主催 帝京大学

共催 Harvard Club of Japan

ProgramIntroduction to Symposium I
Mr. Yoshihito Okinaga
The President, Teikyo University, Tokyo, Japan.

1. Introduction to infection-induced severe pulmonary diseases such as ARDS
Kazuo Suzuki, PhD
Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan.

2. Bacterial identification in septic shock children in Viet Nam National Hospital ofPediatrics
Dien Tran Minh, MD, PhD
National Hospital of Pediatrics, Hanoi, Vietnam

3. Severe ARDS cases due to influenza infection in Vietnamese children- From the cases in PICU of NHP-Hanoi Shoji Kawachi1, 2, Noriko Nakajima2, Hiroyuki Nunoi4, Kazuo Suzuki2, 5,Nguyen Trung Thuy3, Tran Minh Dien3, Liem Thanh Nguyen31National Center for Global Health and Medicine, Tokyo, Japan, 2National Institute of Infectious

Diseases, Tokyo, Japan, 3National Hospital of Pediatrics, Hanoi, Vietnam, 4Miyazaki University,
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Miyazaki, Japan, Teikyo Univeraity, Tokyo, Japan

4. Pathological study of Severe ARDS cases in NHP-Hanoi
Noriko Nakajima1, Yuko Sato1, Hideki Hasegawa1 , Hoang Ngoc Thach2, Nguyen TrungThuy2, Tran Minh Dien2, Nguyen Thanh Liem2, Le Thanh Hai2, Shoji Kawachi3,Kazuo Suzuki4
1National Institute of Infectious Diseases, Tokyo, Japan 2 National Hospital of Pediatrics,Hanoi, Vietnam 3 National Center for Global Health and Medicine, Tokyo, Japan 4 Teikyo
University, Tokyo, Japan

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ABSTRACT

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1. Introduction to infection-induced severe pulmonary diseases such as ARDS
Kazuo Suzuki, PhD
Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan.
Since the outbreak of highly pathogenic avian H5N1 influenza virus infection inhumans in 2003, the WHO has reported a mortality rate of about 60%. Drs. Liem, Kawachiand Nakajima et al (1,2) have reported that many H5N1-infected patients develop acuterespiratory distress syndrome and died. In the case of the influenza pandemic thatoccurred in 2009, infected pneumocytes in some patients showed severe respiratory failure
similar to that seen for H5N1 infection. H5N1 infection cases have resulted in death at theNational Hospital of Pediatrics Hanoi (3). In addition, Dr. Thuy (4, 5) has reported
evidences of cytokine storm in spacemen of the patients and culture of lung epithelial cells
under JSPS-RONPAKU program.
On the other hand, drug candidate for severe influenza-induced pneumonia has beenfound by ours group using screening from a macrolide compound library which has been
established in Prof. Sunazuka’s lab in Kitasato Univeristy. One of them, LM-A3, which has
been found by Dr. Sugamata et al. (6) , showed the highest survival rate (80.9%) and
induced alleviative effects on lung pathology and viral proliferation in model mice weestablished (7). These observations provide valuable evidences for knowledge ofmechanisms of leukocytes infiltration from blood to lung lavage passing thorough lungendothelium-endothelium barrier with active/potential molecules along viral activity.
Based on our previous research, we will focus to pulmonary diseases induced with
infection of influenza virus and M. tuberculosis. Then, JST is supporting our research byJST e-ASIA joint research project among Japan-Vietnam-Philippines with Dr. Kato’s teamon M. tuberculosis.
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Nguyen TL, Nakajima N, Phuc P¸ Sato Y, Hoang NT, Pham VH, Luong TS, Katano H, Kumasaka T,Oka T, Kawachi S, Matsushita T, Sata T, Kudo K, Suzuki K. H5N1-infected cells in lung with diffuse
alveolar damage in exudative phase from a fatal case in Vietnam. Jpn J Infectious Dis 2008; 61:
157-160.
Kawachi S, Luong ST, Shigematsu M, Furuya H, Phung TTB, Phan PH, Nunoi H, Nguyen LT, Suzuki
K. Risk parameters of fulminant acute respiratory distress syndrome followed by avian influenza(H5N1) infection in Vietnamese children. J Infectious Dis 2009; 200: 510-515.
Nakajima N, Ngo VT, Sato Y, Hoang NT, Katano H, Pho HD, Kumasaka T, Nguyen TT, Hasegawa H,Long TS, Kawachi S, Nguyen TL, Suzuki K, Sata T, Pathological study of archival lung tissues from 5
fatal cases of avian H5N1 influenza in Vietnam. Modern Pathol 2012; Modern Pathol
dx.doi.org/10.1038/modpathol.2012.193.
Phung TTB, Luong ST, Kawachi S, Nunoi H, Nguyen LT, Nakayama T, Suzuki K. IL-12 andmyeloperoxidase (MPO) in Vietnamese children with acute respiratory distress syndrome andinduced avian influenza (H5N1) infection. J Infect. 2011; 62: 104-108.
Phung TTB, Sugamata R, Uno K, Aratani Y, Ozato K, Kawachi S, Nguyen LT, Nakayama T, Suzuki K.
Key role of RANTES (regulated upon activation normal T-cell expressed and secreted), nonstructuralprotein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8(A/H1N1) infection
in A549 bronchial epithelial cells. Microbiol Immunol. 2011;55(12):874-884.
Sugamata R, Sugawara A, Nagao T, Suzuki K, Hirose T, Yamamoto K, Oshima M, Kobayashi K,Sunazuka T, Akagawa KS, Omura S, Nakayama T, Suzuki. Leucomycin A3 (LM-A3), a 16-memberedmacrolide antibiotic, inhibits Influenza A virus infection and disease progression. J. Antibiotics 2003;
in press.
Sugamata R, Dobashi H, Nagao T, Yamamoto K, Nakajima N, Sato Y, Aratani Y, Oshima M, Sata T,
Kobayashi K, Kawachi S, Nakayama T, Suzuki K. The contribution of neutrophil-derived
myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced byinfluenza virus infection. Microbiol Immunol. 2012 ;56(3):171-82.

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452. Bacterial identification in septic shock children in Viet Nam National
Hospital of Pediatrics
Dien Tran Minh, MD, PhD
National Hospital of Pediatrics, Hanoi, Vietnam

Objectives: To define the kinds of bacteria in pediatric septic shock patients.

Subjects and methods : a prospective descriptive study of 102 cases suffered fromseptic shock at the National Hospital of Pediatrics, during 3 years from 2006 to 2008,
diagnostic criteria for septic shock as the International Pediatric Sepsis Consensus
Conference 2002 (IPSCC 2002), identified the bacteria by blood culture before
using antibiotics and culture body fluids, bacterial identification and do theantibiogram.

Results: The rate of positive blood cultures was 14.7 %, a positive blood culture is
not related to outcome (survival/non-survivor). Of the 58 stains of bacteria isolated
from blood and body fluids, rate of Gr (+) is 38 %, Gr (-) is 59 %, with 2 cases ofCandida albicans infection. Image bacterias were:
Klebsiella pneumoniae(22.4 %), and othersprospectively are (17.2 %) of S. aureus, Pneumococcus, E.coli,
H.influenza are 12,1 %, 10.3 % , 8.6 % , 6.8 %. On the antibiogram result, the Gr
negative bacteria are resistant to nearly all of antibiotics, especially, the third generation cephalosporins, S.aureus are sensitive to almost antibiotics.

Conclusions: The rate of positive blood cultures in children with septic shock is
14.7 %, Gr negative bacteria have 59 %, and 38 % of Gr positive. The Gr negative
bacteria are nearly resistant to all of antibiotics.

Current data including viral infection and Acinetobacter in NHP will be presented inthis symposium.

Keywords: Pediatric septic shock, bacteria, antibiotic resistance.

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3. Severe ARDS cases due to influenza infection in Vietnamese children- From the cases in PICU of NHP-Hanoi Shoji Kawachi1, 2, Noriko Nakajima 2, Hiroyuki Nunoi4, Kazuo Suzuki2, 5,Nguyen Trung Thuy3, Tran Minh Dien3, Liem Thanh Nguyen3
skawachi@hosp.ncgm.go.jp
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National Center for Global Health and Medicine, Tokyo, Japan, 2National Institute of Infectious Diseases,Tokyo, Japan, 3National Hospital of Pediatrics, Hanoi, Vietnam, 4Miyazaki University, Miyazaki, Japan,5Teikyo Univeraity, Tokyo, Japan

ARDS associated with A(H5N1) avian influenza virus infection develops severe ARDS [ JID
2009, Kawachi, et al ], and with other types of influenza, severe ARDS sometimes occurs amongchildren. It is an urgent mission to elucidate the mechanism of influenza -ARDS and to make atherapeutic strategy. For this purpose, we have been co-operating the prospective study forsevere ARDS with National Hospital of Pediatrics–Hanoi (NHP-Hanoi) from October 2007. 102
patients were diagnosed as severe ARDS matched in the criteria of prospective study during
2007/10-2013/3. In 8 patients among 102, the influenza viruses were detected from NPA/TLF
samples with PCR; A(H5N1) (3), A(H1N1)pdm09 (4), H3N2 (1 ) and before 2007/10, 10
H5N1-ARDS patients were admitted in PICU of NHP-Hanoi. We analyzed the clinical data intotally 18 cases of influenza associated ARDS (influenza group). In 22 cases other viruses weredetected (not-influenza group): CMV(13), Rhinovirus(8), Adenovirus (5), RSV(5), Measles (1).
Significant differences were observed in pH and PaCO2(ABGA) and also AST/ALT values,
white blood cells and platelets counts in the serum. Survival probability analysis showed thedifferences between groups (p=0.0023 by log-lank test, p=0.0013 by Wilcoxon test) resulting
longer survival days in not-influenza group (Influ: 14, not-Influ: 31 days).

インフルエンザによる重症 ARDS 症例の検討−ベトナムハノイ国立小児病院 PICU における Study : 2005-2013 より−
河内正治 1, 2、中島典子 2、布井 博幸 4、鈴木和男 2,、
Nguyen Trung Thuy3, Tran Minh Dien3, Liem Thanh Nguyen31

国立国際医療研究センター、2 国立感染症研究所、3National Hospital of Pediatrics, Hanoi, Vietnam、

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宮崎大学、5 帝京大学

インフルエンザによる severe ARDS は、最終病理像は肺胞の広範囲な障害（DAD ; Diffuse
Alveolar Damage）であるが、死亡に到るまでが数日から 2 週間と急速に進行し死亡することが特徴で [ Moderen Pathol 2013, Nakajima, et al ]、このときの死亡原因は ARDS による呼吸死であると考えられる。現在までにハノイ国立小児病院(NHP-Hanoi)PICU にて、ARDS に対する先行的研究によって得られたインフルエンザ症例は 18 例で、他のウイルスに起因する症例が 22 例であった。今回は NHP-Hanoi における H5N1 を含むインフルエンザ症例と他のウイルス性肺炎を主因とした severe ARDS の症例集計結果を提示し比較検討して報告する。

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<Memo>94.

Pathological study of Severe ARDS cases in NHP-Hanoi

Noriko Nakajima 1, Yuko Sato 1, Hideki Hasegawa 1, Hoang Ngoc Thach 2, Nguyen Trung Thuy 2,Tran Minh Dien 2, Nguyen Thanh Liem 2, Le Thanh Hai2, Shoji Kawachi 3, Kazuo Suzuki 4
1
National Institute of Infectious Diseases, Tokyo, Japan 2 National Hospital of Pediatrics, Hanoi,Vietnam 3 National Center for Global Health and Medicine, Tokyo, Japan 4 Teikyo University,Tokyo, Japan

We examined the lung pathology of fatal cases of severe ARDS in NHP-PICU. The ARDS
induced by influenza virus infection is generally classified as severe ARDS with P/Fratio<100mg and the patients die due to respiratory failure. First, we show the results ofhistopathological study of lung tissues with highly pathogenic avian H5N1 influenza virus(H5N1) infection, and then, those with non-influenza virus infection. Methods:
Formalin-fixed paraffin-embedded lung tissues were analyzed with several methods asfollows: Immunohistochemistry for viral antigens, proinflammatory cytokines andchemokines, double immunofluorescence staining with cell marker proteins, real timequantitative reverse-transcription polymerase chain reaction methods for viral RNA andcytokine/chemokine mRNA. Results: H5N1 infected lung tissues showed a spectrum ofhistopathological changes of diffuse alveolar damages (DAD). Myeloperoxidase(MPO)-positiveand/orCD68(cloneKP-1)-positive
neutrophils
andmonocytes/macrophages infiltrated prominently in the alveolar septa and alveolar spaces.
Viral antigen-positive cells were mainly alveolar epithelial cells andmonocytes/macrophages. The expression levels of TNF-α, IL-6, IL-8, RANTES and IP-10
were correlated with H5N1-RNA copy numbers. Double immunofluorescence staining
revealed that TNF-α, IL-6, IL-8 and IP-10 were expressed in epithelial cells and/ormonocytes/macrophages. In particular, IL-6 was also expressed in endothelial cells. As forpathological study of ARDS cases with non-influenza virus infection, some were revealed
to be CMV systemic infection and others were diagnosed aspergilosis. Conclusions:Pathological study clarified not only the pathogen which caused ARDS but also the local
inflammatory responses in the lung. H5N1 infected alveolar epithelial cells and injured
them directly. Marked accumulation of neutrophils and monocytes/macrophages suggested
neutrophil-mediated lung injury. The expression levels of cytokines and chemokines
suggested local uncontrolled inflammatory responses induced by H5N1 infection. These
factors may work together and cause ARDS.

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