). However, more PLAs in the HN group were associated with thicker abscess wall (37.1% vs. 19.4%, P < 0.01), septal lobulation (77.1% vs. 58%, P < 0.02), gaseous cavitation (17% vs. 7.8%, P = 0.03), portal thrombophlebitis (11.4% vs. 1.8%, P < 0.01) and aerobilia (25.9% vs. 5.5%, P < 0.01). Mixed bacterial growth (40% vs. 15.2%, P < 0.01) and Gram-negative bacilli (22.8% vs. 60.4%, P < 0.01) were dominant isolates in PLAs with and without HN, respectively. Although incidence of the complications was comparable between the two groups, patients with HN had a higher mortality rate than those without (71.4% vs. 8.8%, P < 0.01). Multivariate logistic regression analysis revealed underlying active malignancy [odds ratio (OR): 40.45, 95% CI: 14.76-111.65], hypoalbuminemia (OR: 1.22, 95% CI: 1.14-1.38), disseminated intravascular coagulation (OR: 3.32, 95% CI: 1.19-9.69) and acute coronary syndrome (OR: 4.48, 95% CI: 1.08-17.8) were independent risk factors associated with mortality. However, several HN cases, presented concurrently with PLAs, were found to have curative resectable tumors and had good prognosis after surgery. CONCLUSION: PLA associated with HN tends to form a distinct clinical syndrome with a different extent of clinical manifestations, radiological and microbiological features and complications.