今日の臨床サポート

伝染性単核球症

著者: 土戸康弘 京都府立医科大学 感染制御検査医学教室/京都府立医科大学附属病院 臨床検査部・感染対策部・感染症科

監修: 山本舜悟 京都市立病院 感染症科/京都大学 医療疫学(非常勤講師) 

著者校正/監修レビュー済:2021/07/14
患者向け説明資料

概要・推奨   

  1. 伝染性単核球症を疑う場合は典型的な徴候とされる発熱、咽頭炎、リンパ節腫脹、倦怠感、リンパ球増多を確認する。またそうした症状にしばしば先行してみられる筋痛、頭痛、微熱などの症状も確認する(推奨度1)
  1. 伝染性単核球症を想起する状況では、同時に単核球症様疾患を来す疾患も念頭に置いて診療を進める(推奨度1)
  1. 伝染性単核球症の診断には白血球、リンパ球、異型リンパ球の測定が有用で、その結果を踏まえて可能性を評価する(推奨度1)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
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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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
土戸康弘 : 特に申告事項無し[2021年]
監修:山本舜悟 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、コンタクトスポーツの禁止に関する内容を中心に加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 伝染性単核球症(infectious mononucleosis、IM)はEpstein-Barr virus(EBV)の感染によって発症し、発熱、咽頭炎、リンパ節腫脹、倦怠感、異型リンパ球増多を特徴とする。発症時期は主に5~25歳に多く、咽頭痛で受診する16~20歳の8%を占めるとされている。脾腫、肝腫大、黄疸、脾破裂などの合併症を生じることがある。
  1. 19世紀末頃にFilatovとPfeifferがほぼ同時に発熱、咽頭炎、リンパ節腫張を3主徴とする疾患を腺熱(glandular fever)として報告した。1920年SpruntとEvansらは腺熱の患者の末梢血にリンパ球増多と異型リンパ球(細胞質が広く濃染した核を持つ単核球)増多がみられることからIMという名称を用いた。1932年PaulとBunnellがIM患者の血清が羊の赤血球を凝集させる特徴があることを発見し、異好抗体(heterophile antibody)の存在が血清学的診断に有用であることを報告した。1964年Epstein、Barrらによって新しいヘルペスウイルスが発見され、Epstein-Barr virus(EBV)と命名され、1968年Henleらが初めてIMとEBVとの関係性を報告した。
  1. EBVはヘルペスウイルス科ガンマヘルペスウイルス亜科に属する約172kbp の2本鎖DNAウイルスで、直径は約150~220nm。通常ヒトにのみ感染し生涯にわたり体内に存在する。ほとんどの場合初感染によるIMとして発症するが、まれに慢性活動性感染として発症することもある。
  1. EBVは唾液中に排出され、密な接触を介してヒトからヒトへと感染する。成人では90~95%が抗体陽性で既感染。小児では発展途上国で100%近くが抗体陽性、米国で社会経済的に低い層では25~50%が抗体陽性。小児期での密接な接触と悪い衛生状態がより早い時期での感染とその後の感染拡大に関係している。
  1. 小児期に感染するとしばしば無症候性で、発症するのは感染した小児の10%以下である。10歳代から成人早期にかけて症候性感染の頻度は増加する。大規模研究によると15~24歳に発症の頻度はピークとなる[1]。英国での研究では年齢があがるにつれ重症度は増し、入院を要するケースが増えている[2]。小児と早期成人との症状の違いはウイルスが感染するB細胞による細胞性免疫応答の強度や感染時のウイルスサイズに関連しているとされている。
  1. 扁桃上皮細胞に感染し増殖したウイルスは主にBリンパ球に感染する。EBVが増殖サイクルに入ると唾液中のウイルス量が増加する。ウイルス量は感染後1年間で減少し生涯にわたり持続する。EBVの感染、増殖を宿主側はナチュラルキラー細胞やウイルス特異的Tリンパ球を介して排除しようとする。そうしたリンパ球から産生される炎症性サイトカインによる過剰な免疫反応の結果、発熱などのさまざまな臨床症状が生じる。その後EBV感染Bリンパ球は潜伏感染し、限られた遺伝子のみが発現し、宿主の免疫機構を回避する。免疫抑制状態などの何らかの理由で再活性化することがある。
問診・診察のポイント  
ポイント
  1. 典型的な徴候とされる発熱、咽頭炎、リンパ節腫脹、倦怠感、リンパ球増多を確認する。またそうした症状にしばしば先行してみられる筋痛、頭痛、微熱などの症状も確認する[3][4][5]
  1. 成人では典型的な徴候を呈しないことがしばしばあり注意する。40歳以上では咽頭炎、筋痛が多く、頚部リンパ節腫脹は少ない。発熱も数週間持続することがある[6]
  1. 非典型例では単核球症様疾患(mononucleosis-like illness、MLI)である可能性もあり、EBV以外も鑑別疾患として考慮する。

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文献 

著者: C W Heath, A L Brodsky, A I Potolsky
雑誌名: Am J Epidemiol. 1972 Jan;95(1):46-52.
Abstract/Text
PMID 5007364  Am J Epidemiol. 1972 Jan;95(1):46-52.
著者: M C Morris, W J Edmunds
雑誌名: J Infect. 2002 Aug;45(2):107-9.
Abstract/Text
PMID 12217713  J Infect. 2002 Aug;45(2):107-9.
著者: T D Rea, J E Russo, W Katon, R L Ashley, D S Buchwald
雑誌名: J Am Board Fam Pract. 2001 Jul-Aug;14(4):234-42.
Abstract/Text BACKGROUND: Knowledge regarding the clinical characteristics and natural history of acute infectious mononucleosis is based largely on older, often retrospective, studies without systematic follow-up. Differences in diagnosis, methodology, or treatment between historical and current practice might affect an understanding of this illness.
METHODS: Using a prospective case series design, we enrolled 150 persons with an acute illness serologically confirmed as Epstein-Barr virus infection. The goal of the study was to assess symptoms, physical examination findings, laboratory tests, and functional status measures during the acute presentation and 1, 2, and 6 months later.
RESULTS: Acutely, infectious mononucleosis was characterized by the symptoms of sore throat and fatigue and substantial functional impairment. Objective physical and laboratory examination findings included pharyngitis and cervical lymphadenopathy, a moderate absolute and atypical lymphocytosis, and mildly elevated transaminase levels. The traditional signs of fever and splenomegaly were relatively uncommon. By 1 month, most symptoms and signs and all laboratory tests had returned to normal. Fatigue, cervical lymphadenopathy, pharyngitis, and functional health status improved more slowly.
CONCLUSIONS: In contemporary practice most of the classical illness features of infectious mononucleosis are observed. Symptoms, signs, and poor functioning might be protracted in some patients.

PMID 11458965  J Am Board Fam Pract. 2001 Jul-Aug;14(4):234-42.
著者: Mark H Ebell
雑誌名: Am Fam Physician. 2004 Oct 1;70(7):1279-87.
Abstract/Text Infectious mononucleosis should be suspected in patients 10 to 30 years of age who present with sore throat and significant fatigue, palatal petechiae, posterior cervical or auricular adenopathy, marked adenopathy, or inguinal adenopathy. An atypical lymphocytosis of at least 20 percent or atypical lymphocytosis of at least 10 percent plus lymphocytosis of at least 50 percent strongly supports the diagnosis, as does a positive heterophile antibody test. False-negative results of heterophile antibody tests are relatively common early in the course of infection. Patients with negative results may have another infection, such as toxoplasmosis, streptococcal infection, cytomegalovirus infection, or another viral infection. Symptomatic treatment, the mainstay of care, includes adequate hydration, analgesics, antipyretics, and adequate rest. Bed rest should not be enforced, and the patient's energy level should guide activity. Corticosteroids, acyclovir, and antihistamines are not recommended for routine treatment of infectious mononucleosis, although corticosteroids may benefit patients with respiratory compromise or severe pharyngeal edema. Patients with infectious mononucleosis should be withdrawn from contact or collision sports for at least four weeks after the onset of symptoms. Fatigue, myalgias, and need for sleep may persist for several months after the acute infection has resolved.

PMID 15508538  Am Fam Physician. 2004 Oct 1;70(7):1279-87.
著者: P G Auwaerter
雑誌名: JAMA. 1999 Feb 3;281(5):454-9.
Abstract/Text
PMID 9952206  JAMA. 1999 Feb 3;281(5):454-9.
著者: Jillian E Sylvester, Benjamin K Buchanan, Scott L Paradise, Joshua J Yauger, Anthony I Beutler
雑誌名: Sports Health. 2019 Nov Dec;11(6):543-549. doi: 10.1177/1941738119873665. Epub 2019 Sep 24.
Abstract/Text BACKGROUND: Infectious mononucleosis is typically a self-limited disease commonly affecting young adults. Splenic rupture is a rare but serious complication affecting 0.1% to 0.5% of patients with mononucleosis. Current guidelines (based on published case reports) recommend complete activity restriction for 3 weeks after onset of mononucleosis symptoms to reduce rupture risk. We examined actual timing of mononucleosis-associated splenic injury using a large repository of unpublished patient data.
HYPOTHESIS: The risk of splenic injury after infectious mononucleosis will remain elevated longer than previously estimated.
STUDY DESIGN: Retrospective case series.
LEVEL OF EVIDENCE: Level 4.
METHODS: The Military Health System Management Analysis and Reporting Tool (M2) was used to conduct a retrospective chart review. Coding records of TRICARE beneficiaries aged 5 to 65 years between 2006 and 2016 were screened. Patients diagnosed with both splenic injury and mononucleosis-like symptoms were identified, and their medical records were reviewed for laboratory confirmation of infection and radiographically evident splenic injury.
RESULTS: A total of 826 records of splenic injury were found in M2. Of these, 42 cases met the study criteria. Mean time to splenic injury was 15.4 (±13.5) days. Only 73.8% (n = 31) of injuries occurred within 21 days, and 90.5% (n = 38) of splenic injuries occurred within 31 days of symptom onset.
CONCLUSION: A substantial number of splenic injuries occur between 21 and 31 days after symptom onset. While most splenic injuries were atraumatic, consideration should be given to extending return-to-play guidelines to 31 days after symptom onset to minimize risk. Risk of chronic pain after splenic injury may be higher than previously believed.
CLINICAL RELEVANCE: The risk for postmononucleosis splenic injuries remains elevated longer than current guidelines suggest. Restricting activity for 31 days after mononucleosis symptom onset may reduce the risk of splenic injury.

PMID 31550435  Sports Health. 2019 Nov Dec;11(6):543-549. doi: 10.1177・・・
著者: A Bartlett, R Williams, M Hilton
雑誌名: Injury. 2016 Mar;47(3):531-8. doi: 10.1016/j.injury.2015.10.071. Epub 2015 Oct 31.
Abstract/Text INTRODUCTION: Infectious mononucleosis (IM) is a common viral illness that predominantly causes sore throat, fever and cervical lymphadenopathy in adolescents and young adults. Although usually a benign, self-limiting disease, it is associated with a small risk of splenic rupture, which can be life-threatening. It is common practice therefore to advise avoiding vigorous physical activity for at least 4-6 weeks, however this is not based on controlled trials or national guidelines. We reviewed published case reports of splenic rupture occurring in the context of IM in an attempt to ascertain common factors that may predict who is at risk.
METHOD: A search of MEDLINE and EMBASE databases was performed for case reports or series published between 1984 and 2014. In total, 52 articles or abstracts reported 85 cases. Data was extracted and compiled into a Microsoft Excel(®) spreadsheet.
RESULTS: The average patient age was 22 years, the majority (70%) being male. The average time between onset of IM symptoms and splenic rupture was 14 days, with a range up to 8 weeks. There was a preceding history of trauma reported in only 14%. Abdominal pain was the commonest presenting complaint of splenic rupture, being present in 88%. 32% were successfully managed non-operatively, whereas 67% underwent splenectomy. Overall mortality was 9%.
CONCLUSIONS AND RECOMMENDATIONS: From our data, it appears that men under 30 within 4 weeks of symptom onset are at highest risk of splenic rupture, therefore particular vigilance in this group is required. As cases have occurred up to 8 weeks after the onset of illness, we would recommend avoidance of sports, heavy lifting and vigorous activity for 8 weeks. Should the patient wish to return to high risk activities prior to this, an USS should be performed to ensure resolution of splenomegaly. The majority of cases reviewed had no preceding trauma, although previous studies have suggested this may be so minor as to go unnoticed by the patient. It is therefore prudent to warn patients about the symptoms of splenic rupture to ensure prompt presentation and minimise treatment delay rather than focusing purely on activity limitation.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26563483  Injury. 2016 Mar;47(3):531-8. doi: 10.1016/j.injury.201・・・
著者: Gabriela Gayer, Gisele Zandman-Goddard, Elena Kosych, Sara Apter
雑誌名: Emerg Radiol. 2003 Apr;10(1):51-2. doi: 10.1007/s10140-002-0263-2. Epub 2003 Feb 25.
Abstract/Text Spontaneous splenic rupture after infectious mononucleosis (IM) is a rare, potentially fatal complication of IM, occurring in 0.1-0.5% of patients with proven IM. It usually occurs several weeks after the onset of symptoms, but may, rarely, be the initial manifestation of the disease. The patient is usually examined as an emergency due to severe abdominal pain and a falling hematocrit. The radiologist should be aware of the pathologic conditions involving the spleen which may lead to its spontaneous rupture.

PMID 15290533  Emerg Radiol. 2003 Apr;10(1):51-2. doi: 10.1007/s10140-・・・
著者: Ryota Inokuchi, Haruyasu Iida, Fumihito Ohta, Susumu Nakajima, Naoki Yahagi
雑誌名: Emerg Med J. 2014 Jul;31(7):561. doi: 10.1136/emermed-2013-203197. Epub 2013 Sep 26.
Abstract/Text
PMID 24071946  Emerg Med J. 2014 Jul;31(7):561. doi: 10.1136/emermed-2・・・
著者: A L Bruu, R Hjetland, E Holter, L Mortensen, O Natås, W Petterson, A G Skar, T Skarpaas, T Tjade, B Asjø
雑誌名: Clin Diagn Lab Immunol. 2000 May;7(3):451-6.
Abstract/Text Ten microbiological departments in Norway have participated in a multicenter evaluation of the following commercial tests for detection of Epstein-Barr virus (EBV)-specific and heterophile antibodies: CAPTIA Select viral capsid antigen (VCA)-M/G/EBNA (Centocor Inc.), Enzygnost anti-EBV/immunoglobulin M (IgM) and IgG (Dade Behring), Vironostika EBV VCA IgM/IgG/EBNA enzyme-linked immunosorbent assay (ELISA) (Organon Teknika), SEROFLUOR immunofluorescence assay and EBV Combi-Test (Institute Virion Ltd.), anti-EBV recombinant IgM- and IgG-early antigen/EBNA IgG ELISA (Biotest Diagnostics), EBV IgM/IgG/EBNA ELISA (Gull Laboratories), Paul-Bunnell-Davidsohn test (Sanofi Diagnostics Pasteur), Monosticon Dri-Dot (Organon Teknika), Avitex-IM (Omega Diagnostics Ltd.), Alexon Serascan infectious mononucleosis test (Alexon Biomedical Inc. ), Clearview IM (Unipath Ltd.), and Cards+/-OS Mono (Pacific Biotech, Inc.). The test panel included sera from patients with primary EBV infection, immunocompromised patients with recent cytomegalovirus infection, healthy persons (blood donors), and EBV-seronegative persons. Among the tests for EBV-specific antibodies the sensitivity was good, with only small differences between the different assays. However, there was a greater variation in specificity, which varied between 100% (Enzygnost) and 86% (Biotest). Tests for detection of heterophile antibodies based on purified or selected antigen (Avitex, Alexon, Clearview IM, and Cards+/-OS Mono) were more sensitive than the Paul-Bunnell-Davidsohn and Monosticon tests.

PMID 10799460  Clin Diagn Lab Immunol. 2000 May;7(3):451-6.
著者: A S Evans
雑誌名: Am J Med Sci. 1978 Nov-Dec;276(3):325-39.
Abstract/Text The "mono syndrome" is an acute febrile disease of older children and young adults which involves the lymphatic system and is characterized hematologically by the presence of 50% or more lymphocytes and monocytes and 10% or more atypical lymphocytes. Epstein-Barr virus (EBV) causes over 90% of the syndrome, cytomegalovirus (CMV) about 5% to 7%, and Toxoplasma gondii less than 1%. Viral hepatitis, adenovirus, rubella, and herpes simplex are rare causes. Only EBV produces classical heterophile-positive infectious mononucleosis. This article reviews the epidemiological and clinical features of this syndrome.

PMID 217270  Am J Med Sci. 1978 Nov-Dec;276(3):325-39.
著者: Christopher Hurt, Dominick Tammaro
雑誌名: Am J Med. 2007 Oct;120(10):911.e1-8. doi: 10.1016/j.amjmed.2006.12.011.
Abstract/Text Clinicians face a diagnostic challenge when a patient with the classic fever, pharyngitis, and lymphadenopathy triad of infectious mononucleosis has a negative "spot" heterophile antibody test. This screening test, although commonly considered sensitive for the presence of Epstein-Barr virus (EBV) infection, may be negative early after infection. A growing number of pathogens have been reported to cause heterophile-negative mononucleosis-like illnesses, including cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human immunodeficiency virus (HIV), adenovirus, herpes simplex virus (HSV), Streptococcus pyogenes, and Toxoplasma gondii. Other infectious and noninfectious disorders also may present in ways that mimic mononucleosis, but fail to generate EBV's archetypal triad of clinical findings. A systematic approach to the diagnosis of mononucleosis-like illnesses ensures that conditions warranting specific therapy are distinguished from others requiring only supportive care.

PMID 17904463  Am J Med. 2007 Oct;120(10):911.e1-8. doi: 10.1016/j.amj・・・
著者: Takamasa Ishii, Yosuke Sasaki, Tadashi Maeda, Fumiya Komatsu, Takeshi Suzuki, Yoshihisa Urita
雑誌名: J Infect Chemother. 2019 Jun;25(6):431-436. doi: 10.1016/j.jiac.2019.01.012. Epub 2019 Feb 15.
Abstract/Text INTRODUCTION: Infectious mononucleosis (IM) is a common viral infection that typically causes fever, pharyngitis, and lymphadenopathy in young patients. The Epstein-Barr virus (EBV) is the most common cause of IM, followed by cytomegalovirus (CMV). Given that serological testing is associated with limitations regarding its accuracy, availability, and time to receive results, clinical differentiation based on symptoms, signs, and basic tests would be useful. We evaluated whether clinical findings could be used to differentiate EBV-IM from CMV-IM.
METHODS: In this single-center retrospective case-control study, we evaluated >14-year-old patients with serologically confirmed EBV-IM or CMV-IM during 2006-2017. We compared the patients' symptoms, physical findings, blood counts, and serum biomarkers to create three regression models: model 1 (symptoms and signs), model 2 (model 1 plus sonographic hepatosplenomegaly and blood counts), and model 3 (model 2 plus hepatobiliary biomarkers).
RESULTS: Among the 122 patients (72.6%) with EBV-IM and 46 patients (27.4%) with CMV-IM, the median age was 25 years and 82 patients (48.8%) were male. The median age was 10 years older in the CMV-IM group (p < 0.001) and the median interval from onset to visit was 5 days longer in the CMV-IM group (p < 0.001). Logistic regression revealed that EBV-IM was predicted by younger age, short onset-to-visit interval, lymphadenopathy, tonsillar white coat, hepatosplenomegaly, atypical lymphocytosis, and elevations of lactate dehydrogenase and gamma-glutamyl transferase. All regression models had areas under the curve of >0.9.
CONCLUSION: History and physical findings, especially when used with atypical lymphocytosis and sonographic hepatosplenomegaly, can help physicians differentiate EBV-IM from CMV-IM.

Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 30773381  J Infect Chemother. 2019 Jun;25(6):431-436. doi: 10.101・・・
著者: Burke A Cunha, Karishma Chawla
雑誌名: Eur J Clin Microbiol Infect Dis. 2018 Jul;37(7):1373-1376. doi: 10.1007/s10096-018-3262-2. Epub 2018 Apr 20.
Abstract/Text Fever of unknown origin (FUO) refers to fevers of > 101 °F that persist for > 3 weeks and remain undiagnosed after a focused inpatient or outpatient workup. FUO may be due to infectious, malignant/neoplastic, rheumatic/inflammatory, or miscellaneous disorders. The FUO category determines the focus of the diagnostic workup. In the case presented of an FUO in a young woman, there were clinical findings of both CMV infectious mononucleosis or a lymphoma, e.g., highly elevated ESR, elevated ferritin levels, and elevated ACE level, β-2 microglobulins. The indium scan showed intense splenic uptake. Lymph node biopsy, PET scan, and flow cytometry were negative for lymphoma. CMV infectious mononucleosis was the diagnosis, and she made a slow recovery.

PMID 29679253  Eur J Clin Microbiol Infect Dis. 2018 Jul;37(7):1373-13・・・
著者: Dennis M Wolf, Ilka Friedrichs, Abbad G Toma
雑誌名: Arch Otolaryngol Head Neck Surg. 2007 Jan;133(1):61-4. doi: 10.1001/archotol.133.1.61.
Abstract/Text OBJECTIVE: To find a quickly available screening tool for the differentiation of patients with glandular fever from those with acute purulent tonsillitis. The null hypothesis was that there was no difference between the lymphocyte-white blood cell count (L/WCC) ratio between the 2 patient groups.
DESIGN: Retrospective pilot study based on laboratory tests for lymphocyte counts, white blood cell counts, and the mononucleosis spot test.
SETTING: Ear, Nose, and Throat Department, St George's Hospital, London, England.
PATIENTS: One hundred twenty patients with glandular fever and 100 patients with bacterial tonsillitis.
MAIN OUTCOME MEASURES: Results from the mononucleosis spot test in conjunction with the clinical picture and the L/WCC ratio were analyzed. Significant differences were evaluated using the Mann-Whitney test and Fisher exact test.
RESULTS: The L/WCC ratio was significantly different in the 2 groups (P<.001). The mean L/WCC ratio in the glandular fever group was 0.54 and the mean L/WCC ratio in the bacterial tonsillitis group was 0.10. A ratio higher than 0.35 had a specificity of 100% and a sensitivity of 90% for the detection of glandular fever.
CONCLUSIONS: We recommend that the L/WCC ratio should be used as an indicator to decide whether mononucleosis spot tests should be requested. A ratio higher than 0.35 had a high specificity in our study group.

PMID 17224526  Arch Otolaryngol Head Neck Surg. 2007 Jan;133(1):61-4. ・・・
著者: Ben Z Katz, Yukiko Shiraishi, Cynthia J Mears, Helen J Binns, Renee Taylor
雑誌名: Pediatrics. 2009 Jul;124(1):189-93. doi: 10.1542/peds.2008-1879.
Abstract/Text OBJECTIVE: The goal was to characterize prospectively the course and outcome of chronic fatigue syndrome in adolescents during a 2-year period after infectious mononucleosis.
METHODS: A total of 301 adolescents (12-18 years of age) with infectious mononucleosis were identified and screened for nonrecovery 6 months after infectious mononucleosis by using a telephone screening interview. Nonrecovered adolescents underwent a medical evaluation, with follow-up screening 12 and 24 months after infectious mononucleosis. After blind review, final diagnoses of chronic fatigue syndrome at 6, 12, and 24 months were made by using established pediatric criteria.
RESULTS: Six, 12, and 24 months after infectious mononucleosis, 13%, 7%, and 4% of adolescents, respectively, met the criteria for chronic fatigue syndrome. Most individuals recovered with time; only 2 adolescents with chronic fatigue syndrome at 24 months seemed to have recovered or had an explanation for chronic fatigue at 12 months but then were reclassified as having chronic fatigue syndrome at 24 months. All 13 adolescents with chronic fatigue syndrome 24 months after infectious mononucleosis were female and, on average, they reported greater fatigue severity at 12 months. Reported use of steroid therapy during the acute phase of infectious mononucleosis did not increase the risk of developing chronic fatigue syndrome.
CONCLUSIONS: Infectious mononucleosis may be a risk factor for chronic fatigue syndrome in adolescents. Female gender and greater fatigue severity, but not reported steroid use during the acute illness, were associated with the development of chronic fatigue syndrome in adolescents. Additional research is needed to determine other predictors of persistent fatigue after infectious mononucleosis.

PMID 19564299  Pediatrics. 2009 Jul;124(1):189-93. doi: 10.1542/peds.2・・・
著者: I Petersen, J M Thomas, W T Hamilton, P D White
雑誌名: QJM. 2006 Jan;99(1):49-55. doi: 10.1093/qjmed/hci149. Epub 2005 Dec 5.
Abstract/Text BACKGROUND: Fatigue has been found to complicate infectious mononucleosis (IM) when patients are directly asked about it. We do not know whether such fatigue is clinically significant, nor whether IM is a specific risk for fatigue (or whether it can follow other common infections). Various risk markers for post-infectious fatigue have been identified, but findings are inconsistent.
AIM: To determine the risk of clinically reported fatigue (compared with depression) after IM (compared with both influenza and tonsillitis) in patients attending primary care, and to examine risk markers for post-IM fatigue.
DESIGN: Comparison of matched primary-care cohorts.
METHODS: We identified 1438 adult patients with a positive heterophil antibody test for IM from the UK General Practice Research Database. These patients were individually matched on age, sex and practice to two comparison groups; one with a clinical diagnosis of influenza and the other of tonsillitis.
RESULTS: The odds ratios (ORs) (95%CI) for reported fatigue after IM vs. influenza and tonsillitis were 4.4 (2.9-6.9) and 6.6 (4.2-10.4), respectively. Risk markers for post-IM fatigue included female sex and premorbid mood disorder. By comparison, the ORs for depression after IM vs. influenza and tonsillitis were 1.6 (0.9-2.6) and 2.3 (1.4-3.9), respectively.
DISCUSSION: IM is a specific and significant risk for clinically reported fatigue, which is both separate from, and more common than, depression. Female sex and premorbid mood disorder are risk markers for fatigue. These can be used both to target prevention strategies and to explore aetiological mechanisms.

PMID 16330509  QJM. 2006 Jan;99(1):49-55. doi: 10.1093/qjmed/hci149. E・・・
著者: E Tynell, E Aurelius, A Brandell, I Julander, M Wood, Q Y Yao, A Rickinson, B Akerlund, J Andersson
雑誌名: J Infect Dis. 1996 Aug;174(2):324-31.
Abstract/Text Ninety-four patients with infectious mononucleosis and symptoms < or = 7 days were randomized to treatment with oral acyclovir (800 mg 5 times/day) and prednisolone (0.7 mg/kg for the first 4 days, which was reduced by 0.1 mg/kg on consecutive days for another 6 days; n = 48), or placebo (n = 46) for 10 days. Oropharyngeal Epstein-Barr virus (EBV) shedding was significantly inhibited during the treatment period (P = .02, Mann-Whitney rank test). No significant effect was observed for duration of general illness, sore throat, weight loss, or absence from school or work. The frequency of latent EBV-infected B lymphocytes in peripheral blood and the HLA-restricted EBV-specific cellular immunity, measured 6 months after onset of disease, was not affected by treatment. Thus, acyclovir combined with prednisolone inhibited oropharyngeal EBV replication without affecting duration of clinical symptoms or development of EBV-specific cellular immunity.

PMID 8699062  J Infect Dis. 1996 Aug;174(2):324-31.
著者: B Candy, M Hotopf
雑誌名: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004402. doi: 10.1002/14651858.CD004402.pub2. Epub 2006 Jul 19.
Abstract/Text BACKGROUND: Glandular fever (infectious mononucleosis) is associated with fatigue, fever, sore throat and swollen lymph nodes. The severity of symptoms can vary. In extreme cases, breathing difficulties because of swelling in the throat and other complications can require hospitalization. The duration of symptoms is also variable; in some instances they can last for months. There are few treatments available. There are no universal criteria for using steroids in glandular fever. While their use is generally reserved for severe complications, there are reports of practitioners treating most symptomatic people with steroids. As glandular fever often affects young people at a time in their studies where they need to be continually productive, the potential duration of the condition is perhaps a key factor in prescribing such a potent drug for symptom control.
OBJECTIVES: To determine the efficacy and safety of steroid therapy for symptom control in glandular fever.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005); MEDLINE (January 1966 to November 2005); EMBASE (January 1974 to November 2005); and the UK National Research Register (November 2005).
SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared the effectiveness for symptom control of a steroid to placebo or to another intervention for people of any age with documented glandular fever were included.
DATA COLLECTION AND ANALYSIS: Authors independently assessed trial inclusion according to predetermined criteria. Results are presented separately for each symptom and, where possible, it was intended to combine results in a meta-analysis.
MAIN RESULTS: Seven trials were included. The diagnosis, steroid regime, outcomes and methodological quality varied between trials. The sample size ranged from 24 to 94. For sore throat the results of two studies suggest a benefit at 12 hours of steroid therapy over placebo; however this benefit was not maintained. The evidence from one trial suggests a longer benefit when the steroid is combined with an antiviral drug. There was evidence from one trial that steroids may improve resolution of fatigue around four weeks; however it is unclear if this is only in combination with an antiviral. Two trials reported severe complications in participants in the steroid group.
AUTHORS' CONCLUSIONS: There is insufficient evidence - the trials were few, heterogeneous and some were of poor quality, to recommend steroid treatment for symptom control in glandular fever. There is also a lack of research on the side effects, potential adverse effects or complications, particularly in the long term.

PMID 16856045  Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004402. d・・・
著者: Scott K Thompson, Timothy D Doerr, Arthur S Hengerer
雑誌名: Arch Otolaryngol Head Neck Surg. 2005 Oct;131(10):900-4. doi: 10.1001/archotol.131.10.900.
Abstract/Text OBJECTIVE: Although many studies have examined the effects of systemic corticosteroid therapy (SCT) on the clinical course of infectious mononucleosis (IM), few have evaluated the influence of these studies on treatment patterns and outcomes. The purpose of this study was to review current therapeutic strategies and outcomes in uncomplicated and complicated IM.
DESIGN: Retrospective case series.
SETTING: Tertiary care center.
PATIENTS: We identified 206 immunocompetent patients with IM diagnosed during the previous 5 years. Patient information, including age, sex, history and physical findings at presentation, pertinent laboratory data, management practices, and treatment outcomes, were analyzed.
INTERVENTIONS: Systemic corticosteroid therapy was used in 44.7% of patients. Evaluation of treatment indications for SCT revealed that 8.0% of the study population qualified by traditional criteria for the use of corticosteroids; 92.0% of patients received SCT for other indications. Factors associated with the observed increase in corticosteroid use included a history of repeat visits, inpatient admission, and otolaryngology consultation.
MAIN OUTCOME MEASURES: Diagnosis was made on the basis of a positive heterophil antibody test (monospot test) with appropriate clinical findings (97.5% of patients) or by the presence of lymphocytosis with appropriate clinical findings (2.4% of patients).
RESULTS: Systemic corticosteroid therapy was not positively associated with fever, decreased oral intake, tonsillar hypertrophy, or duration of symptoms. No significant differences in incidence of disease complications, rates of hospital admission, or length of hospital stay were noted between the steroid and nonsteroid treatment groups.
CONCLUSIONS: Despite consistent and uniform acceptance in the medical literature that SCT in the setting of IM should be reserved for patients with impending airway obstruction, corticosteroids continue to be used on a much broader scale at this tertiary care institution. This observation suggests that clinicians see value in SCT for treatment of IM beyond the classically accepted reasons. Moreover, despite previous reports of possible adverse consequences of SCT in IM, our review failed to demonstrate any such trend.

PMID 16230594  Arch Otolaryngol Head Neck Surg. 2005 Oct;131(10):900-4・・・
著者: D L Wohl, J E Isaacson
雑誌名: Ear Nose Throat J. 1995 Sep;74(9):630-8.
Abstract/Text Epstein-Barr Virus (EBV) infection generally has a benign clinical course. Upper airway obstruction is a known complication requiring the otolaryngologist's attention. EBV is usually associated with adolescence but has been increasingly documented in younger children. We review 36 pediatric admissions for infectious mononucleosis over a 12-year period at our institution, 11 of which required consultation for airway obstruction. Airway management was based on clinical severity and ranged from monitored observation, with or without nasopharyngeal stenting, to prolonged intubation or emergent tonsilloadenoidectomy. A rare case of a four-year-old with near total upper airway obstruction secondary to panpharyngeal and transglottic inflammatory edema prompted this review and is reported. The otolaryngologist must recognize the potential severity of EBV-related airway compromise and be prepared to manage it.

PMID 8565864  Ear Nose Throat J. 1995 Sep;74(9):630-8.
著者: D Torre, R Tambini
雑誌名: Scand J Infect Dis. 1999;31(6):543-7.
Abstract/Text A meta-analysis of 5 randomized controlled trials (RCT), involving 339 patients with acute infectious mononucleosis (IM) treated with acyclovir (ACV) was performed. ACV was given intravenously in 2 RCTs, which included patients with more severe disease, and orally in the remaining 3 RCTs, which included patients with mild to moderate IM. Both clinical and virological endpoint data available from RCT were evaluated in this study. There was a trend towards clinical effectiveness of ACV treatment, but no statistically significant results were achieved. In contrast, a significant reduction in the rate of oropharyngeal EBV shedding was observed at the end of the therapy (overall OR: 6.62; 95% CI: 3.56-12.29; p < 0.00001). However, no difference in EBV shedding was observed 3 weeks later. There was no significant difference on adverse events in the groups of patients treated with ACV or placebo. In conclusion, clinical data do not support use of ACV for the treatment of acute IM, despite good virological activity of this drug. There is a need for more effective treatment of EBV infection.

PMID 10680982  Scand J Infect Dis. 1999;31(6):543-7.
著者: Paul G Auwaerter
雑誌名: Clin Sports Med. 2004 Jul;23(3):485-97, xi. doi: 10.1016/j.csm.2004.02.005.
Abstract/Text Infectious mononucleosis most commonly affects adolescents and young adults with a febrile illness accompanied by pharyngitis,lymph node enlargement, and transient fatigue. The diagnosis is usually confirmed with demonstration of heterophile antibodies. Typical signs and symptoms are reviewed, along with pitfalls in diagnosis and management. The rare complication of splenic rupture serves to focus recommendations for returning athletes to strenuous physical activities. Because careful prospective studies of infectious mononucleosis in athletes are lacking, review of available literature suggests that clinicians may recommend a return to all sports in those without spleen enlargement 4 weeks after the onset of illness.

PMID 15262384  Clin Sports Med. 2004 Jul;23(3):485-97, xi. doi: 10.101・・・
著者: Shinsaku Imashuku, Kikuko Kuriyama, Rika Sakai, Yoshitaka Nakao, Shin-ichi Masuda, Norimasa Yasuda, Fumio Kawano, Kimikazu Yakushijin, Akiko Miyagawa, Taisei Nakao, Tomoko Teramura, Yasuhiro Tabata, Akira Morimoto, Shigeyoshi Hibi
雑誌名: Med Pediatr Oncol. 2003 Aug;41(2):103-9. doi: 10.1002/mpo.10314.
Abstract/Text BACKGROUND: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), also known as EBV-associated hemophagocytic syndrome, develops mostly in children and young adults and may be fatal. Early etoposide treatment has been confirmed to be effective in children. However, it is unclear whether the same treatment is useful in adults.
PROCEDURE: To assess whether etoposide is effective in treating young adult cases, we retrospectively studied the therapeutic measures taken and outcomes in 20 young adult cases of EBV-HLH. Eleven cases were registered in our HLH study center in Kyoto and nine derived from the literature. The patients were between 17 and 33 years old and eight were males. The influence of gender, cell lineage (T- or natural killer-), EBV serology pattern, jaundice and treatment on the outcome was assessed.
RESULTS AND CONCLUSIONS: Patients receiving etoposide within four weeks after diagnosis had a good prognosis as five of the seven patients survived compared to one of 13 not treated with etoposide or treated late (chi-square test for survival, P = 0.0095). The Kaplan-Meier analysis showed the 2.5-year survival of 85.7 +/- 13.2% in the early etoposide-treated patients, compared to 10.3 +/- 9.4% in the remaining patients (log-rank test, P = 0.0141). Thus, early etoposide treatment is effective in treating EBV-HLH in young adults as well as in children.

Copyright 2003 Wiley-Liss, Inc.
PMID 12825212  Med Pediatr Oncol. 2003 Aug;41(2):103-9. doi: 10.1002/m・・・
著者: Jan-Inge Henter, Annacarin Horne, Maurizio Aricó, R Maarten Egeler, Alexandra H Filipovich, Shinsaku Imashuku, Stephan Ladisch, Ken McClain, David Webb, Jacek Winiarski, Gritta Janka
雑誌名: Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039.
Abstract/Text In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.

PMID 16937360  Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.10・・・
著者: Eiichi Ishii, Shouichi Ohga, Shinsaku Imashuku, Masaki Yasukawa, Hiroyuki Tsuda, Ikuo Miura, Ken Yamamoto, Hisanori Horiuchi, Kenzo Takada, Koichi Ohshima, Shigeo Nakamura, Naoko Kinukawa, Kazuo Oshimi, Keisei Kawa
雑誌名: Int J Hematol. 2007 Jul;86(1):58-65. doi: 10.1532/IJH97.07012.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

PMID 17675268  Int J Hematol. 2007 Jul;86(1):58-65. doi: 10.1532/IJH97・・・

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