Tzong Shiann Ho

Enterovirus 71, one virus and many stories.

Enterovirus 71 (EV71) has emerged as a significant cause of brainstem encephalitis and acute flaccid paralysis in Taiwan. It may be complicated by autonomic nervous system dysregulation and pulmonary edema (PE). Cytokines in the central nervous system and systemic inflammatory responses play important roles in the pathogenesis of EV71-associated PE. Pathogenesis-based management with intravenous immunoglobulin and milrinone has been associated with reduced mortality in children with severe EV71 infections.

Historical Review of Pandemic Influenza A in Taiwan, 2009

Influenza is an important disease in children. In April 2009, human infections caused by a novel swine H1N1 virus were reported in Mexico, followed by a pandemic. As of 14 March 2010, more than 213 countries and overseas territories or communities have reported laboratory-confirmed cases of pandemic influenza H1N1 2009, including at least 16,813 deaths. This influenza pandemic is unique in many respects. Large outbreaks occurred outside the usual season for influenza infection. The virus also caused severe illnesses and deaths in younger people, with many deaths caused by severe pneumonia. A comprehensive approach to pandemic control has been launched, including infection control interventions, antiviral drugs and vaccines. Vaccination is the most efficient way to control morbidity and mortality resulting from influenza infections in humans. For the first time, an influenza vaccine against a pandemic strain became available before the winter. However, the initially smooth influenza vaccination program was disturbed by the fear of possible adverse events following immunization. In Taiwan, mistrust of the influenza vaccination has also caused significant social impacts towards the end of 2009. Lessons learned from this pandemic influenza H1N1 2009 might help health authorities and physicians shape their preparedness for the next pandemic.

Infiltrated cells in experimental allergic encephalomyelitis by additional intracerebral injection in myelin-basic-protein-sensitized B6 mice

We previously reported that murine experimental allergic encephalomyelitis can be induced by an additional intraperitoneal and intracerebral (i.c.) restimulation in resistant B6 mice after standard immunization with myelin antigens in complete Freunds adjuvant and Bordetella pertussis coadjuvant. Neutrophils infiltrated into perivascular spaces at 12 h, followed by mononuclear cells 24 h after i.c. injection. In this study, we report that the i.c. injection induced the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The kinetic expression of ICAM-1 or VCAM-1 on brain endothelial cells paralleled the infiltration of neutrophils and mononuclear cells, respectively. The infiltrated lymphocytes also expressed very late antigen-4 (VLA-4) molecules. The microvascular endothelial cells were positive for VCAM-1, whereas the surrounding mononuclear cells were VLA-4 positive. Furthermore, we found a unique subpopulation of cells with characteristics of CD4(-)CD8(-)V(beta)8(+) markers. The kinetic studies of this population showed that these cells were transiently depleted from 12 to 24 h after i.c. challenge (before the development of clinical symptoms) in cervical lymph nodes. These CD4(-)CD8(-)V(beta)8(+) cells can be expanded by in vitro culture with myelin basic protein or IL-2. No significant changes of CD4(+)/CD8(+) cells were noted. CD4(+)CD8(-)CD3(+) cells were also found in brain by double histochemical stains and were the major infiltrating cells at 24 or 48 h after i.c. challenge.

Long-term Characteristics of Healthcare-associated Infections in a Neonatal Intensive Care Unit

BACKGROUND/PURPOSE Healthcare-associated infections in neonatal intensive care units (NICUs) are associated with a significant risk of morbidity and mortality. Knowledge regarding pathogens, primary sources of infection and antibiotic resistance in the NICU is essential for developing management strategies. This study aimed to analyze the long-term characteristics of healthcare-associated infections in a tertiary referral center in southern Taiwan. METHODS Infants < 30 days old, with positive blood, cerebrospinal fluid, urine or tissue fluid cultures during hospitalization in the NICU of National Cheng Kung University Hospital from July 1989 to June 2008 were included in the study. RESULTS In total, 1,417 organisms and episodes were identified during the study period. Gram-positive organisms, Gram-negative organisms and fungi constituted 923 (65.1%), 358 (25.3%) and 136 (9.6%) of the pathogens, respectively. Of the Gram-positive organisms, coagulase-negative staphylococci (51.5%), Staphylococcus aureus (34.8%) and Enterococcus spp. (6.1%) were the major pathogens; and 27% of Staphylococcus aureus isolates were oxacillin-resistant. For the Gram-negative organisms, Klebsiella pneumoniae (22%), Pseudomonas aeruginosa (21.8%), Escherichia coli (16.7%) and Enterobacter cloacae (16.7%) were dominant. Also, Candida albicans accounted for 50% of fungal infections. The most common source of infection was bloodstream infection (59.0%), and 5.6% of these were catheter-related. Skin and soft tissue infections were also frequent (26.3%). CONCLUSION Bloodstream and skin/soft tissue infections caused by commensal species play an important role in healthcare-associated infections in the NICU. New measures should be developed in response to the changing patterns in the NICU.

Childhood invasive pneumococcal disease caused by non-7-valent pneumococcal vaccine (PCV7) serotypes under partial immunization in Taiwan

BACKGROUND/PURPOSE Emerging non-7-valent pneumococcal conjugate vaccine (PCV7) serotypes have replaced PCV7 serotypes in childhood invasive pneumococcal disease (IPD). This study was designed to describe the IPD caused by non-PCV7 serotypes under partial PCV7 immunization in Taiwan. METHODS All children <18 years of age diagnosed with IPD at National Cheng Kung University Hospital from 1998 to 2010 were enrolled. Clinical and laboratory information was collected. Pneumococcal isolates were tested for antimicrobial susceptibility and interpreted using Clinical Laboratory Standard Institute guidelines (2008). Serotypes were determined using the capsular swelling method. RESULTS One hundred and five patients with IPD were identified, including 75 PCV7 and 30 non-PCV7 isolates. Pneumonia (63.3%) was the leading clinical manifestation of non-PCV7 IPDs and 78.9% of pneumonia cases were associated with necrotizing pneumonia or empyema. Children with non-PCV7 IPDs had longer febrile days, required longer intensive care unit stays, and had a higher C-reactive protein level than those with PCV7 IPDs (p < 0.05). Serotype 3 is the most common non-PCV7 serotype (46.7%) and possesses the highest potential for pulmonary complications (p < 0.05, odds ratio: 0.114; 95% confidence interval, 0.013 - 0.973). CONCLUSION The changing epidemiology of IPDs following the introduction of PCV7 has been noted. Expanded serotype coverage of the vaccine is warranted.

Echovirus 18 meningitis in southern Taiwan.

Eighty cases of echovirus 18 infection among young children during an outbreak in 2006 in Taiwan were enrolled. Twenty percent of the patients had a comorbid condition. Twenty-five cases (31%) were complicated by aseptic meningitis. The most frequent diagnoses in children without meningitis were pharyngitis/tonsillitis (35%) and vesicular viral exanthem (33%). The case-fatality rate among the children with meningitis was 4%. Echovirus 18 was isolated from the cerebrospinal fluid of 68% of the children.

Resveratrol treatment reveals a novel role for HMGB1 in regulation of the type 1 interferon response in dengue virus infection

Dengue is one of the most significant mosquito-borne virus diseases worldwide, particularly in tropical and subtropical regions. This study sought to examine the antiviral activity of resveratrol (RESV), a phytoalexin secreted naturally by plants, against dengue virus (DENV) infection. Our data showed that RESV inhibits the translocation of high mobility group box 1 (HMGB1), a DNA binding protein that normally resides in the nucleus, into the cytoplasm and extracellular milieu. HMGB1 migrates out of the nucleus during DENV infection. This migration is inhibited by RESV treatment and is mediated by induction of Sirt1 which leads to the retention of HMGB1 in the nucleus and consequently helps in the increased production of interferon-stimulated genes (ISGs). Nuclear HMGB1 was found to bind to the promoter region of the ISG and positively regulated the expression of ISG. The enhanced transcription of ISGs by nuclear HMGB1 thus contributes to the antiviral activity of RESV against DENV. To the best of our knowledge, this is the first report to demonstrate that RESV antagonizes DENV replication and that nuclear HMGB1 plays a role in regulating ISG production.

Enterovirus 71 virion-associated galectin-1 facilitates viral replication and stability.

Enterovirus 71 (EV71) infection causes a myriad of diseases from mild hand-foot-and-mouth disease or herpangina to fatal brain stem encephalitis complicated with pulmonary edema. Several severe EV71 endemics have occurred in Asia-Pacific region, including Taiwan, and have become a serious threat to children’s health. EV71 infection is initiated by the attachment of the virion to the target cell surface. Although this process relies primarily upon interaction between viruses and cell surface receptors, soluble factors may also influence the binding of EV71 to host cells.Galectin-1 has been reported to participate in several virus infections, but is not addressed in EV71. In this study, we found that the serum levels of galectin-1 in EV71-infected children were higher than those in non-infected people. In EV71 infected cells, galectin-1 was found to be associated with the EV71 VP1 and VP3 via carbohydrate residues and subsequently released and bound to another cell surface along with the virus. EV71 propagated from galectin-1 knockdown SK-N-SH cells exhibited lower infectivity in cultured cells and less pathogenicity in mice than the virus propagated from parental cells. In addition, this galectin-1-free EV71 virus was sensitive to high temperature and lost its viability after long-term storage, which could be restored following supplement of recombinant galectin-1. Taken together, our findings uncover a new role of galectin-1 in facilitating EV71 virus infection.

Changes in measles seroepidemiology of healthcare workers in southern Taiwan.

To assess the measles seroepidemiology of healthcare workers (HCWs), from 2004 to 2009 all newly recruited staff at a university hospital in Taiwan, were tested for specific immunoglobulin G antibodies for measles virus using enzyme-linked immunosorbent assays. A total of 1584 HCWs were included. The positivity rate of measles antibody for physicians and nurses was about 90%. The positivity of measles antibody in different age groups was 78·1%, 93·9% and 94·2% for 20-29, 30-39 and ≥40 years age groups, respectively. Equivocal results were more frequent in the 20-29 (17·1%) years age group. A lack of antibody against measles was reported for 66 (4·2%) of those tested. Medical student (8·3%) and housekeeping personnel (5·3%) had the greatest lack of antibodies. This study demonstrates the waning measles immunity in younger HCWs in Taiwan, which poses the potential risk of nosocomial transmission of measles. Periodic surveillance and revaccination of susceptible HCWs is recommended.

Antibodies Against Modified NS1 Wing Domain Peptide Protect Against Dengue Virus Infection

Dengue is the most common mosquito-transmitted viral infection for which an improved vaccine is still needed. Although nonstructural protein-1 (NS1) immunization can protect mice against dengue infection, molecular mimicry between NS1 and host proteins makes NS1-based vaccines challenging to develop. Based on the epitope recognized by the anti-NS1 monoclonal Ab (mAb) 33D2 which recognizes a conserved NS1 wing domain (NS1-WD) region but not host proteins, we synthesized a modified NS1-WD peptide to immunize mice. We found that both mAb 33D2 and modified NS1-WD peptide immune sera could induce complement-dependent lysis of dengue-infected but not un-infected cells in vitro. Furthermore, either active immunization with the modified NS1-WD peptide or passive transfer of mAb 33D2 efficiently protected mice against all serotypes of dengue virus infection. More importantly, dengue patients with more antibodies recognized the modified NS1-WD peptide had less severe disease. Thus, the modified NS1-WD peptide is a promising dengue vaccine candidate.