15:30-17:30, Friday, April 16, 2010
Frontiers of Translational Research in Pediatrics 2
Moderator: Li-Min HUANG (Taiwan), Ren-Bin TANG (Taiwan)
FTRP2-01 Studies from Enterovirus 71 Infections to Kawasaki Disease in Taiwan Luan-Yin CHANG (Taiwan)
FTRP2-02 Immunopathogenesis of EV71, Dengue, SARS and Novel H1N1 Infections Kuender D. YANG (Taiwan)
FTRP2-03 Community-associated MRSA in Taiwan and the World Yhu-Chering HUANG (Taiwan)
FTRP2-04 Improving Child Health: Bridging Research and Practice Cheng T. Cho (USA)


                           
FTRP2-01 STUDIES FROM ENTEROVIRUS 71 INFECTIONS TO KAWASAKI DISEASE IN TAIWAN

STUDIES FROM ENTEROVIRUS 71 INFECTIONS TO KAWASAKI DISEASE IN TAIWAN

Luan-Yin CHANG
Attending Physician, Division of Pediatric Infectious Disease, Department of Pediatrics, National Taiwan University Hospital

The enterovrius 71 (EV71) outbreak in Taiwan in 1998 is very well-known to cause a lot of fatal children cases. In 1998 epidemic, there were 405 severe cases with 78 deaths. In 2000 to 2002, there were still dozens of fatal EV71 cases each year. In addition, in 2008 EV71 outbreak occurred again in Taiwan as well as in mainland China and there were hundreds of severe cases and dozens of fatal cases. A stage-based management was thus developed to reduce the case-fatality but most survivors of brainstem encephalitis plus cardiopulmonary failure might have neurologic sequelae and impaired cognition.

We studied 433 family members from 94 families in which EV71 positively isolated. The overall enterovirus 71 transmission rate of household contacts was 52% (176/339): 84% (70/83) siblings, 83% (19/23) cousins, 41% (72/175) parents, 28% (10/36) grandparents and 26% (5/19) uncles/aunts. So, enterovirus 71 household transmission rates are high for children, medium for parents and low for other adults. Being male and being less than 6 years old were associated with increased risk of EV71 infection. Continuous EV71 disease and laboratory surveillance is warranted to allow for possible earlier control and prevention measures.

Kawasaki disease (KD) is the most important worldwide acquired heart disease in children after the incidence of rheumatic heart disease is decreasing during the recent decades. There is some mystery in KD such as different incidences in different countries, the easy involvement of coronary arteries and the unsolved infectious pathogen. We propose that infection with a single pathogen or infection with certain pathogens may trigger Kawasaki disease in certain hosts (more in the male, young children, and the oriental), and the infection may be transmitted within households, and the majority have only mild illness but only a small percentage of children with certain host genetics will develop Kawasaki disease.

To investigate the infectious etiology of Kawasaki disease, a prospective case and household cohort study for Kawasaki disease is ongoing. The KD cases received virological isolation, molecular workup including polymerase chain reaction (PCR) for pan-enterovirus, pan-coronavirus, rhinovirus, metapneumovirus, pan-adenovirus and other possible viruses, cDNA RDA (representational difference analysis-subtractive cloning), VIDSICA (virus discovery based on the cDNA amplified restriction-length polymorphism) and viral gene chips for unknown pathogens, bacterial culture (blood, throat swabs and stool: bacterial culture and stored strain for further toxin or superantigen detection), and serological workup for the most potential pathogen. Household members of KD cases were asked to undergo screening by virus isolation of throat swabs, and received the first blood sample during acute illness of the KD case, and second blood sample during the convalescent stage of the KD case. If specific potential pathogen is found in Kawasaki cases, samples from the household members will be workup for the specific pathogen.

Till now, a total of 229 KD cases and about 900 of their household members have been enrolled. During 1 to 10 days prior to their KD illness, 53.9% cases had contact with ill household members, and 10.3% had positive contact with extra-familial ill people. In 59% families, at least one other family member had illness after KD cases’ disease onset.


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FTRP2-02 Immunopathogenesis of EV71, Dengue, SARS and Novel H1N1 Infections

Immunopathogenesis of EV71, Dengue, SARS and Novel H1N1 Infections

Kuender D. Yang
Professor & Chair, Department of Medical Research Chang Gung Memorial Hospital at Kaohsiung, and Chang Gung University, Taiwan

Changes of global ecology expose humans to novel pathogens for emerging infections arising from microbial mutation, vector-borne and/or zoonotic transmission. The authors have encountered and studied four emerging infections including enterovirus 71 encephalitis, dengue hemorrhagic fever and severe acute respiratory syndrome (SARS) and novel influenza A (H1N1) in the past decade. Here they described and summarized immune mechanisms of common emerging infections into four categories: 1) host naïve immunodeficiency with disseminated infection; 2) early immunosuppression with and without later augmented immunity; 3) augmented innate immunity with vascular insults; and 4) cross-enhancement of secondary heterotypic infections. A practical guide to identify the fatal mechanism of an emerging infection is described to early diagnose and early treat the life-threatening infection. Based on the evolution of common emerging infections, a 4-step strategy is formulated for the prevention of a potential emerging infection during pre-outbreak, sporadic early outbreak, endemic outbreak and pandemic outbreak.


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FTRP2-03 Community-associated methicillin-resistant Staphylococcus aureus in Taiwan and the world

Community-associated methicillin-resistant Staphylococcus aureus in Taiwan and the world

Yhu-Chering Huang
Chang Gung Memorial Hospital and Chang Gung University, Kweishan, Taiwan

Staphylococcus aureus is an important pathogen in humans and causes a broad spectrum of diseases, ranging from skin and soft tissue infection to life-threatening infections of septicemia, necrotizing fasciitis, and toxic shock syndrome. Methicillin-resistant S. aureus (MRSA) is usually considered a nosocomial pathogen, and if acquired in the community, most infections were traditionally confined to individuals with health care-associated risk factors. However, the changing epidemiology of MRSA became evident in the 1990s when MRSA infections occurred in previously healthy children without established risk factors for MRSA acquisition. The term “community-associated” (CA) MRSA infection was used to describe this disease entity.

CA-MRSA was first reported from infections in remote populations in Australia, and in the USA by the end of the 1990s. Since then, MRSA infections have also been reported from Europe, the near East, Asia and Oceania. CA-MRSA strains have been recognized as a novel pathogen which is genetically different from the healthcare-associated (HA) MRSA in the US. They are usually characterized by limited antibiotic resistance (except to β-lactams), possess different exotoxin gene profiles (e.g. Panton-Valentine leukocidin, PVL), carry type IV or V staphylococcal cassette chromosome (SCCmec IV, V), and the major clinical manifestations are usually cellulitis and abscess. However, CA-MRSA clones vary in different continents, countries and even areas; for example, clones with multilocus sequence types (ST) 1 (USA400) and 8 (USA300) are mostly found in the United States and Canada, clones with ST80 are mostly found in Europe, while clones with ST30 are found worldwide, including US, Europe, Oceania, Japan. CA-MRSA has become a matter of concern worldwide, in particular in the USA.

In Taiwan, CA-MRSA, though not uncommon, had not drawn any concern in 1990s until cases of fatal infections in children were reported in Minnesota and North Dakota in the US. CA-MRSA infections have been increasingly reported in pediatric patients since 2000. The rate of methicillin resistance among CA S. aureus infections in children without risk factors increased from 9.8% between 1999 and 2000 to 56% between 2004 and 2005. Likewise, the nasal carriage rate of MRSA among previously healthy children increased significantly from 1.9% in 2001 to 10.2% during the period 2007 to 2008. The increasing trend of nasal MRSA colonization prevalence might account for the increasing incidence of CA-MRSA infection in children in Taiwan. Most CA-MRSA clinical isolates in Taiwan are genetically different from HA-MRSA isolates and are characterized by ST59 or its variant ST338, a specific pulsed-field gel electrophoresis (PFGE) pattern (similar to USA 1000), resistance to clindamycin and erythromycin, containing a specific type of SCCmec (type VT, also tentatively designated as type VII lately) gene, and possessing PVL genes.


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FTRP2-04 Improving Child Health: Bridging Research and Practice

Improving Child Health: Bridging Research and Practice

Cheng T. Cho
Professor & Chair, Department of Medical Research Chang Gung Memorial Hospital at Kaohsiung, and Chang Gung University, Taiwan

The goal of pediatric research is to improve child health. Clinical investigators have traditionally played a major role in translating new knowledge from research into clinical practice. However a significant gap between research and practice remains, for there are many barriers to getting research findings into science-based clinical practice. Clearly further efforts are needed to find the most effective strategies for bridging the gap between research and practice. Flexner’s report (1910) transformed medical education and medical research in the United States. Recent recommendations (“Crossing the Quality Chasm)” by the Institute of Medicine (2001) will undoubtedly have a significant impact on improving quality of health care in the years ahead.

Knowledge derived from basic research, translational research, and clinical trials have formed the scientific basis of our contemporary medical practice. Activities to improve and enhance patient care (such as outcomes research, health care delivery research, and behavioral research) have also attracted much attention in recent years. It is likely that these efforts will also help to bridge the gap between research and practice.

Steps needed to move from research to practice involve synthesis of new research findings, creation of evidence-based clinical policies, and application of policies (guidelines) in practice. It is apparent that our ability to generate critical evidence-based guidelines is limited and often inadequate. Thus practice guidelines often generate more questions and controversies and are infrequently followed in practice. Obviously the guidelines cannot replace the physician’s discriminatory skills and critical thinking. It is increasingly clear that physicians must be trained to identify pertinent literature and resources and to find answers that are lacking in the “evidence-based “guidelines. In a highly commercialized environment, it is also known that commercial interest can distort interpretations of the scientific evidence and hence responses to it. Special efforts should be made to support the development of practice guidelines without conflict of interest. Past history indicates that there is mostly one-way diffusion of medical discovery and knowledge from university to community. More work is needed to bring practice to research in order to capture potentially valuable insights and observations that might be offered by the practicing clinicians in the community.

Barriers and challenges to bridging the gap between research and practice are many. Most of these barriers relate to physicians, patients, and health system, and will require continued efforts to find coherent solutions to the challenges. Future goals should also include supporting programs that attract and retain clinical investigators and physician-scientists, promoting effectiveness research, and improving quality of health care.


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