Impact of multidrug resistance on outcomes in hematologic cancer patients with bacterial bloodstream infections.

Despite the improved outcomes in patients with hematological malignancies, infections caused by multidrug-resistant organisms (MDROs) pose a new threat to these patients. We retrospectively reviewed the patients with hematological cancer and bacterial bloodstream infections (BSIs) at a tertiary hospital between 2003 and 2022 to assess the impact of MDROs on outcomes. Among 328 BSIs, 81 (24.7%) were caused by MDROs. MDRO rates increased from 10.3% (2003-2007) to 39.7% (2018-2022) (P < 0.001). The 30-day mortality rate was 25.0%, which was significantly higher in MDRO-infected patients than in non-MDRO-infected patients (48.1 vs. 17.4%; P < 0.001). The observed trend was more pronounced in patients with newly diagnosed diseases and relapsed/refractory disease but less prominent in patients in complete remission. Among MDROs, carbapenem-resistant Gram-negative bacteria exhibited the highest mortality, followed by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and extended-spectrum ß-lactamase-producing Enterobacteriaceae. Multivariate analysis identified independent risk factors for 30-day mortality as age ≥ 65 years, newly diagnosed disease, relapsed/refractory disease, MDROs, polymicrobial infection, CRP ≥ 20 mg/L, and inappropriate initial antibiotic therapy. In conclusion, MDROs contribute to adverse outcomes in patients with hematological cancer and bacterial BSIs, with effects varying based on the underlying disease status and causative pathogens. Appropriate initial antibiotic therapy may improve patient outcomes.

Recommendations for Adult Immunization by the Korean Society of Infectious Diseases, 2023: Minor Revisions to the 3rd Edition.

The Korean Society of Infectious Diseases has been regularly developing guidelines for adult immunization since 2007. In 2023, the guidelines for the following seven vaccines were revised: influenza, herpes zoster, pneumococcal, tetanus-diphtheria-pertussis (Tdap), human papillomavirus (HPV), meningococcal, and rabies vaccines. For the influenza vaccine, a recommendation for enhanced vaccines for the elderly was added. For the herpes zoster vaccine, a recommendation for the recombinant zoster vaccine was added. For the pneumococcal vaccine, the current status of the 15-valent pneumococcal conjugate vaccine and 20-valent PCV was described. For the Tdap vaccine, the possibility of using Tdap instead of tetanus-diphtheria vaccine was described. For the HPV vaccine, the expansion of the eligible age for vaccination was described. For the meningococcal vaccine, a recommendation for the meningococcal B vaccine was added. For the rabies vaccine, the number of pre-exposure prophylaxis doses was changed. This manuscript documents the summary and rationale of the revisions for the seven vaccines. For the vaccines not mentioned in this manuscript, the recommendations in the 3rd edition of the Vaccinations for Adults textbook shall remain in effect.

Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease.

Dystrophic neurites (DNs) are abnormal axons and dendrites that are swollen or deformed in various neuropathological conditions. In Alzheimer's disease (AD), DNs play a crucial role in impairing neuronal communication and function, and they may also contribute to the accumulation and spread of amyloid beta (Aß) in the brain of AD patients. However, it is still a challenge to understand the DNs of specific neurons that are vulnerable to Aß in the pathogenesis of AD. To shed light on the development of radiating DNs, we examined enriched dystrophic hippocampal axons in a mouse model of AD using a three-dimensional rendering of projecting neurons. We employed the anterograde spread of adeno-associated virus (AAV)1 and conducted proteomic analysis of synaptic compartments obtained from hippocampo-septal regions. Our findings revealed that DNs were formed due to synaptic loss at the axon terminals caused by the accumulation of extracellular vesicle (EV). Abnormal EV-mediated transport and exocytosis were identified in association with primary cilia, indicating their involvement in the accumulation of EVs at presynaptic terminals. To further address the regulation of DNs by primary cilia, we conducted knockdown of the Ift88 gene in hippocampal neurons, which impaired EV-mediated secretion of Aß and promoted accumulation of axonal spheroids. Using single-cell RNA sequencing, we identified the septal projecting hippocampal somatostatin neurons (SOM) as selectively vulnerable to Aß with primary cilia dysfunction and vesicle accumulation. Our study suggests that DNs in AD are initiated by the ectopic accumulation of EVs at the neuronal axon terminals, which is affected by neuronal primary cilia.

Use of Antibiotics Within the Last 14 Days of Life in Korean Patients: A Nationwide Study.

BACKGROUND: Antimicrobial prescriptions for serious chronic or acute illness nearing its end stages raise concerns about the potential for futile use, adverse events, increased multidrug-resistant organisms, and significant patient and social cost burdens. This study investigated the nationwide situation of how antibiotics are prescribed to patients during the last 14 days of life to guide future actions. METHODS: This nationwide multicenter retrospective cohort study was conducted at 13 hospitals in South Korea from November 1 to December 31, 2018. All decedents were included in the study. Antibiotic use during the last two weeks of their lives was investigated. RESULTS: A total of 1,201 (88.9%) patients received a median of two antimicrobial agents during the last two weeks of their lives. Carbapenems were prescribed to approximately half of the patients (44.4%) in the highest amount (301.2 days of therapy per 1,000 patient-days). Among the patients receiving antimicrobial agents, 63.6% were inappropriate and only 327 patients (27.2%) were referred by infectious disease specialists. The use of carbapenem (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.13-2.03; P = 0.006), underlying cancer (OR, 1.56; 95% CI, 1.20-2.01, P = 0.047), underlying cerebrovascular disease (OR, 1.88; 95% CI, 1.23-2.89, P = 0.004), and no microbiological testing (OR, 1.79; 95% CI, 1.15-2.73; P = 0.010) were independent predictors for inappropriate antibiotic prescribing. CONCLUSION: A considerable number of antimicrobial agents are administered to patients with chronic or acute illnesses nearing their end-of-life, a high proportion of which are prescribed inappropriately. Consultation with an infectious disease specialist, in addition to an antimicrobial stewardship program, may be necessary to induce the optimal use of antibiotics.

Clostridium difficile infection after orthopedic surgery: Incidence, associated factors, and impact on outcome.

BACKGROUND: To identify the incidence, associated factors, and impact of hospital-acquired Clostridium difficile infection (CDI) among patients who have undergone orthopedic surgery. METHODS: We retrospectively reviewed the charts of all adults patients who underwent orthopedic surgery from January 2016 through December 2017 at a tertiary hospital. RESULTS: Of 7,363 patients who underwent orthopedic surgical procedures, 52 (0.7%) developed hospital-acquired CDI. The independent factors associated with CDI were age ≥65 years (adjusted odds ratio [aOR], 3.4; P < .001), preoperative hospital stay ≥3 days (aOR, 3.7; P < .001), operating time ≥3 hours (aOR, 2.5; P < .005), and antibiotic use for infection treatment (aOR, 4.3; P < .001). After adjusting for the timing of CDI using a multistate model, the mean excess LOS attributable to CDI was 2.8 days (95% confidence interval [CI], 0.4-5.3). The impact of CDI on excess LOS was more evident among patients aged ≥65 years (4.4 days; 95% CI, 1.8-7.0) and those with any comorbidity (5.6 days; 95% CI, 3.0-8.1). CONCLUSIONS: The overall incidence of CDI after orthopedic surgery was 0.7%. The occurrence of CDI after orthopedic surgery contributes to increased LOS. The greatest impact of CDI on LOS occurs among elderly patients and patients with comorbidities.

Dual respiratory virus detection in adult patients with acute respiratory illness.

BACKGROUND: Nonrandom multiple respiratory virus (RV) detection provides evidence for viral interference among respiratory viruses. However, little is known as to whether it occurs randomly. METHODS: The prevalence of dual RV detection (DRVD) in patients with acute respiratory illnesses (ARIs) at 4 academic medical centers was investigated; data about the prevalence of 8 RVs were collected from the Korean national RV surveillance dataset. Linear regression analysis was performed to assess the correlation between observed and estimated prevalence of each type of DRVD. RESULTS: In total, 108 patients with ARIs showing DRVD were included in this study between 2011 and 2017. In several types of regression analysis, a strong correlation was observed between the observed and estimated prevalence of each type of DRVD. Excluding three DRVD types (influenza/picornavirus, influenza/human metapneumovirus, and adenovirus/respiratory syncytial virus), the slope of the regression line was higher than that of the line of random occurrence (1.231 > 1.000) and the 95% confidence interval of the regression line was located above the line of random occurrence. CONCLUSIONS: Contrary to the results of previous epidemiologic studies, most types of DRVD occur more frequently than expected from the prevalence rates of individual RV, except for three underrepresented pairs above.

Clinical implications of multidrug-resistant microorganisms and fungi isolated from patients with intra-abdominal infections in the Republic of Korea: a multicenter study.

The purpose of this study was to evaluate the clinical significance of fungi and multidrug-resistant organisms (MDROs) isolated from patients with intra-abdominal infections (IAIs). This multicenter study included consecutive patients admitted for microbiologically proven IAIs at 6 university-affiliated hospitals in South Korea between 2016 and 2018. A total of 1571 patients were enrolled. Multivariable logistic regression analysis revealed that the isolation of MDROs, isolation of Candida spp., underlying renal diseases, Charlson comorbidity score ≥ 3, septic shock, failure to receive a required surgery or invasive intervention, secondary bacteremia due to IAIs, and lower body mass index were found to be independent predictors for 28-day mortality. However, the isolation of Enterococcus spp. was not identified as a significant risk factor. MDROs and Candida spp. were found in 42 (2.7%) and 395 (25.1%), patients respectively. The isolation of MDROs or Candida spp. was a surrogate marker of 28-day mortality.

Machine-Learning-Based Approach to Differential Diagnosis in Tuberculous and Viral Meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is the most severe form of tuberculosis, but differentiating between the diagnosis of TBM and viral meningitis (VM) is difficult. Thus, we have developed machine-learning modules for differentiating TBM from VM. MATERIAL AND METHODS: For the training data, confirmed or probable TBM and confirmed VM cases were retrospectively collected from five teaching hospitals in Korea between January 2000 - July 2018. Various machine-learning algorithms were used for training. The machine-learning algorithms were tested by the leave-one-out cross-validation. Four residents and two infectious disease specialists were tested using the summarized medical information. RESULTS: The training study comprised data from 60 patients with confirmed or probable TBM and 143 patients with confirmed VM. Older age, longer symptom duration before the visit, lower serum sodium, lower cerebrospinal fluid (CSF) glucose, higher CSF protein, and CSF adenosine deaminase were found in the TBM patients. Among the various machine-learning algorithms, the area under the curve (AUC) of the receiver operating characteristics of artificial neural network (ANN) with ImperativeImputer for matrix completion (0.85; 95% confidence interval 0.79 - 0.89) was found to be the highest. The AUC of the ANN model was statistically higher than those of all the residents (range 0.67 - 0.72, P <0.001) and an infectious disease specialist (AUC 0.76; P = 0.03). CONCLUSION: The machine-learning techniques may play a role in differentiating between TBM and VM. Specifically, the ANN model seems to have better diagnostic performance than the non-expert clinician.

Management and outcomes of Burkholderia cepacia complex bacteremia in patients without cystic fibrosis: a retrospective observational study.

Burkholderia cepacia complex (BCC) is an emerging pathogen of nosocomial infection in chronic or critically ill patients without cystic fibrosis (CF). The objective was to evaluate the management and outcomes of BCC bacteremia in patients without CF. We conducted a retrospective study of non-CF adult patients with BCC bacteremia between January 1997 and December 2016 at 4 tertiary hospitals in South Korea. A total of 216 non-CF patients with BCC bacteremia were identified. Most cases were hospital-acquired (79.2%), and the most common source was a central venous catheter (CVC) (42.1%). The rates of susceptibility to trimethoprim-sulfamethoxazole and piperacillin-tazobactam of BCC isolates were high as 92.8% and 90.3%, respectively. The rates of susceptibility to ceftazidime, meropenem, and levofloxacin were 75.5%, 72.3%, and 64.1%, respectively. The 14-day, 30-day, and in-hospital mortality rate was 19.4%, 23.1%, and 31.0%, respectively. Female (OR = 3.1; 95% CI, 1.4-6.8), liver cirrhosis (OR = 6.2; 95% CI, 1.6-16.6), septic shock (OR = 11.2; 95% CI, 5.1-24.8), and catheter-related infection (OR = 2.6, 95% CI, 1.2-5.8) were the independent risk factors for 30-day mortality. The outcome did not differ according to type of antibiotics used. Among 91 patients with CVC-related BCC bacteremia, delayed CVC removal (> 3 days) had a higher rate of persistent bacteremia (54.5 vs. 26.1%; P = 0.03) and lower rate of clinical response (49.0 vs. 71.9%; P = 0.04), compared with early CVC removal (within 3 days). BCC bacteremia occurring in non-CF patients was mostly hospital-acquired and CVC-related. Early removal of the catheter is crucial in treatment of CVC-related BCC bacteremia.

Factors associated with sequelae after treatment of hematogenous pyogenic vertebral osteomyelitis.

OBJECTIVES: Functional disability may persist after completing treatment for hematogenous pyogenic vertebral osteomyelitis (HPVO). The objective of this study was to identify factors associated with residual sequelae after treatment of HPVO. METHODS: We conducted a retrospective study of patients diagnosed with HPVO at 5 tertiary-care hospitals between January 2005 and December 2012. Sequelae were defined as an inability to walk without assistance, bladder/bowel incontinence, and/or unresolved pain that required analgesic therapy at 12 months after completing the HPVO treatment. RESULTS: Of the 279 patients with microbiologically proven HPVO, 79 (28.3%) had sequelae at 12 months posttherapy. Independent risk factors for sequelae were neurologic deficit (adjusted odds ratio [aOR], 3.38), recurrence within 12 months (aOR, 2.45), age ≥ 65 years (aOR, 2.05), C-reactive protein level ≥ 10 mg/dL (aOR, 2.01), and epidural/paravertebral abscess (aOR, 2.00). Among 58 patients with neurologic deficit, sequelae rates differed according to the surgical strategy, as follows: 28.6% (early surgery [<48 h]), 55.0% (delayed surgery [≥48 h]), and 66.7% (no surgery) (P = 0.03). Among the 170 patients with abscess, early drainage (<72 h) was an independent protective factor for sequelae (aOR, 0.35). The 12-month recurrence rates differed according to the total duration of antibiotic treatment, as follows: 20.5% (4-6 weeks), 18.4% (6-8 weeks), and 5.2% (≥8 weeks) (P < 0.001). CONCLUSIONS: A substantial proportion of patients with HPVO experienced sequelae after completing treatment. Early surgery for neurologic deficit, early drainage of abscess, and antibiotic therapy of appropriate duration to reduce recurrence may prevent development of sequelae in patients with HPVO.

Therapeutic outcome of spinal implant infections caused by Staphylococcus aureus: A retrospective observational study.

Spinal implant infection is a rare but significant complication of spinal fusion surgery, and the most common pathogen is Staphylococcus aureus. It is difficult to treat due to this pathogen's biofilm-forming ability and antibiotic resistance. We evaluated the therapeutic outcome of treatments for S aureus spinal implant infections. We retrospectively reviewed all patients with S aureus spinal implant infections at 11 tertiary-care hospitals over a 9-year period. Parameters predictive of treatment failure and recurrence were analyzed by Cox regression. Of the 102 patients with infections, 76 (75%) were caused by methicillin-resistant S aureus (MRSA) and 51 (50%) were late-onset infections. In all, 83 (81%) patients were managed by debridement, antibiotics, and implant retention (DAIR) and 19 (19%) had their implants removed. The median duration of all antibiotic therapies was 52 days. During a median follow-up period of 32 months, treatment failure occurred in 37 (36%) cases. The median time to treatment failure was 113 days, being <1 year in 30 (81%) patients. DAIR (adjusted hazard ratio [aHR], 6.27; P = .01) and MRSA infection (aHR, 4.07; P = .009) were independently associated with treatment failure. Rifampin-based combination treatments exhibited independent protective effects on recurrence (aHR, 0.23; P = .02). In conclusion, among patients with S aureus spinal implant infections, MRSA and DAIR were independent risk factors for treatment failure, and these risk factors were present in the majority of patients. In this difficult-to-treat population, the overall treatment failure rate was 36%; rifampin may improve the outcomes of patients with S aureus spinal implant infections.

Prosthetic Valve Endocarditis caused by HACEK Organisms: a Case Reports and Systematic Review of the Literature.

HACEK is a rare cause of prosthetic valve endocarditis (PVE). We describe 42-year-old male patient who presented with Aggregatibacter aphrophilus PVE and cerebral infarct. A. aphrophilus was isolated from his blood cultures as the sole pathogen, which was confirmed by subsequent 16S rRNA sequencing. He was treated with valve replacement surgery and an 8 week course of pathogen-directed antibiotic therapy and followed for 20 months without recurrence.

The acceptable duration between occupational exposure to hepatitis B virus and hepatitis B immunoglobulin injection: Results from a Korean nationwide, multicenter study.

BACKGROUND: Postexposure prophylaxis for occupational exposure to hepatitis B virus (HBV) plays an important role in the prevention of HBV infections in health care workers (HCWs). We examined data concerning the acceptable duration between occupational exposure and administration of a hepatitis B immunoglobulin (HBIG) injection in an occupational clinical setting. METHODS: A retrospective analysis was conducted with data from 143 cases of HCWs exposed to HBV in 15 secondary and tertiary teaching hospitals between January 2005 and June 2013. Data were taken from the infection control records of each hospital. RESULTS: Active vaccination after HBV exposure was started in 119 cases (83.2%) and postvaccination testing for hepatitis B antibody showed positive seroconversion in 93% of cases. In 98 cases (68.5%), HBIG was administered within 24 hours after HBV exposure; however, 45 HCWs (31.5%) received an HBIG injection more than 24 hours postexposure and 2 among the 45 received an injection after 7 days. Although 31.5% received an HBIG injection more than 24 hours postexposure, no cases of seroconversion to hepatitis b antibody positivity occurred. CONCLUSIONS: For susceptible HCWs, HBIG administered between 24 hours and 7 days postexposure may be as effective as administration within 24 hours in preventing occupational HBV infection.

Clinical and economic consequences of failure of initial antibiotic therapy for patients with community-onset complicated intra-abdominal infections.

OBJECTIVES: Complicated intra-abdominal infection (cIAI) is infection that extends beyond the hollow viscus of origin into the peritoneal space, and is associated with either abscess formation or peritonitis. There are few studies that have assessed the actual costs and outcomes associated with failure of initial antibiotic therapy for cIAI. The aims of this study were to evaluate risk factors and impact on costs and outcomes of failure of initial antibiotic therapy for community-onset cIAI. METHODS: A retrospective study was performed at eleven tertiary-care hospitals. Hospitalized adults with community-onset cIAI who underwent an appropriate source control procedure between August 2008 and September 2011 were included. Failure of initial antibiotic therapy was defined as a change of antibiotics due to a lack of improvement of the clinical symptoms and signs associated with cIAI in the first week. RESULTS: A total of 514 patients hospitalized for community-onset cIAI were included in the analysis. The mean age of the patients was 53.3 ± 17.6 years, 72 patients (14%) had health care-associated infection, and 48 (9%) experienced failure of initial antibiotic therapy. Failure of initial antibiotic therapy was associated with increased costs and morbidity. After adjustment for covariates, patients with unsuccessful initial therapy received an additional 2.9 days of parenteral antibiotic therapy, were hospitalized for an additional 5.3 days, and incurred $3,287 in additional inpatient charges. Independent risk factors for failure of initial antibiotic therapy were health care-associated infection, solid cancer, and APACHE II ≥13. CONCLUSIONS: To improve outcomes and costs in patients with community-onset cIAI, rapid assessment of health care-associated risk factors and severity of disease, selection of an appropriate antibiotic regimen accordingly, and early infection source control should be performed.

Therapeutic outcomes of hematogenous vertebral osteomyelitis with instrumented surgery.

BACKGROUND: Patients with hematogenous vertebral osteomyelitis (HVO) occasionally require instrumentation for spinal stabilization. However, placing instrumentation in the setting of spinal infection raises concerns about recurrent infection due to bacteria adhering to the foreign material. In this study, we evaluated the therapeutic outcomes of patients with HVO who underwent instrumented surgery. METHODS: We conducted a retrospective chart review of adult patients with microbiologically diagnosed HVO who underwent surgical intervention in 5 tertiary care hospitals over an 8-year period. RESULTS: A total of 153 patients with HVO underwent surgical management for their infections. Of these 153 patients, 94 (61.4%) underwent surgical debridement alone (noninstrumented surgery) and 59 (38.6%) underwent surgical debridement and instrumentation (instrumented surgery). The median durations of antibiotic therapy were 66 and 80 days for the noninstrumentation and instrumentation groups, respectively (P = .22). Clinical outcomes were similar between the groups, including rates of infection-related death (2.1% vs 0%; P = .52), primary failure (1.1% vs 5.1%; P = .30), and recurrence (4.8% vs 6.8%; P = .72). Among the instrumentation group, there was a significant decreasing trend for recurrence according to total duration of antibiotic therapy: 22.2% (4-6 weeks), 9.1% (6-8 weeks), and 2.6% (≥ 8 weeks; P = .04). Duration of pre-instrumentation antibiotic therapy and single-stage operation (vs 2-stage operation) were not risk factors for recurrence. CONCLUSIONS: Spinal instrumentation in patients with HVO may be safe with pathogen-directed prolonged antibiotic therapy and should not be abandoned or delayed solely because of the risk of recurrence.

Bone involvement in secondary syphilis: a case report and systematic review of the literature.

Bone involvement is an unusual manifestation of secondary syphilis, but little information is available in the English-language literature. We carried out a systematic review of the English-language literature from 1964 to 2013, describing cases of secondary syphilis with bone involvement. We also describe a case of secondary syphilis with multiple osteolytic lesions, mimicking metastatic cancer or myeloma, which was included in an analysis of 37 eligible cases of secondary syphilis with bone involvement. Of these 37 patients, 28 (76%) patients were male, and the median age was 32 years (range, 12-64 years). Eleven (30%) patients had human immunodeficiency virus (HIV) infection with a median CD4 lymphocyte count of 343 cells/mm (range, 130-689 cells/mm). The diagnosis of early syphilis was suspected based on mucocutaneous findings in 28 (76%) cases. In the remaining 9 (24%) cases, high titers of nontreponemal serologic tests were the only evidence of early syphilis. The median venereal disease research laboratory (VDRL) titer was 1:64 (range, 1:8-1:320), and median rapid plasma reagin (RPR) titer was 1:64 (range, 1:16-1:512). The bones most often affected were long bones of the limbs (n = 22) and skull (n = 21). The bone lesions were multifocal in 27 (73%) cases and osteolytic in 19 (51%) cases. The treatment of syphilitic bone lesions was medical only in most patients, and prognosis was favorable with high-dose penicillin therapy. Clinical features and outcome between HIV-uninfected and HIV-infected patients were not different. Knowledge of this rare entity may lead to early diagnosis and appropriate management.

Incidence and outcomes of paradoxical lymph node enlargement after anti-tuberculosis therapy in non-HIV patients.

OBJECTIVES: Limited data are available regarding the incidence and outcomes of lymphadenopathy after completing tuberculosis (TB) treatment. METHODS: We prospectively evaluated the incidence and outcomes of post-treatment lymphadenopathy in 154 patients with newly diagnosed lymph node TB (group 1) and in 12 patients previously treated for TB (group 2). We assessed the rates of microbiological recurrence, clinical recurrence, and post-treatment paradoxical response (PR) (defined as no microbiological recurrence with spontaneous improvement). RESULTS: Post-treatment lymphadenopathy occurred in 24 (15.6%) patients of group 1 and in 12 patients of group 2. Re-biopsy was performed in 23 of these 36 patients. AFB stain was positive in four (17.4%) cases, and TB-PCR was positive in 11 (47.8%), but all samples were sterile (no microbiological recurrence). Granuloma was present in 12 (52.2%) histological specimens. Thirty-three (91.7%) of the 36 patients with lymphadenopathy improved spontaneously (post-treatment PR) and 3 (8.3%) were improved with retreatment (clinical recurrence). The overall incidence of post-treatment PR in patients with lymph node TB (group 1) was 8.6 per 100 person-years (95% CI, 5.8-12.7). CONCLUSIONS: Lymphadenopathy after TB treatment was more likely to be associated with post-treatment PR rather than with microbiological recurrence, and it should be monitored until PR resolve.

Erythropoietin decreases carbon tetrachloride-induced hepatic fibrosis by inhibiting transforming growth factor-beta.

BACKGROUND: In addition to hematopoietic effect, the erythropoietin is known as a multifunctional cytokine with anti-fibrosis and organ-protective activities. The purpose of this study was to evaluate the effect of recombinant human erythropoietin (rhEPO) on hepatic fibrosis and hepatic stellate cells (HSCs). METHODS: Carbon tetrachloride (CCl(4)) induced hepatic fibrosis mice models were used for in vivo study and HSCs line for in vitro study. CCl(4) and rhEPO (0, 200 or 1000 U/kg) was injected intraperitoneally in BALB/c mice three times a week for 4 weeks. Immunohistochemistry and immunoblotting were performed to evaluate expressions of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and fibronectin in explanted liver. Immunoblotting of α-SMA, phophorylated Smad-2 and Smad-2/3 was performed in HSCs treated with TGF-ß1 and/or rhEPO. RESULTS: Expressions of TGF-ß1, α-SMA, and fibronectin were increased in CCl(4) injected mice livers, but significantly attenuated by co-treatment with CCl(4) and rhEPO. Co-treatment of rhEPO markedly suppressed fibrosis in Masson's trichrome compared with treatment of only CCl(4). TGF-ß1 increased phosphorylated α-SMA, Smad-2 expressions in HSCs, which were decreased by rhEPO co-treatment. CONCLUSIONS: Treatment of rhEPO effectively suppressed fibrosis in CCl(4)-induced liver fibrosis mice models. Anti-fibrosis effect of rhEPO could be related to inhibition of TGF-ß1 induced activation of HSCs.