Molecular Diagnosis of Severe Angiostrongylus cantonensis-Induced Eosinophilic Meningitis: A Case Report Emphasizing the Need for Accurate Detection Methods.

BACKGROUND Angiostrongylus cantonensis, also known as the rat lungworm, is the most common parasitic cause of human eosinophilic meningitis. A. cantonensis infection is an emergent disease causing permanent neurological injury or even death when not diagnosed and treated promptly. Usually, human infection occurs through ingestion of food contaminated by intermediated hosts or the third stage larvae of A. cantonensis. Indicators for diagnosis include clinical signs of meningitis; contact history, such as that from eating raw or improperly cooked intermediated hosts or contaminated vegetables; and cerebrospinal fluid (CSF) eosinophilia. However, diagnosis is now primarily defined through polymerase chain reaction (PCR) assay of CSF or serum. CASE REPORT A 66-year-old homeless man with unclear exposure history presented with fever and conscious change. The initial hemogram showed eosinophilia without neutrophilic leukocytosis. Non-contrast computed tomography (CT) and magnetic resonance imaging (MRI) of the head revealed no evidence of stroke. A lumbar puncture was performed and showed eosinophilic meningitis. The patient was ultimately diagnosed through PCR and sequencing for A. cantonensis infection, and dexamethasone treatment was started immediately. Although his general condition improved after dexamethasone treatment, his mental status did not improve completely. CONCLUSIONS Our report highlights the importance of applying molecular techniques in diagnosis of angiostrongylosis, especially in individuals who have unknown contact history.

Outcomes of corticosteroid treatment in critical Ill adult patients with respiratory viruses-related community acquired pneumonia - a propensity-matched case control study.

OBJECTIVES: To assess the outcomes of corticosteroid treatment in critically ill patients with respiratory virus-related community-acquired pneumonia (CAP). MATERIALS/METHODS: Adult patients who were admitted to the intensive care unit and had a polymerase chain reaction-confirmed diagnosis of respiratory virus-related CAP were included. Patients with and without corticosteroid treatment during the hospital course were retrospectively compared using a propensity score-matched case-control analysis. RESULTS: From January 2018 to December 2020, 194 adult patients were enrolled with 1:1 matching. The 14-day and 28-day mortality rates did not differ significantly between patients treated with and without corticosteroids (14-day mortality: 7% versus 14%, P = 0.11; 28-day mortality: 15% versus 20%, P = 0.35). However, multivariate analysis by using a Cox regression model revealed that corticosteroid treatment was an independent factor predicting decreased mortality (adjusted odds ratio, 0.46; 95% confidence interval, 0.22-0.97, P = 0.04). Subgroup analysis revealed lower 14-day and 28-day mortality rates in patients younger than 70 years treated with corticosteroids than in those not treated with corticosteroids (14-day mortality: 6% versus 23%; P = 0.01 and 28-day mortality: 12% versus 27%; P = 0.04). CONCLUSIONS: Non-elderly patients with severe respiratory virus-related CAP are more likely to benefit from corticosteroid treatment than elderly patients.

The influence of low-level viremia on CD4+ cell count in human immunodeficiency virus-infected patients.

BACKGROUND: Following initiation of combined antiretroviral therapy, the majority of human immunodeficiency virus-infected patients experience immune reconstitution indicated by virologic suppression and an increase in peripheral CD4+ T-cell counts. Some patients may suffer from low-level viremia, which was reported to be significantly associated with acquired immunodeficiency syndrome cases, virologic failure, and death. We aimed to further investigate the influence of low-level viremia on CD4+ T-cell count. METHODS: In our study, we included human immunodeficiency virus-seropositive patients on combined antiretroviral therapy, for at least 6 months, who received at least one assessment of human immunodeficiency virus plasma viral load and CD4+ cell count every 6 months, from January 2009 to January 2019. The copy-year viremia was determined by calculating the area under the curve of the plasma human immunodeficiency virus viral load. RESULTS: When comparing patients with a mean CD4+ cell count <200 cells/µL, there was no significant difference between patients with a mean viral load <1000 copies/mL and patients with a mean viral load ≥1000 copies/mL (p = 0.219). Among those with a mean viral load <1000 copies/mL, a higher proportion of patients had a mean CD4+ cell count ≥500 cells/µL (p < 0.001). The mean CD4+ cell count of patients with copy-years viremia (log10) <4 (577.7, interquartile range 429.2-736.7) was significantly higher than that of patients with copy-years viremia (log10) ≥4 (443.3, interquartile range 319.0-558.4) (p < 0.001). In multivariate logistic regression analysis, we observed that malignancy without history, lower copy-years viremia, and high nadir CD4+ cell count were independent predictors of mean CD4+ cell count ≥500 cells/µL. CONCLUSION: Human immunodeficiency virus-infected patients with a history of malignancy, high copy-year viremia, and lower nadir CD4+ cell counts should be monitored carefully in clinical settings.

Cytomegalovirus viral interleukin-10 in patients with Aspergillus infection and effects on clinical outcome.

BACKGROUND: Human cytomegalovirus (CMV) is associated with aspergillosis, but the simultaneous presence of CMV viral interleukin-10 (cmvIL-10) and aspergillosis has never been investigated. CmvIL-10 is produced by CMV-infected cells and acts as an immune modulator during CMV infection. The aim of this study was to evaluate cmvIL-10 levels in peripheral blood and its influence on the clinical outcomes of Aspergillus infection. METHODS: Patients who visited or were admitted to the hospital with suspected Aspergillus infection, including invasive aspergillosis (IA) and chronic pulmonary aspergillosis (CPA), were prospectively enrolled. The cmvIL-10, human IL-10 (hIL-10), IL-1B, IL-6, IL-8, IFN-γ, and TNF-α levels in peripheral blood were measured. RESULTS: Patients with Aspergillus infection had a higher level of cmvIL-10 than the control group (158 ± 305 vs 27.9 ± 30.4 pg/ml, p < .05). The level of cmvIL-10 was not correlated with CMV viremia or end-organ disease. The cmvIL-10 but not hIL-10 level was positively correlated with the IFN-γ level (p < .05) and marginally negatively correlated with IL-1B and IL-8 levels (p < .1). In patients with CPA, a high level of cmvIL-10 (≥100 pg/ml) was a poor prognostic factor for long-term survival (p < .05). In contrast, CMV viremia or end-organ disease was associated with poor survival in patients with IA (p = .05). CONCLUSIONS: Aspergillus infection was associated with CMV coinfection with cmvIL-10 in blood. A cmvIL-10 concentration ≥100 pg/ml was a predictor for unfavourable outcome in CPA patients.

Detection of influenza and non-influenza respiratory viruses in lower respiratory tract specimens among hospitalized adult patients and analysis of the clinical outcome.

BACKGROUND: Lower respiratory tract infection (LRTI) is one of the most fatal diseases for adults. Influenza is a well-recognized cause of severe pneumonia; however, the outcomes of LRTI caused by non-influenza respiratory viruses (NIRVs) have not been sufficiently investigated. This study aimed to describe the characteristics and outcomes of LRTI associated with respiratory viruses (RVs) in adults. MATERIALS/METHODS: A retrospective review was performed using medical records of adult patients whose lower respiratory tract (LRT) specimens (endotracheal aspirate and bronchoalveolar lavage fluid) tested positive for RVs using multiplex PCR. Underlying comorbidities, laboratory data, and clinical outcomes were analyzed. RESULTS: Among the 808 LRT specimens collected from 666 adult patients, RV was identified in 115 specimens (14%) from 106 patients (16%). The underlying comorbidities and laboratory data did not differ between patients with influenza- and NIRV-related LRTI. The 14-day and 30-day mortality rates were higher in the influenza group than in the NIRV group (24% versus 7%, p = 0.03 and 33% versus 13%, p = 0.02, respectively), whereas the 90-day mortality rate did not. In a multivariate Cox model to predict 90-day mortality, shock and acute kidney injury independently predicted a higher mortality rate (hazard ratio (HR): 4.28, 95% CI: 1.46-12.58, p = 0.01 and HR: 2.80, 95% CI: 1.28-6.15, p = 0.01, respectively), whereas the detection of influenza did not. CONCLUSIONS: Influenza and NIRVs were associated with increased mortality due to LRTI in adults. Therefore, NIRVs are among key pathogens causing LRTI and should not be neglected by clinicians.

The epidemiology and etiologies of respiratory tract infection in Northern Taiwan during the early phase of coronavirus disease 2019 (COVID-19) outbreak.

BACKGROUND: Coronavirus disease 2019 (COVID-19) manifests symptoms as common etiologies of respiratory tract infections (RTIs). During the pandemic of COVID-19, identifying the etiologies correctly from patients with RTI symptoms was crucial in not only disease control but preventing healthcare system from collapsing. By applying sensitive PCR-based molecular assays, we detected the etiologic agents and delineated the epidemiologic picture of RTIs in the early phase of COVID-19 pandemic. METHODS: From December 2019 to February 2020, we screened patients presented with RTIs using multiplex PCR-based diagnostic assays. Data from pediatric and adult patients were compared with different months and units in the hospital. RESULTS: Of all 1631 patients including 1445 adult and 186 pediatric patients screened, 8 viruses and 4 bacteria were identified. Positive rates were 25% in December, 37% in January, and 20% in February, with pediatric patients having higher positive rates than adults (Ps < 0.001). In pediatric patients, RhV/EnV was the most commonly detected, followed by parainfluenza viruses. Most Mycoplasma pneumoniae infection occurred in pediatric patients. RhV/EnV was the most commonly detected agent in pediatric patients admitted to intensive care units (ICUs), while influenza accounted for the majority of adult cases with critical illness. Noticeably, seasonal coronavirus ranked second in both adult and pediatric patients with ICU admission. CONCLUSION: While we focused on the pandemic of COVID-19, common etiologies still accounted for the majority of RTIs and lead to severe diseases, including other seasonal coronaviruses.

Differentiating impacts of non-pharmaceutical interventions on non-coronavirus disease-2019 respiratory viral infections: Hospital-based retrospective observational study in Taiwan.

BACKGROUND: Physical distancing and facemask use are worldwide recognized as effective non-pharmaceutical interventions (NPIs) against the coronavirus disease-2019 (COVID-19). Since January 2020, Taiwan has introduced both NPIs but their effectiveness on non-COVID-19 respiratory viruses (NCRVs) remain underexplored. METHODS: This retrospective observational study examined electronic records at a tertiary hospital in northern Taiwan from pre-COVID (January-December 2019) to post-COVID period (January-May 2020). Patients with respiratory syndromes were tested for both enveloped (eg, influenza virus and seasonal coronavirus) and non-enveloped RVs (eg, enterovirus and rhinovirus) using multiplex reverse transcription polymerase chain reaction assays. Monthly positivity rates of NCRVs among adult and pediatric patients were analyzed with comparison between pre- and post-COVID periods. RESULTS: A total of 9693 patients underwent 12 127 multiplex RT-PCR tests. The average positivity rate of NCRVs reduced by 11.2% (25.6% to 14.4%) after nationwide PHIs. Despite the COVID-19 pandemic, the most commonly identified enveloped and non-enveloped viruses were influenza virus and enterovirus/rhinovirus, respectively. Observed reduction in NCRV incidence was predominantly contributed by enveloped NCRVs including influenza viruses. We did not observe epidemiological impacts of NPIs on non-enveloped viruses but an increasing trend in enterovirus/rhinovirus test positivity rate among pediatric patients. Our data were validated using Taiwan's national notification database. CONCLUSIONS: Our frontline investigation suggests that the current NPIs in Taiwan might not effectively control the transmission of non-enveloped respiratory viruses, despite their protective effects against influenza and seasonal coronavirus. Health authorities may consider using hydrogen peroxide or chloride-based disinfectants as additional preventative strategies against non-enveloped respiratory viruses in the post-COVID-19 era.

Clinical significance of post-treatment viral load of cytomegalovirus in patients with hematologic malignancies.

OBJECTIVES: Patients with hematologic diseases were at high risk for cytomegalovirus (CMV) diseases. In the present study, we compare various prognostic factors during CMV viremia, with specific emphasis on the relationship between viremia eradication and the long-term prognosis of patients after each episode. METHODS: Adult patients with hematologic diseases who had a detectable CMV viral load (VL) (equal to or above 150 copies/mL) were included in the study. Medical records were reviewed for demographic data including age, sex, hematologic and other underlying diseases, status of stem cell transplantation, antiviral medication, serum CMV viral load before and after antiviral treatment. RESULTS: A total of 101 episodes of CMV viremia occurred in patients with hematologic diseases. Comparison of various prognostic factors revealed non-survivors more frequently suffered from pneumonia and concomitant bacterial or fungal infections, had less frequently undergone hematopoietic stem cell transplantation (HSCT), and had higher peak VLs during viremic episodes. After antiviral therapy, eradication of viremia was much less frequently achieved in non-survivors. The Kaplan-Meier curves revealed that patients with detectable end-treatment VL had lower survival rates even if the antivirals were administered for more than 21 days. In a multivariate Cox proportional-hazard model, a detectable VL at the end of antiviral therapy independently predicted mortality within 180 days. CONCLUSIONS: In patients with hematologic diseases suffering CMV viremia, failure to eradicate viremia after antiviral therapy indicates a higher chance of mortality and can be regarded as a useful indicator in evaluating the patient's long-term prognosis.

Detection of respiratory viruses in adults with respiratory tract infection using a multiplex PCR assay at a tertiary center.

BACKGROUND: Respiratory viruses (RVs) are among the most common pathogens for both upper and lower respiratory tract infections (RTIs). However, the viral epidemiology of RV-associated RTIs in adults has long been under-recognized. Through a sensitive molecular assay, it would be possible to have a better understanding of the epidemiology of RV-associated RTIs. MATERIAL AND METHODS: Respiratory tract (RT) specimens from adults hospitalized due to RTIs were tested for RVs, using the multiplex PCR-based Luminex xTAG® Respiratory Viral Panel assay. A total of nineteen RVs, including influenza viruses and non-influenza respiratory viruses (NIRVs) were detected. Positive rates were compared using a chi-square test. RESULTS: A total of 2292 samples from adult patients hospitalized with RTIs were screened for RVs. The overall positive rate was 22%, with 17.8% samples positive for at least one NIRV. NIRVs had a higher positive rate in non-winter seasons. As many as 12.7% (46/363) of the samples collected through broncho-alveolar lavage and 20.5% (176/859) of the samples collected in ICUs were positive for RVs. Distribution of corona virus (CoV), human metapneumovirus (hMPV) and parainfluenza virus (PIV) demonstrated seasonal variation. Also, temperature was associated with the positive rates of specific viruses, including CoV, respiratory syncytial virus (RSV), hMPV and PIV. CONCLUSION: Respiratory viruses, notably NIRVs, were frequently detected in adults hospitalized with RTIs. Several RVs were detected with distinctive seasonal variations. A substantial number of RVs were identified in lower RT specimens or from patients admitted to ICU, highlighting their important role in causing severe respiratory infection.

The clinical manifestations and interval changes of reverse-transcriptase quantitative polymerase chain reactions among different specimens of coronavirus disease 2019 patients.

BACKGROUND: Since December 2019, a number of cases and deaths due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have been reported worldwide. In spite of clinical manifestations similar to the SARS-CoV epidemic in 2003, affected organs and severity are yet to be defined. Moreover, viral load alterations and viral shielding among different specimens remained scarce. Therefore, clarifying clinical presentations and correlations among viral loads, disease severity, and viral shielding of SARS-CoV-2 infection is crucial in the disease prevention. METHODS: The clinical courses of SARS-CoV-2 cases were presented through Gantt charts. Laboratory examinations and reverse-transcriptase quantitative polymerase chain reactions (RT-qPCR) among different specimens were tested periodically. Cycle thresholds (CT) were recorded and presented as viral loads. RESULTS: From March 2020 to April 2020, 4 SARS-CoV-2 cases were presented, of which, cases 1 and 2 manifested the symptoms severer than cases 3 and 4, along with higher serum lactate dehydrogenase levels and graded for lymphocytopenia. Case 4 initially exhibited anosmia but recovered within a short period. Curves of the CT of all the cases, except case 2, concaved upward after prescribing hydroxychloroquine (HCQ) and azithromycin. Except for case 4, the CT in most stool specimens remained undetectable; however, none of the cases presented gastrointestinal symptoms. Surprisingly, the CT values of the saliva specimens were inconsistent with those of the nasopharyngeal swabs and sputum. CONCLUSION: SARS-CoV-2 manifests various symptoms. Sudden onset of central nervous system symptoms should be considered. The timing of HCQ and azithromycin administration might be a key factor in the viral load reduction. Positive prediction values of RT-qPCR of different specimens should be tested carefully to prevent false-negative results.

Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis.

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.

Severe acute hypokalaemia associated with piperacillin/tazobactam in an HIV-infected patient under antiretroviral therapy with tenofovir alafenamide: case report and literature review.

Piperacillin/tazobactam is a commonly prescribed antimicrobial agent. Tenofovir alafenamide (TAF) is increasingly being used in antiretroviral therapy (ART) of HIV. Herein we report a case of a 57-year-old male with AIDS receiving TAF-containing ART in whom severe refractory hypokalaemia developed after coadministration of piperacillin/tazobactam for suspected hospital-acquired infection. Upon withdrawal of piperacillin/tazobactam, serum potassium concentrations returned to normal within 2 days. Hypokalaemia is a rare adverse effect of piperacillin/tazobactam and may be aggravated with the underlying use of TAF. We also reviewed past reported cases of hypokalaemia after piperacillin/tazobactam administration. We want to highlight that a more cautious approach should be considered when combining piperacillin/tazobactam and TAF in clinical practice.

Clinical significance of human cytomegalovirus viruria and the effect of antiviral therapy in hematopoietic stem cell transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) causes life-threatening infections in immunocompromised host. The clinical significance of asymptomatic CMV viruria in patients receiving hematopoietic stem cell transplantation (HSCT) remains unclear. This study aims to clarify whether antiviral therapy is associated with a favorable clinical outcome. METHODS: HSCT recipients whose urine was culture-positive for CMV were retrospectively reviewed and followed. Viruria episodes were divided according to whether or not antiviral therapy was used. Mortality and the estimated glomerular filtration rate (eGFR) in 2 years following CMV viruria were compared between patients with and without antiviral therapy. RESULTS: Sixty-two episodes of culture-proven asymptomatic CMV viruria were identified in 28 HSCT recipients. Antiviral therapy was used in 35 (56.5%) and spared in 27 (43.5%) viruric episodes. Compared with the baselines, there were no significant difference in the decrements of eGFR between the two groups at the end the 1st year (4.78 vs 5.02 mL/min/1.73 m2, p = 0.968) and the 2nd year (1.13 vs 7.66 mL/min/1.73 m2, p = 0.276). Antiviral therapy for asymptomatic CMV viruria was also not associated with a favorable survival (p = 0.288). On the other hand, presence of CMV viremia correlated with a poorer survival (2-year mortality rate 60% vs 13.33%, p < 0.001). CONCLUSION: Antiviral therapy for asymptomatic CMV viruria is not associated with a clear clinical benefit in HSCT recipients. Further studies may be needed to identify if specific patient populations may benefit from antiviral therapy in CMV viruria.

The incidence rate, trend and microbiological aetiology of prosthetic joint infection after total knee arthroplasty: A 13 years' experience from a tertiary medical center in Taiwan.

BACKGROUND/PURPOSE: Total knee arthroplasty (TKA) improves the patient's quality of life by relieving pain, correcting the deformity, and helping the patient resume normal activities. However, post-TKA prosthetic joint infection leads to implant failure, is difficult to treat, and causes a significant burden both economically and health-wise. Therefore, an understanding of the current trends in this infection and microbiology data is essential for preventing and treating it. METHODS: A retrospective study was conducted on 10,768 patients who underwent primary TKA at Taipei Veterans General Hospital, Taiwan, from 2002 to 2014. The incidence of post-TKA prosthetic joint infection in different time periods was investigated, and microbiological results in early- (<3 months post-TKA) and delay-onset prosthetic joint infection were analyzed. RESULTS: The 2 years incidence of post-TKA prosthetic joint infection was 1.93% (2002-2006), 1.05% (2007-2010), and 0.76% (2011-2014). The incidence of post-TKA prosthetic joint infection decreased significantly from 2002 to 2014. Although Staphylococcus species was most commonly isolated, a significantly higher proportion of gram-negative bacteria were isolated from early-onset compared with delay-onset post-TKA prosthetic joint infection patients: 9/29 (31.0%) versus 13/100 (13%); p = 0.023. CONCLUSIONS: The results showed that the risk of post-TKA prosthetic joint infection is decreasing. Microbiology results showed that early-onset post-TKA prosthetic joint infection is associated with a higher risk of gram-negative bacterial infection. Physicians should be aware of this risk in order to correctly select empirical agents.

Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells.

Increasing evidence suggests a link between persistent human cytomegalovirus (HCMV) infection and cancer. Although the role of HCMV in cancer is still elusive, recent studies revealed the presence of HCMV nucleic acids and proteins in different cancer types such as glioblastoma, colorectal, breast, and prostate cancers, and neuroblastoma. Although HCMV may not be directly associated with the neoplastic transformation, the presence of HCMV DNA in the tumorous tissue has been associated with altered clinical outcomes in cancer patients. However, the mechanisms involved in the association between colorectal cancer (CRC) and HCMV are unclear. In this study, we investigated the influence of HCMV infection on CRC or their derived cells. Proliferation and migration assays revealed a high infection efficiency in CRC-derived HT29 and SW480 'stem­like' cells. After 24, 48 and 72 h of HCMV infection, both HT29 and SW480 parental and stem­like cells showed a significant increase in cell proliferation and viability (p<0.0001). Moreover, HCMV infection promoted cell migration. These results demonstrate a significant phenotypic alteration in the CRC cell line upon HCMV infection. Using epithelial to mesenchymal transition (EMT) assays, we demonstrated that the EMT markers and driver genes were upregulated during the virus infection. The WNT signaling pathway, which is associated with the proliferation and migration of CRC cells, was upregulated (6-fold) in HCMV-infected cells as compared to the non­infected cells at day 7 from infection.

Implementation and outcomes of an antimicrobial stewardship program: Effectiveness of education.

BACKGROUND: Unnecessary use of antibiotics is a common occurrence in hospitals. Implementation of antibiotic stewardship programs (ASPs) has been shown to reduce both unnecessary antibiotic use and drug-resistant bacteria. Education is a fundamental component of an ASP. However, the effectiveness of proper uses of antibiotics education has not been clearly analyzed. METHODS: In a 520-bed university hospital located in northeastern Taiwan, a significantly increasing prescription of carbapenems, specifically imipenem and meropenem, was observed. An educational program highlighting the judicious use of carbapenems was started, beginning in October 2013. A multidisciplinary ASP was implemented starting in January 2014. The consumption of antibiotics, measured by defined daily dose per 1000 occupied bed-days, was compared among the pre-educational, posteducational, and post-ASP periods. RESULTS: Compared with the pre-educational period, there was a significant reduction in antibiotics consumption of 13% total inpatient antibiotics (p = 0.008), 29.8% carbapenems (p = 0.001), 34.9% imipenem and meropenem (p < 0.001), and 27% glycopeptides (p = 0.015), in the posteducational and post-ASP periods. The major reduction emerged during the posteducational period and was sustained after the ASP. The percentage of inpatients prescribed with antibiotics was significantly decreased (16.2%; p < 0.001). The rate of carbapenem-resistant Acinetobacter baumannii decreased from 70.8% to 29.6% within 7 months. CONCLUSION: A focused educational program is effective in controlling the prescription of specific antibiotic classes in the early phase of a multidisciplinary ASP.

Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients.

Increasing evidence suggests that human cytomegalovirus (HCMV) plays an oncomodulatory role in human cancers. In colorectal cancer (CRC), presence of HCMV in tumours has been associated with a poor outcome in elderly patients. This study aimed to investigate the association between HCMV and the outcome of non-elderly patients with CRC. In tumour samples, HCMV DNA was detected by PCR. Viral transcript and protein were detected by in situ hybridization (ISH) and immunohistochemical staining (IHC), respectively. Clinical, pathological and survival data were compared between patients with HCMV-positive and -negative tumours. Quantitative reverse transcription PCR (qRT-PCR) was used to analyse the expression levels of cellular signals related to CRC progression and metastasis. Among 89 CRC non-elderly patients aged <65 years, HCMV was detected in 31 (34.8 %) tumour samples by PCR. By ISH and IHC, viral transcript and protein specifically localized to the cytoplasm of neoplastic mucosal epithelium. Outcome analysis revealed a more favourable disease-free survival (DFS) rate in patients with HCMV-positive tumours (P<0.01), specifically in patients with stage III disease. In a multivariate Cox proportional-hazard model, tumoural presence of HCMV independently predicted a higher DFS rate (hazard ratio 0.22; 95 % confidence interval 0.075-0.66, P<0.01). By qRT-PCR, the tumoural levels of interleukin-1 were relatively lower in samples positive for HCMV. The results suggest that HCMV may influence the outcome of CRC in an age-dependent manner and possibly has a dual oncomodulatory effect. How the virus interacts with the tumour microenvironment should be further studied.

Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours.

Colorectal cancer (CRC) is amongst the leading causes of cancer-related mortality worldwide. Emerging evidence suggests that human cytomegalovirus (HCMV) exists in the tumour tissue of CRC and is associated with disease outcome. To study whether tumoral HCMV is related to viral reactivation in blood, tumour specimens and pre- and post-operative blood samples from CRC patients were collected prospectively. PCR and quantitative PCR were performed to detect HCMV DNA. HCMV IgG and IgM antibodies were measured using a microparticle enzyme immunoassay. Transcription of a spliced HCMV UL73 gene transcript was analysed by quantitative reverse transcription PCR. HCMV was detected in 42.2% (35/83) of the tumour samples, with a low median viral load (30.08, range 2.33-5704 copies per 500  ng genomic DNA). The vast majority (80/81, 98.8%) of the CRC patients were seropositive for HCMV IgG. HCMV DNA was positive in 11.3% (22/194) of the pre-operative and 8.9% (15/168) of the post-operative blood samples. However, presence of HCMV and its viral load in tumours were not associated with the detection or viral loads in blood samples. About 26.67% (8/30) of the HCMV-positive tumours with available RNA had detectable viral UL73 transcripts, whilst none of the blood samples were positive for viral RNA (P < 0.0001). Therefore, presence of HCMV in tumours does not correlate with the serological or viraemic status of CRC patients. Active viral gene transcription occurred in the tumour but not in the blood of CRC patients. HCMV reactivation in CRC patients is possibly due to virus-cancer interactions in the CRC tumour microenvironment.

Genetic polymorphisms of the human cytomegalovirus UL144 gene in colorectal cancer and its association with clinical outcome.

Human cytomegalovirus (HCMV) has been increasingly detected in colorectal cancer (CRC), and genetic polymorphisms in HCMV affect its pathogenesis. This study aimed to investigate HCMV genetic polymorphisms in CRC and its correlation with the clinical outcomes. We performed PCR and sequencing of a viral immunomodulatory gene, UL144, in clinical isolates and CRC specimens. The nucleotide and amino acid sequences were aligned, and a phylogenetic tree was constructed. The clinical, pathological and survival data were compared among tumours with different UL144 genotypes. HCMV was detected in 49 (47.8 %) of the tumour specimens. Genotype A predominated in 43 samples (22/43; 51.2 %) with successful sequencing, followed by genotype B (13/43; 30.2 %) and genotype C (8/43; 18.6 %). The genotypic distribution was similar to that of the clinical isolates and those reported in other Asian populations. The amino acid sequence of genotype B was the most conserved. For stage II and III CRC patients with HCMV-positive tumours, disease-free survival (DFS) varied among the three major genotypes (P50.0046). The presence of genotype B virus in the tumours was associated with a shorter DFS and independently predicted tumour recurrence in a multivariate Cox proportional hazards model (hazard ratio, 5.79; 95 % confidence interval, 1.30­25.81; P50.021). By reverse transcription PCR, tumour samples with genotype B viruses had the highest rate of UL144 expression. Our results suggest that genetic polymorphisms of HCMV UL144 are associated with clinical outcome in CRC and that HCMV may play an immunomodulatory role in the tumour microenvironment of CRC.

The oncomodulatory role of human cytomegalovirus in colorectal cancer: implications for clinical trials.

Increasing evidence suggests that human cytomegalovirus (HCMV), a beta-herpes virus that chronically infects human beings, is associated with colorectal cancer (CRC). The viral nucleic acids specifically localized to the neoplastic mucosal epithelium of CRC, while tumoral presence of HCMV independently predicted a poor outcome in elderly patients. In the past decade, the concept of "oncomodulation" of HCMV in human cancers has been formulated. In CRC, changes in the tumor microenvironment are closely related to cancer behavior and prognosis, while the underlying mechanism driving these changes remains unclear. As HCMV affects multiple cellular functions, including signal pathways that regulate angiogenesis, apoptosis, cell invasiveness, and anti-cancer immunity, the virus potentially exerts oncomodulatory effects in the tumor microenvironment of CRC. Here, we summarize the current knowledge about the association between HCMV and CRC and suggest future perspectives on both research and anti-cancer therapy of CRC.