今日の臨床サポート

発熱・不明熱

著者: 横江正道 名古屋第二赤十字病院 総合内科

監修: 野口善令 豊田地域医療センター 総合診療科

著者校正済:2021/07/07
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 発熱を主訴として外来受診する患者は非常に多い。しかし「発熱のみ」という患者は決して多くないはずである。診断を進めていくうえで、発熱以外の症状を問診やROSなどから探し出すことが診断の手掛かりになる(推奨度1)。
  1. 特に見逃すと予後不良となる疾患・病態に関しては、確実にバイタルサインなどを評価し、問診・身体所見から検査前確率(疾患がある可能性の高低)を推測して、確実に必要な検査を進めていくことを推奨する(推奨度2)。
  1. 発熱患者をみるときに行う初期検査項目として最低限、CBC、生化学(AST、ALT、ALP、γGTP、LDH、Na、K、Cl、BUN、Cr)、CRP、尿検査(定性・沈渣・亜硝酸塩)、胸部X線写真、心電図(ECG)などを行うことを強く推奨する。また血液培養も推奨する(推奨度1)。
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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:
横江正道 : 特に申告事項無し[2021年]
監修:野口善令 : 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、ポイントについて加筆を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 体温の上昇(elevated body temperature)は、その発症メカニズムの違いによって、“高体温” (hyperthermia)と“発熱”(fever)の2つに大別される。なお、疫学的に正常体温を調べた研究として1992年のJAMAの研究がある。この研究では18歳から42歳の正常男女の口腔内体温を測定した結果、朝6時では37.2℃、夜6時では37.7℃が正常の40歳以下の男性の99%上限であった。従って、早朝では37.2℃以上を、夕方では37.7℃以上を発熱と呼んでよいのではないかと結論づけている[1]
  1. 発熱を来す病気は非常に多い。診断にあたっては、手がかりとなる発熱以外の随伴症状や身体所見をみつけ出す。ROS(review of systems)なども使用して、確実に問診し身体所見をとる。
  1. 海外からの帰国者に発熱をみた場合は、マラリア、デング熱、腸チフス・パラチフス、チクングニヤ出血熱、ブルセラ症、レプトスピラ症なども鑑別診断に含める。特に流行地域かどうか、現地の生活様式などを確認する。
  1. 薬剤が原因で発熱していることもある。飲んでいる薬剤、新規に開始された薬剤がないか確認し、原因と思われる薬剤があれば中止する。
  1. 発熱と高体温症は区別する。
  1. 尿路感染は発熱の原因として非常に多い。疑った場合は必ず尿検査で確認する。
  1. 外来でフォローする場合は、次回外来まで熱型表をつけてもらう。
 
  1. 発熱の原因がよくわからないと感じるときほど、普段からあまり見慣れていない臓器や部位の疾患をよく理解し、注意深く診察することを強く推奨する[2][3][4][5](推奨度1)。
  1. 発熱を来す病気は非常に多い。多くの内科医は感冒、肺炎、髄膜炎、腎盂腎炎、急性腸炎などはルーチンワークで評価を進めている。しかし、副鼻腔炎や中耳炎、蜂巣炎や痛風・偽痛風でも発熱はする。また、深部静脈血栓症や肺塞栓でも発熱を来すし、側頭動脈炎や肝膿瘍、感染性心内膜炎の評価も必要である。このように、鑑別疾患を多く想起できることが、発熱の診療を確実に進めることになる。そのためには自分の専門外の領域に関する疾患の理解や、幅広い知識の習得が必要である。このことより、普段からあまり見慣れていない臓器や部位の疾患をよく理解し、注意深く診察することを強く推奨する。
 
  1. 発熱と高体温症を区別することを推奨する(推奨度2)。
  1. 熱中症や悪性高熱、悪性症候群、セロトニン症候群などと、感染症やリウマチ膠原病などを原因とする発熱とは区別すべきである。これは検査方法も治療方法もまったく異なるからである。高体温症は常に感染や炎症で起こるものと考えてはいけない。選択的セロトニン再吸収阻害薬(SSRI)などの薬剤が広く使われるようになった昨今、突然の服薬中止などの問診もまた重要である[6]
 
  1. 海外から帰国後の発熱患者では、渡航先での感染症流行情報とともに現地での食生活、日常行動(勤務・レジャー)、外国人や動物との接触などを確認することが強く推奨される(推奨度1)。
  1. 海外から日本への帰国者における発熱では、マラリア、デング熱、腸チフス・パラチフス、チクングニヤ熱、ブルセラ症、レプトスピラ症などを考えなくてはいけない。渡航先を確認するとともに、現地での流行疾患を確認することが重要である。近年では、旅行者の帰国後発熱の原因として、マラリアよりもデング熱が多くなっているとの報告もある。チクングニヤ出血熱にも注意が必要である[7][8]。現地で蚊に刺されたかどうか、食事はどのようなものをとっていたのか、水はどうしていたのか、単なる観光地のみを巡っていたのか、密林に入ったり川や海で泳いだりしたことはないかなど、微生物と感染経路を考慮した問診を行う必要がある[5][9]。また、現地の異性や同性との性交渉はHIVやB型肝炎、梅毒、その他のSTDを考慮するうえで確認すべき事項である。このことより、帰国後の発熱患者では、渡航先での感染症流行情報とともに、現地での食生活、日常行動(勤務・レジャー)、外国人との接触の程度などを確認することが強く推奨される。
問診・診察のポイント  
  1. 診察時に病歴を詳細に聴取する。発熱以外の症状の有無、感染症と考えられるエピソード、癌など悪性腫瘍が考えられるエピソード、膠原病・リウマチ疾患が考えられるエピソードがあるか確認する。薬剤使用歴なども詳しく聴取する。職業・職歴や性交渉状況などプライバシーに関わる事項も、問診することで診断に近づける場合もある。

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文献 

著者: P A Mackowiak, S S Wasserman, M M Levine
雑誌名: JAMA. 1992 Sep 23-30;268(12):1578-80.
Abstract/Text OBJECTIVE: To evaluate critically Carl Wunderlich's axioms on clinical thermometry.
DESIGN: Descriptive analysis of baseline oral temperature data from volunteers participating in Shigella vaccine trials conducted at the University of Maryland Center for Vaccine Development, Baltimore.
SETTING: Inpatient clinical research unit.
PARTICIPANTS: One hundred forty-eight healthy men and women aged 18 through 40 years.
MAIN MEASUREMENTS: Oral temperatures were measured one to four times daily for 3 consecutive days using an electronic digital thermometer.
RESULTS: Our findings conflicted with Wunderlich's in that 36.8 degrees C (98.2 degrees F) rather than 37.0 degrees C (98.6 degrees F) was the mean oral temperature of our subjects; 37.7 degrees C (99.9 degrees F) rather than 38.0 degrees C (100.4 degrees F) was the upper limit of the normal temperature range; maximum temperatures, like mean temperatures, varied with time of day; and men and women exhibited comparable thermal variability. Our data corroborated Wunderlich's in that mean temperature varied diurnally, with a 6 AM nadir, a 4 to 6 PM zenith, and a mean amplitude of variability of 0.5 degrees C (0.9 degrees F); women had slightly higher normal temperatures than men; and there was a trend toward higher temperatures among black than among white subjects.
CONCLUSIONS: Thirty-seven degrees centigrade (98.6 degrees F) should be abandoned as a concept relevant to clinical thermometry; 37.2 degrees C (98.9 degrees F) in the early morning and 37.7 degrees C (99.9 degrees F) overall should be regarded as the upper limit of the normal oral temperature range in healthy adults aged 40 years or younger, and several of Wunderlich's other cherished dictums should be revised.

PMID 1302471  JAMA. 1992 Sep 23-30;268(12):1578-80.
著者: Burke A Cunha
雑誌名: Infect Dis Clin North Am. 2007 Dec;21(4):1137-87, xi. doi: 10.1016/j.idc.2007.09.004.
Abstract/Text The causes of fevers of unknown origin (FUOs) are diverse and may be the result of infectious rheumatic or inflammatory, neoplastic, or miscellaneous disorders. This article reviews the focused diagnostic approach to FUOs, emphasizing relevant history, physical examination, and selected laboratory tests using a clinical syndrome approach. Laboratory tests should be guided by the most likely diagnoses based on the presenting clinical syndrome. Considered in concert, nonspecific laboratory tests may provide important diagnostic clues. Using a sequential diagnostic approach, a focused evaluation diagnoses all but the rarest or most obscure causes of FUO.

PMID 18061092  Infect Dis Clin North Am. 2007 Dec;21(4):1137-87, xi. d・・・
著者: Jill Tolia, Leon G Smith
雑誌名: Infect Dis Clin North Am. 2007 Dec;21(4):917-36, viii. doi: 10.1016/j.idc.2007.08.011.
Abstract/Text Fever of unknown origin (FUO) has fascinated and perplexed clinicians for over a century. No published guidelines exist on the approach to FUO, and studies have demonstrated that a diagnosis is never established in up to 30% of cases. A comprehensive history and physical examination are the keys to establishing a diagnosis in patient with FUO. This article provides a systematic approach to the diagnosis of FUO by delineating the most important elements of a comprehensive history and physical examination.

PMID 18061082  Infect Dis Clin North Am. 2007 Dec;21(4):917-36, viii. ・・・
著者: Edward W Boyer, Michael Shannon
雑誌名: N Engl J Med. 2005 Mar 17;352(11):1112-20. doi: 10.1056/NEJMra041867.
Abstract/Text
PMID 15784664  N Engl J Med. 2005 Mar 17;352(11):1112-20. doi: 10.1056・・・
著者: David O Freedman, Leisa H Weld, Phyllis E Kozarsky, Tamara Fisk, Rachel Robins, Frank von Sonnenburg, Jay S Keystone, Prativa Pandey, Martin S Cetron, GeoSentinel Surveillance Network
雑誌名: N Engl J Med. 2006 Jan 12;354(2):119-30. doi: 10.1056/NEJMoa051331.
Abstract/Text BACKGROUND: Approximately 8 percent of travelers to the developing world require medical care during or after travel. Current understanding of morbidity profiles among ill returned travelers is based on limited data from the 1980s.
METHODS: Thirty GeoSentinel sites, which are specialized travel or tropical-medicine clinics on six continents, contributed clinician-based sentinel surveillance data for 17,353 ill returned travelers. We compared the frequency of occurrence of each diagnosis among travelers returning from six developing regions of the world.
RESULTS: Significant regional differences in proportionate morbidity were detected in 16 of 21 broad syndromic categories. Among travelers presenting to GeoSentinel sites, systemic febrile illness without localizing findings occurred disproportionately among those returning from sub-Saharan Africa or Southeast Asia, acute diarrhea among those returning from south central Asia, and dermatologic problems among those returning from the Caribbean or Central or South America. With respect to specific diagnoses, malaria was one of the three most frequent causes of systemic febrile illness among travelers from every region, although travelers from every region except sub-Saharan Africa and Central America had confirmed or probable dengue more frequently than malaria. Among travelers returning from sub-Saharan Africa, rickettsial infection, primarily tick-borne spotted fever, occurred more frequently than typhoid or dengue. Travelers from all regions except Southeast Asia presented with parasite-induced diarrhea more often than with bacterial diarrhea.
CONCLUSIONS: When patients present to specialized clinics after travel to the developing world, travel destinations are associated with the probability of the diagnosis of certain diseases. Diagnostic approaches and empiric therapies can be guided by these destination-specific differences.

Copyright 2006 Massachusetts Medical Society.
PMID 16407507  N Engl J Med. 2006 Jan 12;354(2):119-30. doi: 10.1056/N・・・
著者: Cinzia Marano, David O Freedman
雑誌名: Curr Opin Infect Dis. 2009 Oct;22(5):423-9. doi: 10.1097/QCO.0b013e32832ee896.
Abstract/Text PURPOSE OF REVIEW: Monitoring disease trends among travelers can inform both pretravel advice and posttravel management. Data from sentinel travelers upon their return to medically sophisticated environments can also benefit local populations in resource-limited countries.
RECENT FINDINGS: Provider-based surveillance of travelers is increasingly sophisticated. Recently, networks such as GeoSentinel have provided cumulative trends in travel-related illness to assess pretravel risk for a mass gathering event--the Beijing Olympic Games. Data provided by the GeoSentinel also helped in determining the seasonality of dengue by region of travel and risk of acquiring schistosomiasis after a single short exposure. For chikungunya fever, detailed study of returned travelers exposed new clinical aspects of a disease previously studied in the tropics only. Clusters of hepatitis A, a vaccine-preventable disease, among European travelers, illustrated continued gaps in the preparation of the traveling public. Plasmodium knowlesi has emerged as the fifth human malaria parasite and is now a consideration in the diagnosis of febrile travelers from Asia. Automated global news scanning software is increasingly being able to detect and prioritize disease events.
SUMMARY: Every year millions of travelers visit countries where they are exposed to pathogens that are usually rare in their home countries. Global surveillance of travel-related disease represents a powerful tool for the detection of infectious diseases. These data should encourage clinicians to take a detailed travel history during every patient encounter.

PMID 19726984  Curr Opin Infect Dis. 2009 Oct;22(5):423-9. doi: 10.109・・・
著者: Cristian Speil, Adnan Mushtaq, Alys Adamski, Nancy Khardori
雑誌名: Infect Dis Clin North Am. 2007 Dec;21(4):1091-113, x. doi: 10.1016/j.idc.2007.08.005.
Abstract/Text The returning traveler with fever presents a diagnostic challenge for the health care provider. When evaluating such a patient, the highest priority should be given to diseases that are potentially fatal or may represent public health threats. A good history is paramount and needs to include destination, time and duration of travel, type of activity, onset of fever in relation to travel, associated comorbidities, and any associated symptoms. Pretravel immunizations and chemoprophylaxis may alter the natural course of disease and should be inquired about specifically. The fever pattern, presence of a rash or eschar, organomegaly, or neurologic findings are helpful physical findings. Laboratory abnormalities are nonspecific but when corroborated with clinical and epidemiologic data may offer a clue to diagnosis.

PMID 18061090  Infect Dis Clin North Am. 2007 Dec;21(4):1091-113, x. d・・・
著者: Diederik van de Beek, Jan de Gans, Allan R Tunkel, Eelco F M Wijdicks
雑誌名: N Engl J Med. 2006 Jan 5;354(1):44-53. doi: 10.1056/NEJMra052116.
Abstract/Text
PMID 16394301  N Engl J Med. 2006 Jan 5;354(1):44-53. doi: 10.1056/NEJ・・・
著者: Karen E Thomas, Rodrigo Hasbun, James Jekel, Vincent J Quagliarello
雑誌名: Clin Infect Dis. 2002 Jul 1;35(1):46-52. doi: 10.1086/340979. Epub 2002 Jun 5.
Abstract/Text To determine the diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity for meningitis, 297 adults with suspected meningitis were prospectively evaluated for the presence of these meningeal signs before lumbar puncture was done. Kernig's sign (sensitivity, 5%; likelihood ratio for a positive test result [LR(+)], 0.97), Brudzinski's sign (sensitivity, 5%; LR(+), 0.97), and nuchal rigidity (sensitivity, 30%; LR(+), 0.94) did not accurately discriminate between patients with meningitis (>/=6 white blood cells [WBCs]/mL of cerebrospinal fluid [CSF]) and patients without meningitis. The diagnostic accuracy of these signs was not significantly better in the subsets of patients with moderate meningeal inflammation (>/=100 WBCs/mL of CSF) or microbiological evidence of CSF infection. Only for 4 patients with severe meningeal inflammation (>/=1000 WBCs/mL of CSF) did nuchal rigidity show diagnostic value (sensitivity, 100%; negative predictive value, 100%). In the broad spectrum of adults with suspected meningitis, 3 classic meningeal signs did not have diagnostic value; better bedside diagnostic signs are needed.

PMID 12060874  Clin Infect Dis. 2002 Jul 1;35(1):46-52. doi: 10.1086/3・・・
著者: T Uchihara, H Tsukagoshi
雑誌名: Headache. 1991 Mar;31(3):167-71.
Abstract/Text We prospectively examined the clinical signs of 54 febrile patients associated with recent-onset headache. They underwent lumbar puncture (LP) on suspicion of meningitis. The relation of each sign to cerebrospinal fluid (CSF) pleocytosis was estimated. Among 34 patients with pleocytosis, 33 had jolt accentuation (sensitivity: 97.1%), while only 5 of them had neck stiffness or Kernig's sign. Among 20 patients without pleocytosis, 12 had no jolt accentuation (specificity: 60%). We found jolt accentuation to be the most sensitive sign of CSF pleocytosis. If jolt accentuation is noted in a febrile patient associated with recent onset headache, the CSF should be examined even in the absence of neck stiffness or Kernig's sign.

PMID 2071396  Headache. 1991 Mar;31(3):167-71.
著者: Charles S Bryan, Divya Ahuja
雑誌名: Infect Dis Clin North Am. 2007 Dec;21(4):1213-20, xi. doi: 10.1016/j.idc.2007.08.007.
Abstract/Text Empiric therapy has little or no role to play in cases of classic fever of unknown origin with three important exceptions: cases that meet criteria for culture-negative endocarditis; cases in which findings or the clinical setting suggests cryptic disseminated tuberculosis (or, occasionally, other granulomatous infections); and cases in which temporal arteritis with vision loss is suspected. Several studies indicate that patients with prolonged, undiagnosed fever of unknown origin generally have a favorable prognosis. A small and largely anecdotal literature suggests a small role for symptomatic use of corticosteroids or nonsteroidal anti-inflammatory agents in highly selected cases.

PMID 18061094  Infect Dis Clin North Am. 2007 Dec;21(4):1213-20, xi. d・・・
著者: Ruchi A Patel, Jason C Gallagher
雑誌名: Pharmacotherapy. 2010 Jan;30(1):57-69. doi: 10.1592/phco.30.1.57.
Abstract/Text Drug fever is a common condition that is frequently misdiagnosed. It is a febrile response that coincides temporally with the administration of a drug and disappears after discontinuation of the offending agent. Drug fever is usually suspected when no other cause for the fever can be elucidated, sometimes after antimicrobial therapy has already been started. In nonsensitized individuals receiving a drug for the first time, the onset of fever is highly variable and differs among drug classes, but most commonly appears after 7-10 days of drug administration and rapidly reverses after discontinuation of the drug. Early diagnosis may reduce inappropriate and potentially harmful and expensive diagnostic and therapeutic interventions. Rechallenge with the offending agent will usually cause recurrence of fever within a few hours, confirming the diagnosis. Rechallenge is controversial and should be performed with extreme caution, since there is a potential for a more severe drug reaction. We describe the mechanisms in the pathophysiology of drug fever and summarize the results of published case reports on the wide variety of agents that are implicated in causing drug fever. Special attention is paid to the role of antimicrobial agents in drug fever.

PMID 20030474  Pharmacotherapy. 2010 Jan;30(1):57-69. doi: 10.1592/phc・・・
著者: E Mylonakis, E T Ryan, S B Calderwood
雑誌名: Arch Intern Med. 2001 Feb 26;161(4):525-33.
Abstract/Text Clostridium difficile causes 300 000 to 3 000 000 cases of diarrhea and colitis in the United States every year. Antibiotics most frequently associated with the infection are clindamycin, ampicillin, amoxicillin, and cephalosporins, but all antibiotics may predispose patients to C difficile infection. The clinical presentation varies from asymptomatic colonization to mild diarrhea to severe debilitating disease, with high fever, severe abdominal pain, paralytic ileus, colonic dilation (or megacolon), or even perforation. The most sensitive and specific test available for diagnosis of C difficile infection is a tissue culture assay for the cytotoxicity of toxin B. However, this test takes 1 to 3 days to complete and requires tissue culture facilities. Detection of C difficile toxin by means of enzyme-linked immunoassay is more rapid and inexpensive. A minority of patients may require more than 1 stool assay to detect toxin. Oral metronidazole or oral vancomycin hydrochloride for 10 to 14 days are equally effective at resolving clinical symptoms; oral metronidazole is preferred in most cases because of lowered cost and less selective pressure for vancomycin-resistant organisms. Approximately 15% of patients experience relapse after initial therapy and require retreatment, sometimes with an extended, tapering regimen. Immunity appears to be incomplete and predominantly mediated by serum IgG to toxin A. Measures for preventing the spread of the pathogen, appropriate diagnostic testing, and treatment may avert morbidity and mortality due to C difficile-associated diarrhea.

PMID 11252111  Arch Intern Med. 2001 Feb 26;161(4):525-33.
著者: D M Musher, V Fainstein, E J Young, T L Pruett
雑誌名: Arch Intern Med. 1979 Nov;139(11):1225-8.
Abstract/Text Fever patterns were studied prospectively in 200 consecutive patients referred for infectious disease consultation and retrospectively in 204 patients with selected infectious or noninfectious diseases. Most patients had remittent or intermittent fever, which, when due to infection, usually followed diurnal variation. Hectic fever occurred less commonly but was observed in patients with all categories of infectious or noninfectious diseases. Although hectic fevers were seen more frequently in patients who had documented bacteremia, there were many nonbacteremic subjects who had this pattern and others without this pattern who had bacteremia. Sustained fever nearly always occurred in patients with Gram-negative pneumonia or CNS damage, although some patients with these diseases had other patterns as well. Our data suggest that, with the possible exception of sustained fever in Gram-negative pneumonia or CNS damage, the fever pattern is not likely to be helpful diagnostically.

PMID 574377  Arch Intern Med. 1979 Nov;139(11):1225-8.
著者: Alan R Roth, Gina M Basello
雑誌名: Am Fam Physician. 2003 Dec 1;68(11):2223-8.
Abstract/Text Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3 degrees C (100.9 degrees F) that lasts for more than three weeks with no obvious source despite appropriate investigation. The four categories of potential etiology of FUO are classic, nosocomial, immune deficient, and human immunodeficiency virus-related. The four subgroups of the differential diagnosis of FUO are infections, malignancies, autoimmune conditions, and miscellaneous. A thorough history, physical examination, and standard laboratory testing remain the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including updated serology, viral cultures, computed tomography, and magnetic resonance imaging, have important roles in the assessment of these patients.

PMID 14677667  Am Fam Physician. 2003 Dec 1;68(11):2223-8.
著者: Ophyr Mourad, Valerie Palda, Allan S Detsky
雑誌名: Arch Intern Med. 2003 Mar 10;163(5):545-51.
Abstract/Text BACKGROUND: Fever of unknown origin (FUO) is defined as a temperature higher than 38.3 degrees C on several occasions and lasting longer than 3 weeks, with a diagnosis that remains uncertain after 1 week of investigation.
METHODS: A systematic review was performed to develop evidence-based recommendations for the diagnostic workup of FUO. MEDLINE database was searched (January 1966 to December 2000) to identify articles related to FUO. Articles were included if the patient population met the criteria for FUO and they addressed the natural history, prognosis, or spectrum of disease or evaluated a diagnostic test in FUO. The quality of retrieved articles was rated as "good," "fair," or "poor," and sensitivity, specificity, and diagnostic yield of tests were calculated. Recommendations were made in accordance with the strength of evidence.
RESULTS: The prevalence of FUO in hospitalized patients is reported to be 2.9%. Eleven studies indicate that the spectrum of disease includes "no diagnosis" (19%), infections (28%), inflammatory diseases (21%), and malignancies (17%). Deep vein thrombosis (3%) and temporal arteritis in the elderly (16%-17%) were important considerations. Four good natural history studies indicate that most patients with undiagnosed FUO recover spontaneously (51%-100%). One fair-quality study suggested a high specificity (99%) for the diagnosis of endocarditis in FUO by applying the Duke criteria. One fair-quality study showed that computed tomographic scanning of the abdomen had a diagnostic yield of 19%. Ten studies of nuclear imaging revealed that technetium was the most promising isotope, showing a high specificity (94%), albeit low sensitivity (40%-75%) (2 fair-quality studies). Two fair-quality studies showed liver biopsy to have a high diagnostic yield (14%-17%), but with risk of harm (0.009%-0.12% death). Empiric bone marrow cultures showed a low diagnostic yield of 0% to 2% (2 fair-quality articles).
CONCLUSIONS: Diagnosis of FUO may be assisted by the Duke criteria for endocarditis, computed tomographic scan of the abdomen, nuclear scanning with a technetium-based isotope, and liver biopsy (fair to good evidence). Routine bone marrow cultures are not recommended.

PMID 12622601  Arch Intern Med. 2003 Mar 10;163(5):545-51.
著者: Kamal Amin, Carol A Kauffman
雑誌名: Postgrad Med. 2003 Sep;114(3):69-75.
Abstract/Text Fever of unknown origin (FUO) remains a challenging clinical problem despite recent advances in diagnostic tools and techniques. Because primary care physicians are often the first ones to encounter a case of FUO, it is important that they be familiar with the best strategy and steps for confronting this problem initially. Here, Drs Amin and Kauffman review the major causes of FUO in adults and describe an in-depth approach to laboratory and radiologic tests that help establish a diagnosis.

PMID 14503400  Postgrad Med. 2003 Sep;114(3):69-75.
著者: Yasuharu Tokuda, Hitoshi Miyasato, Gerald H Stein, Tomokazu Kishaba
雑誌名: Am J Med. 2005 Dec;118(12):1417. doi: 10.1016/j.amjmed.2005.06.043.
Abstract/Text PURPOSE: Patients with acute febrile illness may experience different degrees of chills. To evaluate the different degrees of chills in predicting risk of bacteremia in patients with acute febrile illness, we performed a single-center prospective observational study.
METHODS: We enrolled consecutive adult patients with acute febrile illness presenting to our emergency department. We defined mild chills as cold-feeling equivalent such as the need of an outer jacket; moderate chills as the need for a thick blanket; and shaking chills as whole-body shaking even under a thick blanket. We estimated risk ratios of the different degrees of chills for bacteremia using multivariable adjusted Poisson regression.
RESULTS: Of a total 526 patients, 40 patients (7.6%) had bacteremia. There were 65 patients (12.4%) with shaking chills, 100 (19%) with moderate chills, and 105 (20%) with mild chills. By comparing patients with no chills, the risk ratios of bacteremia were 12.1 (95% confidence interval [CI] 4.1-36.2) for shaking chills, 4.1 (95% CI 1.6-10.7) for moderate chills, and 1.8 (95% CI 0.9-3.3) for mild chills. Shaking chills showed a specificity of 90.3% (95% CI 89.2-91.5) and positive likelihood ratio of 4.65 (95% CI 2.95-6.86). The absence of chills showed a sensitivity of 87.5% (95% CI 74.4-94.5) and negative likelihood ratio of 0.24 (95% CI 0.11-0.51).
CONCLUSION: Evaluation of the degree of chills is important for estimating risk of bacteremia in patients with acute febrile illness. The more severe degree of chills suggests the higher risk of bacteremia.

PMID 16378800  Am J Med. 2005 Dec;118(12):1417. doi: 10.1016/j.amjmed.・・・
著者: Michael Lloyd Towns, William Robert Jarvis, Po-Ren Hsueh
雑誌名: J Microbiol Immunol Infect. 2010 Aug;43(4):347-9. doi: 10.1016/S1684-1182(10)60054-0.
Abstract/Text Just over one-third of sepsis patients have positive blood cultures, mainly due to inadequate sampling volumes (50% of adults have < 1.0 CFU/mL blood) and the prior use of antibiotics. However, 20-30% of sepsis patients are given inappropriate empirical antibiotics. The Clinical and Laboratory Standards Institute guidelines recommend paired culture sets to help discriminate between contaminant organisms and true pathogens; four 10-mL bottles (2 sets) should be used for the initial evaluation to detect about 90-95% of bacteremias and six 10-mL bottles (3 sets) should be used to detect about 95-99% of bacteremias. It has also been shown that the positivity rate increased by 15-35% with resin-based media in patients on antibiotics. For diagnosing catheter-related bloodstream infections, differential time-to-positivity is one method recommended to help determine whether the catheter is truly the source of infection. The proper training of personnel with regard to drawing an appropriate blood volume and the importance of clear labeling of culture bottles is also of critical importance. Furthermore, if the contamination rate is relatively high, hiring dedicated staff who are well-trained in order to get a lower blood culture contamination rate may be cost-effective. It is because high false-positive blood culture rates due to contamination are associated with significantly increased hospital and laboratory charges.

Copyright (c) 2010 Taiwan Society of Microbiology. Published by Elsevier B.V. All rights reserved.
PMID 20688297  J Microbiol Immunol Infect. 2010 Aug;43(4):347-9. doi: ・・・
著者: Thomas G Connell, Mhisti Rele, Donna Cowley, Jim P Buttery, Nigel Curtis
雑誌名: Pediatrics. 2007 May;119(5):891-6. doi: 10.1542/peds.2006-0440.
Abstract/Text OBJECTIVES: The primary aims of this study were to determine the volume of blood submitted for culture in routine clinical practice and to establish the proportion of blood cultures with a blood volume inadequate for reliable detection of bacteremia.
METHODS: The volumes of blood samples submitted for culture from infants and children up to 18 years of age were measured over a 6-month period. Blood cultures were deemed adequate submissions if they contained an appropriate (age-related) volume of blood and were submitted in the correct blood culture bottle type. During the study, an educational intervention designed to increase the proportion of adequate blood culture submissions was undertaken.
RESULTS: The volume of blood submitted in 1358 blood culture bottles from 783 patients was analyzed. Of the 1067 preintervention blood cultures, 491 (46.0%) contained an adequate blood volume and only 378 (35.4%) were adequate submissions on the basis of collection into the correct blood culture bottle type. After the intervention, there were significant increases in both the proportion of blood cultures containing an adequate blood volume (186 [63.9%] of 291 cultures) and the proportion of adequate submissions (149 [51.2%] of 291 cultures). Overall, blood cultures with an adequate blood volume were more likely than those with an inadequate blood volume to yield positive blood culture results (34 [5.2%] of 655 cultures vs 14 [2.1%] of 648 cultures). Similarly, adequate blood culture submissions were more likely than inadequate submissions to yield positive blood culture results (26 [5.1%] of 506 cultures vs 22 [2.8%] of 797 cultures).
CONCLUSIONS: In routine clinical practice, a negative blood culture result is almost inevitable for a large proportion of blood cultures because of the submission of an inadequate volume of blood. Even after an educational intervention, nearly one half of blood cultures were inadequate submissions.

PMID 17473088  Pediatrics. 2007 May;119(5):891-6. doi: 10.1542/peds.20・・・
著者: D H Johnson, B A Cunha
雑誌名: Infect Dis Clin North Am. 1996 Mar;10(1):85-91.
Abstract/Text Drug fever is the febrile response to a drug without cutaneous manifestations. Although the exact incidence of drug fever remains unknown, it has been estimated to occur in approximately 10% of inpatients. The recognition of drug fever is of great clinical importance because, if drug fever is not recognized diagnostically, patients may be subjected to prolonged hospitalization and unnecessary testing or medications. Early diagnosis and treatment of drug fevers are essential in maintaining cost-effective, high-quality medical care.

PMID 8698996  Infect Dis Clin North Am. 1996 Mar;10(1):85-91.
著者: N M Foley, R F Miller
雑誌名: J Infect. 1993 Jan;26(1):39-43.
Abstract/Text We have studied the effect of the HIV epidemic on the incidence of tuberculosis in an inner city area of London which has a high incidence of acquired immunodeficiency syndrome (AIDS). During the period 1985-1991, there was a steady increase in the number of new AIDS cases, whilst the numbers of notifications and laboratory isolates of Mycobacterium tuberculosis remained largely unchanged. Before 1990 there were few cases of tuberculosis in HIV-infected individuals but in the past 2 years there has been a marked increase. In 44% of patients, the site of infection was pulmonary, in 39% extrapulmonary and in 17% pulmonary and extrapulmonary. There were no previous manifestations of immunodeficiency in 58% of patients. This is the first study to show an association between tuberculosis and HIV in the U.K. and supports the suggestion that there is an increased incidence of tuberculosis in patients with HIV infection who are not intravenous drug users.

PMID 8454887  J Infect. 1993 Jan;26(1):39-43.
著者: S D Greenberg, D Frager, B Suster, S Walker, C Stavropoulos, A Rothpearl
雑誌名: Radiology. 1994 Oct;193(1):115-9. doi: 10.1148/radiology.193.1.7916467.
Abstract/Text PURPOSE: To assess the efficacy of chest radiography in the detection of active pulmonary tuberculosis in patients with acquired immunodeficiency syndrome (AIDS).
MATERIALS AND METHODS: Initial interpretations of chest radiographs of 133 adult patients with AIDS and positive sputum or bronchoalveolar lavage cultures for Mycobacterium tuberculosis were reviewed. Radiographic findings were correlated with CD4 T-cell counts, sputum stains for acid-fast bacilli (AFB), and antituberculous drug sensitivity.
RESULTS: Forty-eight (36%) patients had a primary M tuberculosis pattern, 38 (28%) had a postprimary M tuberculosis pattern, 19 (14%) had normal radiographs, 17 (13%) had atypical infiltrates, seven (5%) had minimal radiographic changes, and four (3%) had a miliary pattern. Normal chest radiographs were seen for 10 (21%) of 48 patients with less than 200 T cells per microliter and one (5%) of 20 patients with more than 200 T cells per microliter. Drug sensitivity and sputum staining for AFB did not correlate with radiographic findings. Overall, 19% of cases had multidrug resistance to antituberculous medications.
CONCLUSION: Chest radiographs did not suggest active tuberculosis in 43 (32%) of 133 AIDS patients with active pulmonary tuberculosis.

PMID 7916467  Radiology. 1994 Oct;193(1):115-9. doi: 10.1148/radiolog・・・
著者: P A Mackowiak, C F LeMaistre
雑誌名: Ann Intern Med. 1987 May;106(5):728-33.
Abstract/Text Because no systematic analysis of drug fever has been done, there has been no means for testing the validity of published characterizations of this clinical entity. We reviewed the clinical characteristics of 51 episodes of drug fever in 45 patients hospitalized at two Dallas hospitals between 1959 and 1986, and 97 episodes reported in the English literature between 1966 and 1986. Unlike characterizations found in textbooks and review articles, we found relative bradycardia in a minority of cases reviewed; little risk associated with rechallenge unless underlying cardiovascular disease was present; no characteristic fever pattern; a highly variable lag time between the initiation of the offending agent and the onset of fever; an infrequent association with either rash or eosinophilia; and no apparent association of drug fever with systemic lupus erythematosus, atopy, female sex, or advanced age.

PMID 3565971  Ann Intern Med. 1987 May;106(5):728-33.
著者: P A Mackowiak
雑誌名: Am J Med Sci. 1987 Oct;294(4):275-86.
Abstract/Text Although drug fever is a clinical entity that has received considerable attention in textbooks and review articles, only recently have such writings been subjected to critical analysis. In the present review, mechanisms responsible for drug fever are examined. In addition, published characterizations of the syndrome are compared with the results of a recently published systematic analysis of 148 cases of drug fever. This comparison identified a number of important areas in which descriptions of the clinical entity in textbooks and review articles are at odds with the clinical profile exhibited by actual cases of drug fever.

PMID 3310641  Am J Med Sci. 1987 Oct;294(4):275-86.
著者: M K Roush, K M Nelson
雑誌名: Am Pharm. 1993 Oct;NS33(10):39-42.
Abstract/Text
PMID 8237783  Am Pharm. 1993 Oct;NS33(10):39-42.
著者: P A Tabor
雑誌名: Drug Intell Clin Pharm. 1986 Jun;20(6):413-20.
Abstract/Text Humans maintain body temperature within a narrow range. Drug administration can upset the usual balance and cause a fever. The drug may interfere with heat dissipation peripherally, increase the rate of metabolism, evoke a cellular or humoral immune response, mimic endogenous pyrogen, or damage tissues. The fever may be a result of the pharmacological action of the drug or some other unrelated effect. Drug-induced fever is most commonly the result of a hypersensitivity reaction and its characteristics resemble those of an allergic reaction. The fever most commonly occurs after 7 to 10 days of drug administration, persists as long as the drug is continued, disappears soon after stopping the drug, and will rapidly reappear if the drug is restarted. The agents most commonly associated with causing fever include the penicillins, cephalosporins, antituberculars, quinidine, procainamide, methyldopa, and phenytoin.

PMID 3522163  Drug Intell Clin Pharm. 1986 Jun;20(6):413-20.
著者: D T Durack, A C Street
雑誌名: Curr Clin Top Infect Dis. 1991;11:35-51.
Abstract/Text
PMID 1651090  Curr Clin Top Infect Dis. 1991;11:35-51.
著者: Y Iikuni, J Okada, H Kondo, S Kashiwazaki
雑誌名: Intern Med. 1994 Feb;33(2):67-73.
Abstract/Text Since its first rigid definition in 1961 by Petersdorf and Beeson, fever of unknown origin (FUO) has been a major clinical challenge. In this clinical investigation, a retrospective study was conducted on 153 patients meeting the classic criteria of FUO. Collagen-vascular disease was found to be the most common cause of FUO, a change since our last study conducted from 1971 to 1982, replacing infection as the most common disease category of FUO. FUO in elderly patients was also analyzed. By comparing previously documented studies, we observed a new variation in the diseases that are possible causes of FUO. This report will define the present status of FUO in Japan, as well as a comparison with our previous study and other documented studies to determine the shift in the spectrum of diseases causing FUO.

PMID 8019044  Intern Med. 1994 Feb;33(2):67-73.
著者: P H Kazanjian
雑誌名: Clin Infect Dis. 1992 Dec;15(6):968-73.
Abstract/Text This study describes the clinical features of fever of unknown origin (FUO) in 86 patients in a community setting from 1984 to 1990. Infectious diseases remain the most common category of illnesses causing FUO; in this study, infectious diseases including recently described diseases--such as AIDS (three cases) and Lyme disease (one case)--caused FUO in 28 patients. Although percutaneous computed tomography-guided procedures were useful for obtaining diagnostic specimens (15 cases), a noninvasive approach established the diagnosis in many instances (37 cases). In all but nine cases, diagnostic testing was guided by abnormalities detected during the physical examination or routine laboratory tests.

PMID 1457669  Clin Infect Dis. 1992 Dec;15(6):968-73.
著者: Manuel Unger, Georgios Karanikas, Andreas Kerschbaumer, Stefan Winkler, Daniel Aletaha
雑誌名: Wien Klin Wochenschr. 2016 Nov;128(21-22):796-801. doi: 10.1007/s00508-016-1083-9. Epub 2016 Sep 26.
Abstract/Text Fever of unknown origin (FUO) was originally characterised in 1961 by Petersdorf and Beeson as a disease condition of temperature exceeding 38.3 °C on at least three occasions over a period of at least three weeks, with no diagnosis made despite one week of inpatient investigation. However, since underlying diseases are often reported for classical FUO, these presentations may not be considered to be of "unknown origin". Rather, the aetiology of prolonged fever may resolve, or not resolve. The definition of fever with unresolved cause (true FUO) is difficult, as it is a moving target, given the constant advancement of imaging and biomarker analysis. Therefore, the prevalence of fever with unresolved cause (FUO) is unknown.In this review, we report such a case of prolonged fever, which initially has presented as classical FUO, and discuss current literature. Furthermore, we will give an outlook, how a prospective study on FUO will allow to solve outstanding issues like the utility of different diagnostic investigations, and the types and prevalence of various underlying diseases.

PMID 27670857  Wien Klin Wochenschr. 2016 Nov;128(21-22):796-801. doi:・・・
著者: E M de Kleijn, J P Vandenbroucke, J W van der Meer
雑誌名: Medicine (Baltimore). 1997 Nov;76(6):392-400.
Abstract/Text Internal medicine wards in all 8 university hospitals in the Netherlands participated in this prospective study of fever of unknown origin (FUO) from January 1992 until January 1994 in order to update information on the spectrum of diseases causing FUO. We used fixed epidemiologic entry criteria to achieve completeness of enrollment and to avoid unintended selection bias. After entry, immunocompetent patients were included using criteria for FUO according to Petersdorf and Beeson (30). A standardized diagnostic protocol was used, and potentially diagnostic clues (PDCs) and their use in the diagnostic process were prospectively registered. Thus, the criteria of classic FUO have been adjusted to modern times: immunocompromised patients are excluded, and the time-criterion "1 week in hospital without a diagnosis" has been replaced by a quality-criterion stating that certain investigations must be performed as a minimum, and PDCs must be followed adequately for at least 1 week, without a diagnosis being reached. A total of 167 immunocompetent patients with FUO were thus retrieved, of whom 43 (25.7%) had infections, 21 (12.6%) had neoplasms, and 40 (24.0%) had noninfectious inflammatory diseases. No diagnosis was made in 50 patients (29.9%), 37 of whom recovered spontaneously. This study confirms the changing spectrum of diseases causing FUO. Indeed, as shown by another recent study, the group of patients with FUO in whom no diagnosis can be made is expanding, and mostly it concerns self-limiting or benign fevers. Others have suggested that this trend is not really occurring (29). We did not place patients with diseases of unknown origin in the "nondiagnosis" group, and indeed made presumptive diagnoses when necessary. Nevertheless, this category of undiagnosed fevers is increasing. We believe that the higher percentage of undiagnosed cases can be attributed to the greater use of advanced diagnostic techniques attendant on an increased number of self-limited illnesses in patients meeting criteria for FUO. Because of ongoing development in diagnostic techniques and the prospective influence on the spectrum of diseases causing FUO, studies should be performed regularly to update information on this subject. Because the number of outpatient evaluations for FUO is expected to increase, patients seen on an outpatient basis should be included in future studies. To avoid unwanted selection bias, fixed epidemiologic entry criteria should be used to ensure completeness of enrollment. To shorten the period of collecting data, multicentric studies can be done using standardized diagnostic protocols. In patients with recurrent fever or fever lasting longer than 6 months, the chance of reaching a diagnosis is significantly lower, and especially in this group one should exercise the greatest caution to avoid abundant and extensive diagnostic procedures. The diagnostic process in patients with FUO remains an intriguing problem in medicine. Recent microbiologic techniques may be useful as an approach to the relatively large proportion of patients in whom we now fail to make a diagnosis.

PMID 9413425  Medicine (Baltimore). 1997 Nov;76(6):392-400.
著者: Steven Vanderschueren, Daniel Knockaert, Tom Adriaenssens, Wim Demey, Anne Durnez, Daniël Blockmans, Herman Bobbaers
雑誌名: Arch Intern Med. 2003 May 12;163(9):1033-41. doi: 10.1001/archinte.163.9.1033.
Abstract/Text BACKGROUND: Epidemiological changes and the ongoing expansion of the diagnostic armamentarium warrant a regular update of the spectrum of diseases that present as prolonged febrile illnesses.
METHODS: We prospectively collected a series of 290 immunocompetent patients referred to our university hospital between 1990 and 1999 with a febrile illness (temperature >38.3 degrees C) of uncertain cause, lasting at least 3 weeks. Patients were categorized in 4 groups according to the timing of diagnosis: early diagnosis (within 3 in-hospital days or 3 outpatient visits), intermediate diagnosis (between days 4 and 7), late diagnosis (after day 7), and no diagnosis during index contact or follow-up.
RESULTS: A final diagnosis was established early in 67 patients (23.1%), intermediate in 38 (13.1%), and late in 87 (30.0%). In the remaining 98 (33.8%), no diagnosis was made. The cause of the fever remained obscure in 50 (47.6%) of 105 patients with episodic fever vs 48 (25.9%) of 185 patients with continuous fever (P<.001). Among the 192 patients with a final diagnosis, noninfectious inflammatory diseases represented the most prevalent diagnostic category (35.4%), surpassing infections (29.7%), miscellaneous causes (19.8%), and malignancies (15.1%). Fourteen disorders accounted for over 59% of diagnoses, whether diagnosis was reached early, intermediate, or late. Hematological malignancies made up 11.5% of diagnoses, but were responsible for 14 (58.3%) of the 24 fatalities related to the febrile illness. Of the 80 patients discharged alive without diagnosis and for whom follow-up was available, 3 died, but the deaths were considered to be unrelated to the feverish illness.
CONCLUSIONS: Prolonged febrile illnesses remain a diagnostic challenge. Despite the technological progress of the late 20th century, the origin of the fever remains elusive in many patients, especially in those with episodic fevers. Noninfectious inflammatory diseases emerge as the most prevalent diagnostic category.

PMID 12742800  Arch Intern Med. 2003 May 12;163(9):1033-41. doi: 10.10・・・
著者: Harold W Horowitz
雑誌名: N Engl J Med. 2013 Jan 17;368(3):197-9. doi: 10.1056/NEJMp1212725.
Abstract/Text
PMID 23323894  N Engl J Med. 2013 Jan 17;368(3):197-9. doi: 10.1056/NE・・・
著者: Toshio Naito, Masafumi Mizooka, Fujiko Mitsumoto, Kenji Kanazawa, Keito Torikai, Shiro Ohno, Hiroyuki Morita, Akira Ukimura, Nobuhiko Mishima, Fumio Otsuka, Yoshio Ohyama, Noriko Nara, Kazunari Murakami, Kouichi Mashiba, Kenichiro Akazawa, Koji Yamamoto, Shoichi Senda, Masashi Yamanouchi, Susumu Tazuma, Jun Hayashi
雑誌名: BMJ Open. 2013 Dec 20;3(12):e003971. doi: 10.1136/bmjopen-2013-003971. Epub 2013 Dec 20.
Abstract/Text OBJECTIVE: Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO.
DESIGN: A nationwide retrospective study.
SETTING: 17 hospitals affiliated with the Japanese Society of Hospital General Medicine.
PARTICIPANTS: This study included patients ≥18 years diagnosed with 'classical fever of unknown origin' (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011.
RESULTS: A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19-94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients.
CONCLUSIONS: With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO.

PMID 24362014  BMJ Open. 2013 Dec 20;3(12):e003971. doi: 10.1136/bmjop・・・
著者: Toshio Naito, Mika Tanei, Nobuhiro Ikeda, Toshihiro Ishii, Tomio Suzuki, Hiroyuki Morita, Sho Yamasaki, Jun'ichi Tamura, Kenichiro Akazawa, Koji Yamamoto, Hiroshi Otani, Satoshi Suzuki, Motoo Kikuchi, Shiro Ono, Hiroyuki Kobayashi, Hozuka Akita, Susumu Tazuma, Jun Hayashi
雑誌名: BMJ Open. 2019 Nov 19;9(11):e032059. doi: 10.1136/bmjopen-2019-032059. Epub 2019 Nov 19.
Abstract/Text OBJECTIVE: To identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients.
DESIGN: Multicentre prospective study.
SETTING: Sixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan.
PARTICIPANTS: Patient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017.
INTERVENTION: Japanese standard diagnostic examinations.
OUTCOME MEASURES: Data collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive (CRP) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis.
RESULTS: The most frequent age group was 65-79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in CRP level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified.
CONCLUSIONS: Age may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 31748308  BMJ Open. 2019 Nov 19;9(11):e032059. doi: 10.1136/bmjop・・・
著者: Masashi Yamanouchi, Yuki Uehara, Hirohide Yokokawa, Tomohiro Hosoda, Yukiko Watanabe, Takayoshi Shiga, Akihiro Inui, Yukiko Otsuki, Kazutoshi Fujibayashi, Hiroshi Isonuma, Toshio Naito
雑誌名: Intern Med. 2014;53(21):2471-5. Epub 2014 Nov 1.
Abstract/Text OBJECTIVE: The causes of fever of unknown origin (FUO) vary depending on the region and time period. We herein present a study of patients with classic FUO where we investigated differences based on patient background factors, such as age and causative diseases, and changes that have occurred over time.
METHODS: We extracted and analyzed data from the medical records of 256 patients ≥18 years old who met the criteria for classic FUO and were hospitalized between August, 1994 and December, 2012.
RESULTS: The median age of the patients was 55 years (range: 18-94 years). The cause of FUO was infection in 27.7% of the patients (n=71), non-infectious inflammatory disease (NIID) in 18.4% (47), malignancy in 10.2% (26), other in 14.8% (38), and unknown in 28.9% (74). The most common single cause was human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (n=17). NIID and malignancy were more common in patients ≥65 years old than in patients <65 years old. During 2004-2012, compared to 1994-2003, infections and "other" causes were decreased, whereas NIID, malignancy, and unknown causes were increased.
CONCLUSION: FUO associated with HIV/AIDS is increasing in Japan. In addition, as in previous studies in Japan and overseas, our study showed that the number of patients in whom the cause of FUO remains unknown is increasing and exceeds 20% of all cases. The present study identified diseases that should be considered in the differential diagnosis of FUO, providing useful information for the future diagnosis and treatment of FUO.

PMID 25366005  Intern Med. 2014;53(21):2471-5. Epub 2014 Nov 1.
著者: D C Knockaert, K S Dujardin, H J Bobbaers
雑誌名: Arch Intern Med. 1996 Mar 25;156(6):618-20.
Abstract/Text BACKGROUND: A casual diagnosis cannot be established in 10% to 25% of the patients who are studied for fever of unknown origin (FUO). The long-term clinical outcome of these patients cannot be inferred from the literature. This study describes the results of a 5-year follow-up of 61 patients studied for FUO and discharged from the hospital with no causal diagnosis being established.
METHODS: Patients meeting the classic criteria for FUO who were studied in the 1980s and discharged from the hospital without a casual diagnosis were followed up for at least 5 years or until death. Follow-up was performed by review of the patients' medical records or by consulting the treating physician and occasionally the patients themselves. The final diagnosis, clinical course (resolution of the fever and required treatments), and morality rate were studied.
RESULTS: Of a cohort of 199 patients with FUO, 61 individuals (30%) were discharged from the hospital without a final diagnosis being established. A definite diagnosis could be established in 12 cases, mostly (eight of 12) within 2 months after discharge. Thirty-one individuals became symptom free during hospitalization or shortly following discharge. Eighteen patients had persisting or recurring fever for several months or even years after discharge, but 10 of them were considered to be finally cured. Four patients were treated with corticosteroids and six patients required intermittent therapy with nonsteroidal anti-inflammatory agents. Six patients died, but the cause of death was considered to be related to the disease that caused FUO in only two cases.
CONCLUSION: No single disease, particularly not tuberculosis, was found to be a cause of undiagnosed FUO. Most cases resolved spontaneously, and corticosteroids were seldom required. Most symptomatic patients could be treated with nonsteroidal anti-inflammatory drugs. The mortality rate in patients with undiagnosed FUO who were followed up for 5 years or more was only 3.2%.

PMID 8629872  Arch Intern Med. 1996 Mar 25;156(6):618-20.
著者: Thierry Zenone
雑誌名: Scand J Infect Dis. 2006;38(8):632-8. doi: 10.1080/00365540600606564.
Abstract/Text The spectrum of diseases found in series of fever of unknown origin shows variation in relation to selection bias; particularly, selection of the most difficult cases in tertiary reference university centres. We present a series of 144 patients presenting to a non-university hospital between 1999 and 2005 (secondary level of the health care system) with a community-acquired fever of unknown origin. In 37 cases (25.7%), the reason for fever could not be explained. Among the 107 patients with a final diagnosis (74.3%), non-infectious inflammatory disorders represented the most prevalent category (35.5%), surpassing infections (30.8%), miscellaneous causes (20.6%) and malignancies (13.5%). 13 entities accounted for over 68% of diagnoses (sinusitis and occult dental infections, Q fever, Epstein-Barr virus and cytomegalovirus infections, lymphoma, colo-rectal adenocarcinoma, adult-onset Still disease, systemic lupus erythematosus, giant cell arteritis and/or polymyalgia rheumatica, rheumatoid arthritis, polyarteritis nodosa, factitious fever and habitual hyperthermia). As demonstrated in other studies, non-infectious inflammatory diseases emerge as the most prevalent diagnostic category. Giant cell arteritis and polymyalgia rheumatica were particularly frequent in the elderly. Epstein-Barr virus and cytomegalovirus infections and habitual hyperthermia were particularly frequent in the youngest patients. There were no major differences in repartition of diagnostic categories between this series and historical university series.

PMID 16857607  Scand J Infect Dis. 2006;38(8):632-8. doi: 10.1080/0036・・・
著者: D C Knockaert, L J Vanneste, H J Bobbaers
雑誌名: J Am Geriatr Soc. 1993 Nov;41(11):1187-92.
Abstract/Text OBJECTIVE: To describe the spectrum of diseases that may give rise to fever of unknown origin in elderly patients and to delineate the diagnostic approach in these patients.
DESIGN: Subgroup analysis of a prospectively collected case series followed more than 2 years.
SETTING: General Internal Medicine Service based at University hospital, Leuven, Belgium.
PATIENTS: Forty-seven consecutive patients, older than 65 years, meeting the classic criteria of fever of unknown origin.
MEASUREMENTS: The final diagnosis established and the clinical value of diagnostic procedures.
RESULTS: Infections, tumors and multisystem diseases (encompassing rheumatic diseases, connective tissue disorders, vasculitis including temporal arteritis, polymyalgia rheumatica, and sarcoidosis) were found in 12 (25%), six (12%) and 15 patients (31%), respectively. Drug-related fever was the cause in three patients (6%), miscellaneous conditions were found in five patients (10%), and six patients (12%) remained undiagnosed. Microbiologic investigations were diagnostic in eight cases (16%), serologic tests yielded one diagnosis, immunologic investigations had a diagnostic value in four cases, standard X-rays yielded a diagnostic contribution in 10 cases, ultrasonography and computed tomography were diagnostic in 11 cases, Gallium scintigraphy had a diagnostic contribution in 17 cases, and biopsies yielded the final diagnosis in 18 cases.
CONCLUSIONS: Multisystem diseases emerged as the most frequent cause of fever of unknown origin in the elderly, and temporal arteritis was the most frequent specific diagnosis. Infections, particularly tuberculosis, remain an important group. The percentage of tumors was higher in our elderly patients than in the younger ones but still clearly lower than in other recent series of FUO in adults. The number of undiagnosed cases was significantly lower in elderly patients than in younger individuals (P < or = 0.01). The investigation of elderly patients with FUO should encompass routine temporal artery biopsy and extensive search for tuberculosis if the classic tests such as blood count, chemistry, urinalysis, cultures, chest X-rays, and abdominal ultrasonography do not yield any clue. Gallium scintigraphy should be considered as the next step and not as a last-resort procedure.

PMID 8227892  J Am Geriatr Soc. 1993 Nov;41(11):1187-92.
著者: Verena Schönau, Kristin Vogel, Matthias Englbrecht, Jochen Wacker, Daniela Schmidt, Bernhard Manger, Torsten Kuwert, Georg Schett
雑誌名: Ann Rheum Dis. 2018 Jan;77(1):70-77. doi: 10.1136/annrheumdis-2017-211687. Epub 2017 Sep 19.
Abstract/Text BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET).
METHODS: Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT.
RESULTS: 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001).
CONCLUSION: 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28928271  Ann Rheum Dis. 2018 Jan;77(1):70-77. doi: 10.1136/annrh・・・
著者: Arnaud Hot, Isabelle Jaisson, Charlotte Girard, Martine French, Denis Vital Durand, Hugues Rousset, Jacques Ninet
雑誌名: Arch Intern Med. 2009 Nov 23;169(21):2018-23. doi: 10.1001/archinternmed.2009.401.
Abstract/Text BACKGROUND: Fever of unknown origin (FUO) still remains a diagnostic challenge, while diagnosis may remain obscure for several weeks or months. The role of tissue biopsy is crucial in the diagnostic approach. We report a series of 130 consecutive patients with FUO who had undergone a bone marrow biopsy (BMB).
METHODS: Among 280 consecutive nonimmunocompromised patients hospitalized between 1995 and 2005 for a febrile illness of uncertain cause, lasting at least 3 weeks, with no diagnosis after an appropriate minimal diagnostic workup, 130 underwent BMB.
RESULTS: Overall, a specific diagnosis was achieved by BMB and histological examination in 31 cases (diagnostic yield, 23.7%). Three types of diseases were found: hematological malignant diseases in 25 cases, including 19 patients with malignant lymphoma, 4 with acute leukemia, 1 with hairy cell leukemia, and 1 with multiple myeloma; infectious diseases in 3 cases; systemic mastocytosis in 2 cases; and disseminated granulomatosis in 1 case. Thrombocytopenia (odds ratio, 4.9; 95% confidence interval, 1.04-9.30) and anemia (odds ratio, 3.24; 95% CI, 1.13-9.34) were the most reliable predictive factors regarding the usefulness of BMB. Bone marrow cultures had very limited value in our cohort. Finally, corticosteroid use did not seem to affect the yield of BMB.
CONCLUSIONS: Bone marrow biopsy is a useful technique for the diagnosis of prolonged fever in immunocompetent patients. Thrombocytopenia and anemia seem to be correlated with the value of this test.

PMID 19933965  Arch Intern Med. 2009 Nov 23;169(21):2018-23. doi: 10.1・・・
著者: J Roberts, W Barnes, M Pennock, G Browne
雑誌名: Heart Lung. 1988 Mar;17(2):166-70.
Abstract/Text Various prevalence rates have been estimated for pulmonary complications after abdominal surgery, and fever has been thought to be a diagnostic indicator. This study quantifies the diagnostic accuracy of fever as a measure of postoperative pulmonary complications and includes the sensitivity, specificity, and positive and negative predictive values. Assessments using fever and chest x-ray film were determined for 270 patients after elective intra-abdominal surgery in three hospitals with six practicing surgeons in a Southern Ontario city. With use of reliable chest x-ray reports indicating lung pathologic findings as positive for pulmonary complication, the prevalence of a positive finding was 57%. The prevalence of a fever (temperature greater than or equal to 38 degrees C) was 40%. The sensitivity and negative predictive value of fever were slightly below 50%, and the specificity and positive predictive value of fever was 68% and 66% respectively. Fever was an accurate indicator of x-ray evidence of atelectasis in only 56% of the subjects. Therefore, neither the presence nor the absence of fever can assure clinicians of the presence or absence of a postoperative pathologic pulmonary complication such as atelectasis.

PMID 3350683  Heart Lung. 1988 Mar;17(2):166-70.
著者: M Engoren
雑誌名: Chest. 1995 Jan;107(1):81-4.
Abstract/Text Postoperative fever occurs in many patients. If no infection is found, atelectasis, if present, may be blamed. This study of 100 postoperative cardiac surgery patients followed up from day of surgery through the second postoperative day with daily portable chest radiographs and continuous bladder thermometry was designed to look for an association between atelectasis and fever. The daily incidence of atelectasis increased from 43 to 69 to 79%. However, the incidence of fever, defined as temperature > or = 38.0 degrees C fell from 37 to 21 to 17%. When defined as temperature > or = 38.5 degrees C, the daily incidence of fever fell daily from 14 to 3 to 1%. Using chi 2 analysis, no association could be found between fever and amount of atelectasis. This contradicts common textbook dogma but agrees with previous human study and animal experiments.

PMID 7813318  Chest. 1995 Jan;107(1):81-4.
著者: F Pien, P W Ho, D J Fergusson
雑誌名: Ann Thorac Surg. 1982 Apr;33(4):382-4.
Abstract/Text The occurrence of fever (daily maximal temperature greater than or equal to 38 degrees C) was analyzed in 123 patients after open-heart operation. A statistical difference was found in the incidence of fever after the third postoperative day between patients without infection and patients with bacteremia, wound infection, or pneumonia. Fever after the third day should prompt a diligent search for deep-seated infection.

PMID 7073382  Ann Thorac Surg. 1982 Apr;33(4):382-4.
著者: A P Wilson, T Treasure, R N Grüneberg, M F Sturridge, J Burridge
雑誌名: J Thorac Cardiovasc Surg. 1988 Oct;96(4):518-23.
Abstract/Text The body temperature is measured routinely and carefully charted in our own and presumably all units. Pyrexia is normal after bypass and is discounted on the basis of clinical experience in the first few days. If this pyrexia persists, a search for infection may be instigated and discharge from the hospital may be delayed. A clinical trial of antibiotic prophylaxis provided the opportunity to collect and collate 6-hourly temperature observations for 314 patients for 1 week after operation. The length of bypass and the presence of lower respiratory tract infection were positively correlated with the duration of postoperative fever. However, neither surgical sepsis nor urinary tract infection had any consistent effect on the duration or magnitude of postoperative fever in the first week.

PMID 3050285  J Thorac Cardiovasc Surg. 1988 Oct;96(4):518-23.

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