今日の臨床サポート

ウエストナイルウイルス感染症(脳炎など)

著者: 上田晃弘 日本赤十字社医療センター感染症科

監修: 上原由紀 藤田医科大学医学部感染症科

著者校正/監修レビュー済:2022/07/20
参考ガイドライン:
  1. 米国疾病対策予防センター(Centers for Disease Control and Prevention: CDC): West Nile virus(2022年5月29日閲覧)
  1. 欧州疾病予防管理センター(European Centre for Disease Prevention and Control:ECDC): West Nile virus infection(2022年5月29日閲覧)
  1. Travel Health Pro: West Nile virus(2022年5月29日閲覧)
  1. 国立感染症研究所(National Institute of Infectious Diseases:NIID):ウエストナイル熱/ウエストナイル脳炎とは(2022年5月31日閲覧)
患者向け説明資料

概要・推奨   

  1. 流行地への渡航歴がある患者の発熱、神経症状(髄膜炎、脳炎、急性弛緩性麻痺)などではウエストナイルウイルス感染症を考える(推奨度1)
  1. ウエストナイルウイルス感染症の診断は、国立感染症研究所などと連携して行う。診断にはウイルス学的検査や血清学的検査を用いるが、感度や特異度は必ずしも十分ではなく、診断は容易ではない(推奨度2)
  1. 頭部MRI検査はウエストナイルウイルス感染症に特異的ではなく、偽陰性も多いので注意が必要(推奨度2 O)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
上田晃弘 : 特に申告事項無し[2022年]
監修:上原由紀 : 特に申告事項無し[2022年]

改訂のポイント:
  1.  定期レビューを行い、国内の発生状況、海外での疫学についてアップデートを行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ウエストナイルウイルスは、日本脳炎ウイルスと同じフラビウイルス属に属する。鳥と蚊の間で感染サイクルが成立しているが、蚊を介して人間に感染し、脳炎などさまざまな疾患の原因となる[1]
  1. 2022年5月時点でウエストナイルウイルスは日本に存在しないとされる。2005年に1例海外からの輸入例が報告されている[2]が、それ以降、2020年10月30日までに報告例はない[3]。また、日本にいるコガタアカイエカ(Culex tritaeniorhynchus)やヤマトヤブカ(Aedes japonicus)などが媒介し得るため、ウイルスの侵入により感染が拡大、定着する可能性がある[4]。事実、米国では1999年まで存在しなかったこのウイルスが流行により全米に広がり、毎年多くの感染者を出すようになった(Culex pipiens, Cx. tarsalisとカラスなどの野鳥を介して感染拡大)[5]
  1. 臨床症状は多彩で、有症状者の多くは頭痛、倦怠感、筋肉痛や関節痛などの非特異的な急性ウイルス感染症状として表現される。消化器症状や皮疹もしばしばみられる。神経症状を発症するのは感染者の1%未満であり、典型的には発熱などの前駆症状が1‐7日程度続いたのちに神経症状を発症する。髄膜炎や脳炎、急性弛緩性麻痺などを呈する[6][7]。非特異的な発熱、頭痛、筋肉痛、皮疹といった急性ウイルス感染症状、脳炎や髄膜炎、急性弛緩性麻痺などの神経症状がみられることがある。脈絡網膜炎、肝炎、心筋炎が生じることもある。流行地からの帰国者では本疾患を鑑別に入れることが大切である。なお、80%は不顕性感染である[4]
  1. 本疾患に特異的な治療法は存在せず、対症療法となる。また、ヒトに有効なワクチンも開発されていないため、予防は流行地で蚊に刺されないことで行われる[1][7][8]
  1. 初発患者(index case)を見逃すと、日本に定着してしまうおそれがあるため、公衆衛生的にも重要な感染症である。
  1. ウエストナイル熱は感染症法上では4類感染症であり、全数報告の対象となる。
問診・診察のポイント  
  1. 流行地への渡航歴が最も重要である。流行地はアフリカ、ユーラシア大陸、オーストラリア、北米(カナダ、米国)、中米など多彩である[9][10]
  1. 米国や欧州における流行マップはそれぞれCDC、ECDCのサイトが参考になる[1][11]
  1. 熱帯など通年で蚊に刺される地域では常に感染のリスクがあり、そうでない場合は夏季が問題になる(蚊に刺されない冬などではこの疾患は鑑別には挙がらない)。蚊に刺されても覚えていないこともあるため、刺されていないという病歴は除外には用いられない。ほかにも輸血、臓器移植、母子の垂直感染などが報告されているがきわめてまれである[8]
  1. 潜伏期も重要である。2~14日といわれるが、免疫抑制者ではこれよりも長くなる可能性がある[1][6][8]
  1. 発熱、頭痛、筋肉痛、全身倦怠感、皮疹など、急性発症の非特異的「ウイルス感染」らしい徴候があり、上記渡航歴があれば本疾患を考える。

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文献 

Lyle R Petersen, Aaron C Brault, Roger S Nasci
West Nile virus: review of the literature.
JAMA. 2013 Jul 17;310(3):308-15. doi: 10.1001/jama.2013.8042.
Abstract/Text IMPORTANCE: Since its introduction in North America in 1999, West Nile virus has produced the 3 largest arboviral neuroinvasive disease outbreaks ever recorded in the United States.
OBJECTIVE: To review the ecology, virology, epidemiology, clinical characteristics, diagnosis, prevention, and control of West Nile virus, with an emphasis on North America.
EVIDENCE REVIEW: PubMed electronic database was searched through February 5, 2013. United States national surveillance data were gathered from the Centers for Disease Control and Prevention.
FINDINGS: West Nile virus is now endemic throughout the contiguous United States, with 16,196 human neuroinvasive disease cases and 1549 deaths reported since 1999. More than 780,000 illnesses have likely occurred. To date, incidence is highest in the Midwest from mid-July to early September. West Nile fever develops in approximately 25% of those infected, varies greatly in clinical severity, and symptoms may be prolonged. Neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis) develops in less than 1% but carries a fatality rate of approximately 10%. Encephalitis has a highly variable clinical course but often is associated with considerable long-term morbidity. Approximately two-thirds of those with paralysis remain with significant weakness in affected limbs. Diagnosis usually rests on detection of IgM antibody in serum or cerebrospinal fluid. Treatment is supportive; no licensed human vaccine exists. Prevention uses an integrated pest management approach, which focuses on surveillance, elimination of mosquito breeding sites, and larval and adult mosquito management using pesticides to keep mosquito populations low. During outbreaks or impending outbreaks, emphasis shifts to aggressive adult mosquito control to reduce the abundance of infected, biting mosquitoes. Pesticide exposure and adverse human health events following adult mosquito control operations for West Nile virus appear negligible.
CONCLUSIONS AND RELEVANCE: In North America, West Nile virus has and will remain a formidable clinical and public health problem for years to come.

PMID 23860989
Caren Chancey, Andriyan Grinev, Evgeniya Volkova, Maria Rios
The global ecology and epidemiology of West Nile virus.
Biomed Res Int. 2015;2015:376230. doi: 10.1155/2015/376230. Epub 2015 Mar 19.
Abstract/Text Since its initial isolation in Uganda in 1937 through the present, West Nile virus (WNV) has become an important cause of human and animal disease worldwide. WNV, an enveloped virus of the genus Flavivirus, is naturally maintained in an enzootic cycle between birds and mosquitoes, with occasional epizootic spillover causing disease in humans and horses. The mosquito vectors for WNV are widely distributed worldwide, and the known geographic range of WNV transmission and disease has continued to increase over the past 77 years. While most human infections with WNV are asymptomatic, severe neurological disease may develop resulting in long-term sequelae or death. Surveillance and preventive measures are an ongoing need to reduce the public health impact of WNV in areas with the potential for transmission.

PMID 25866777
Kalliopi A Petropoulou, Steven M Gordon, Richard A Prayson, Paul M Ruggierri
West Nile virus meningoencephalitis: MR imaging findings.
AJNR Am J Neuroradiol. 2005 Sep;26(8):1986-95.
Abstract/Text BACKGROUND AND PURPOSE: Reports of MR imaging in West Nile virus (WNV) meningoencephalomyelitis are few and the described findings limited. The purpose of this study was to review the spectrum of MR imaging findings for WNV meningoencephalomyelitis and investigate whether any of the findings correlates with clinical presentation of flaccid paralysis.
METHODS: We reviewed the MR imaging findings of 17 patients with confirmed WNV encephalitis and/or myelitis. MR imaging brain studies were evaluated for location of signal intensity abnormalities, edema, hydrocephalus, or abnormal enhancement. MR imaging spine studies were evaluated for signal intensity abnormalities in cord and/or enhancement.
RESULTS: Retrospective review of the MR imaging studies of 17 patients was performed by 2 neuroradiologists. Eleven of 16 brain MR images demonstrated abnormalities. Eight (50%) patients had abnormal studies related to meningoencephalitis. All 8 patients had abnormal findings in the deep gray matter and/or brain stem; 2 had additional white matter abnormalities. Three patients with abnormal MR studies of the spine had extremity weakness on examination. The imaging findings included abnormal signal intensity more pronounced in the ventral horns and/or enhancement around the conus medullaris and cauda equina. One patient had additional abnormalities in the pons.
CONCLUSION: Abnormal MR imaging findings in patients with WNV meningoencephalomyelitis are nonspecific but not uncommon. Anatomic areas commonly affected are basal ganglia, thalami, mesial temporal structures, brain stem, and cerebellum. Extremity weakness or flaccid paralysis corresponds to spinal cord/cauda equina abnormalities.

PMID 16155147
Muhammad Ali, Yair Safriel, Jaideep Sohi, Alfred Llave, Susan Weathers
West Nile virus infection: MR imaging findings in the nervous system.
AJNR Am J Neuroradiol. 2005 Feb;26(2):289-97.
Abstract/Text BACKGROUND AND PURPOSE: West Nile virus (WNV) infection is an ongoing seasonal epidemic. We correlated the MR imaging findings with the clinical presentations and outcomes of WNV infection.
METHODS: We reviewed 14 brain and three spinal MR images: nonenhanced and contrast-enhanced T1-weighted images (T1WIs) and T2-weighted images (T2WIs), nonenhanced fluid-attenuated inversion recovery (FLAIR) images (11 patients) and enhanced FLAIR images (three patients), with diffusion-weighted (DW) images and apparent diffusion coefficient maps. WNV infection was diagnosed by means of enzyme-linked immunosorbent assay with a plaque reduction neutralization test. We also correlated the MR findings with the clinical presentation, course, and outcome to determine their prognostic importance.
RESULTS: MR imaging findings included: 1) normal (five patients); 2) DW imaging-only abnormalities in the white matter, corona radiata, and internal capsule (four patients); 3) hyperintensity on FLAIR images and T2WIs in the lobar gray and white matter, cerebellum, basal ganglia, thalamus and internal capsule, pons and midbrain (three patients); 4) meningeal involvement (two patients); and 5) spinal cord, cauda equina, and nerve root involvement (three patients). All patients with finding 1 and all but one with finding 2 recovered completely. Two patients with finding 3 died. Those with finding 4 or 5 had residual neurologic deficits that were severe or moderate to severe, respectively.
CONCLUSION: Patients with normal MR images or abnormalities on only DW images had the best prognosis, while those with abnormal signal intensity on T2WI and FLAIR images had the worst outcomes. No definite predilection for any specific area of the brain parenchyma was noted.

PMID 15709126
D Nash, F Mostashari, A Fine, J Miller, D O'Leary, K Murray, A Huang, A Rosenberg, A Greenberg, M Sherman, S Wong, M Layton, 1999 West Nile Outbreak Response Working Group
The outbreak of West Nile virus infection in the New York City area in 1999.
N Engl J Med. 2001 Jun 14;344(24):1807-14. doi: 10.1056/NEJM200106143442401.
Abstract/Text BACKGROUND: In late August 1999, an unusual cluster of cases of meningoencephalitis associated with muscle weakness was reported to the New York City Department of Health. The initial epidemiologic and environmental investigations suggested an arboviral cause.
METHODS: Active surveillance was implemented to identify patients hospitalized with viral encephalitis and meningitis. Cerebrospinal fluid, serum, and tissue specimens from patients with suspected cases underwent serologic and viral testing for evidence of arboviral infection.
RESULTS: Outbreak surveillance identified 59 patients who were hospitalized with West Nile virus infection in the New York City area during August and September of 1999. The median age of these patients was 71 years (range, 5 to 95). The overall attack rate of clinical West Nile virus infection was at least 6.5 cases per million population, and it increased sharply with age. Most of the patients (63 percent) had clinical signs of encephalitis; seven patients died (12 percent). Muscle weakness was documented in 27 percent of the patients and flaccid paralysis in 10 percent; in all of the latter, nerve conduction studies indicated an axonal polyneuropathy in 14 percent. An age of 75 years or older was an independent risk factor for death (relative risk adjusted for the presence or absence of diabetes mellitus, 8.5; 95 percent confidence interval, 1.2 to 59.1), as was the presence of diabetes mellitus (age-adjusted relative risk, 5.1; 95 percent confidence interval, 1.5 to 17.3).
CONCLUSIONS: This outbreak of West Nile meningoencephalitis in the New York City metropolitan area represents the first time this virus has been detected in the Western Hemisphere. Given the subsequent rapid spread of the virus, physicians along the eastern seaboard of the United States should consider West Nile virus infection in the differential diagnosis of encephalitis and viral meningitis during the summer months, especially in older patients and in those with muscle weakness.

PMID 11407341
Peter A G Tilley, Julie D Fox, Gayatri C Jayaraman, Jutta K Preiksaitis
Nucleic acid testing for west nile virus RNA in plasma enhances rapid diagnosis of acute infection in symptomatic patients.
J Infect Dis. 2006 May 15;193(10):1361-4. doi: 10.1086/503577. Epub 2006 Apr 4.
Abstract/Text Although nucleic acid amplification testing (NAAT) for West Nile virus (WNV) is useful in screening blood donors, such methods have not been studied in symptomatic patients. For diagnosis of WNV infection, 1.0 mL of plasma was tested by NAAT, and WNV-specific immunoglobulin M was assayed. Of 276 WNV cases, 191 were tested by both serology and NAAT. Of these, 86 (45.0%), 111 (58.1%), and 180 (94.2%) were detected by NAAT, serology, and combined NAAT and serology, respectively. NAAT-based screening was most useful within 8 days of the onset of symptoms. Viremia is common in early symptomatic WNV infection, and NAAT enhances diagnostic yield.

PMID 16619182
Daniel R O'Leary, Anthony A Marfin, Susan P Montgomery, Aaron M Kipp, Jennifer A Lehman, Brad J Biggerstaff, Veronica L Elko, Peggy D Collins, John E Jones, Grant L Campbell
The epidemic of West Nile virus in the United States, 2002.
Vector Borne Zoonotic Dis. 2004 Spring;4(1):61-70. doi: 10.1089/153036604773083004.
Abstract/Text Since 1999, health officials have documented the spread of West Nile virus across the eastern and southern states and into the central United States. In 2002, a large, multi-state, epidemic of neuroinvasive West Nile illness occurred. Using standardized guidelines, health departments conducted surveillance for West Nile virus illness in humans, and West Nile virus infection and illness in non-human species. Illnesses were reported to the Centers for Disease Control and Prevention (CDC) through the ArboNET system. In 2002, 39 states and the District of Columbia reported 4,156 human West Nile virus illness cases. Of these, 2,942 (71%) were neuroinvasive illnesses (i.e., meningitis, encephalitis, or meningoencephalitis) with onset dates from May 19 through December 14; 1,157 (28%) were uncomplicated West Nile fever cases, and 47 (1%) were clinically unspecified. Over 80% of neuroinvasive illnesses occurred in the central United States. Among meningitis cases, median age was 46 years (range, 3 months to 91 years), and the fatality-to-case ratio was 2%; for encephalitis cases (with or without meningitis), median age was 64 years (range, 1 month to 99 years) and the fatality-to-case ratio was 12%. Neuroinvasive illness incidence and mortality, respectively, were significantly associated with advanced age (p = 0.02; p = 0.01) and being male (p < 0.001; p = 0.002). In 89% of counties reporting neuroinvasive human illnesses, West Nile virus infections were first noted in non-human species, but no human illnesses were reported from 77% of counties in which non-human infections were detected. In 2002, West Nile virus caused the largest recognized epidemic of neuroinvasive arboviral illness in the Western Hemisphere and the largest epidemic of neuroinvasive West Nile virus ever recorded. It is unknown why males appeared to have higher risk of severe illness and death, but possibilities include higher prevalence of co-morbid conditions or behavioral factors leading to increased infection rates. Several observations, including major, multi-state West Nile virus epidemics in 2002 and 2003, suggest that major epidemics may annually reoccur in the United States. Non-human surveillance can warn of early West Nile virus activity and needs continued emphasis, along with control of Culex mosquitoes.

PMID 15018774
Hetal Patel, Beate Sander, Mark P Nelder
Long-term sequelae of West Nile virus-related illness: a systematic review.
Lancet Infect Dis. 2015 Aug;15(8):951-9. doi: 10.1016/S1473-3099(15)00134-6. Epub 2015 Jul 7.
Abstract/Text We systematically reviewed the clinical outlook of West Nile virus (WNV)-related illness in North America and western Europe. As of March, 2015, more than 45 000 cases of WNV-related illness have been reported in North America. Unlike acute morbidity and mortality, the long-term physical, cognitive, and functional sequelae associated with WNV-related illness are not well characterised. An understanding of WNV-related sequelae and their prognostic factors can support physicians with early diagnosis and tertiary prevention efforts. We searched Ovid Medline, Embase, Scopus, and Environment Complete for studies published between 1999 and 2015. We included 67 studies in our Review. Although muscle weakness, memory loss, and difficulties with activities of daily living were among the most common physical, cognitive, and functional sequelae, respectively, some population groups were reported to be at greater risk of severe neurological disease or death (ie, older men with underlying illnesses such as cardiovascular disease or cancer). A high level of heterogeneity was reported among studies included in this Review, suggesting a need for consistent methods for collecting data and reporting findings. Further, more than half of the studies reporting sequelae relied exclusively on subjective assessment and only two studies used matched control groups. Therefore, opportunities exist for more robust primary studies in future research.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26163373
Fang Tang, Jiu-Song Zhang, Wei Liu, Qui-Min Zhao, Fang Zhang, Xiao-Ming Wu, Hong Yang, Hinh Ly, Wu-Chun Cao
Failure of Japanese encephalitis vaccine and infection in inducing neutralizing antibodies against West Nile virus, People's Republic of China.
Am J Trop Med Hyg. 2008 Jun;78(6):999-1001.
Abstract/Text We examined whether live attenuated Japanese encephalitis (JE) vaccine is effective in preventing West Nile virus (WNV) infection in the People's Republic of China. Three groups were recruited into the study: patients with Japanese encephalitis (JE), healthy controls vaccinated with live attenuated 2 SA14-14-vaccine against JE virus (JEV), and unvaccinated healthy controls. Serum samples were collected and screened for IgG antibodies against JEV by an indirect immunofluorescence assay. Positive samples were then analyzed for levels of antibodies against JEV and neutralizing antibodies against West Nile virus (WNV) by a plaque-reduction neutralization test (PRNT). Although most persons had medium to high levels of JEV-reactive IgG and neutralizing antibodies, only 2 of the 82 unvaccinated control samples were positive for the WNV-reactive antibodies. These findings suggest that previous JEV infection or vaccination did not induce adequate levels of WNV-reactive antibodies in the population studied. However, how these persons would respond to a secondary flavivirus infection and whether their prior experience with wild-type or attenuated JE vaccine will provide some cross-protection against WNV disease still warrants further investigation.

PMID 18541783

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