布氏杆菌病布氏杆菌病,也叫班氏病(牛传染性流产),克里米亚发热,直布罗陀发热,马耳他热,马耳他发热,地中海热,岩石热,或波状热,是一种烈性人畜共患传染病,因食入未经消毒的、受感染动物的奶、肉或密切接触
尿道感染尿道感染(UTI)是一种影响部分泌尿道的细菌感染。当它影响下尿道,便是大家知道的简单的膀胱炎(膀胱感染),当它影响到上尿道,这就是所谓的肾盂肾炎(肾脏感染) 。下尿道感染的症状包括排尿疼痛,以及单有或兼有尿频或尿冲动。肾盂肾炎的症状,除了下尿道感染的症状外,还有发烧,胁痛(身体侧面)。在老年人和很年轻者,症状可能是模糊的、非特异性的。这两种类型的主要病原体是大肠杆菌,而其他细菌、病毒或真菌可能鲜为原因。尿道感染,女性比男性更常发生,女性中有半数,在她们一生中的某个时候有过至少一次尿道感染。复发是常见的。风险因素包括女性解剖、性交及家族病史。肾盂肾炎,如果发生,也常常是紧随膀胱感染,但也可能源于感染血行播散。在年轻健康的女性,仅单凭症状即可诊断。症状不明确的患者,诊断可能是困难的,因为细菌可能存在而没有感染。在复杂病例或治疗失败情况下,尿培养可能是有用的。在频繁感染患者中,低剂量的抗生素可能会被作为一种预防性措施。在无并发症病例,尿道感染很容易以短程抗生素治疗,虽然用于治疗这种疾病的抗生素的抗药性不断增加。在复杂病例,可能需要较长疗程或静脉注射抗生素,如果治疗后两三天症状没有改善,需要进一步的诊断测试。在女性中,尿道感染是细菌感染最常见的形式,每年10%的细菌感染是尿道感染。征象下尿道感染也被称为膀胱感染。最常见的症状是排尿烧灼感,无阴道分泌物时小便频繁(或小便冲动)和显著疼痛。这些症状可能会有从轻微到严重的变化,在健康女性,平均持续6天。可能有一些在耻骨上方或背部下面的疼痛。上尿路感染或肾盂肾炎的患者,除下尿路感染的典型症状外,可能会有胁痛(身体两侧),发热,恶心和呕吐。很少有血尿或脓尿(尿液有脓汁)。儿童在儿童中,发烧可能是尿道感染(UTI)唯一的症状。由于缺乏较明显的症状,当两岁以下的女孩或未受割礼的男孩(6~12岁),不到一年就出现一次发烧,许多医学会推荐尿培养。婴儿可能饮食不佳,呕吐,多睡,或显示黄疸迹象。在年龄较大的儿童,可能会出现新发的尿失禁(膀胱控制丧失)。老年人老年人中往往缺乏尿路症状。表现可能含糊不清,如小便失禁,精神状态的变化,或者唯一症状就是疲劳。然而也可看到以败血症、血液感染,为首发症状。诊断可能是复杂的,加上很多老人先前就有尿失禁或老年痴呆症。起因大肠杆菌是80-85%尿道感染的原因,腐生葡萄球菌为原因的占5%至10%。他们可能很少是由于病毒或真菌感染引起。其他细菌的感染包括:克雷伯氏菌属,变形杆菌属,假单胞菌属和肠杆菌属。这些是不常见的,通常与泌尿系统异常或尿道导管插入术有关。由金黄色葡萄球菌引起的尿道感染,常继发于血液感染。性别在性活跃的年轻女性中,性活动是75%-90%的膀胱感染的原因,感染风险与性生活的频率相关。“蜜月膀胱炎”一词已被应用到早婚期频繁尿道感染这种现象。在绝经后的妇女,性活动不会有得尿道感染的风险。不受性频率支配的杀精子剂的使用,增加了尿道感染的风险。妇女比男性更容易发生尿道感染,因为女性中,尿道要短得多且更接近肛门。女人的更年期雌激素水平下降,尿道感染的风险增加,是由于起保护作用的阴道菌群丧失。导尿管尿道导管插入术增加尿道感染的风险。菌尿(在尿液中的细菌)的风险每天在3 %至6%之间,预防性的抗生素在减少症状的感染中无效果。只有必要时导尿管的插入可以降低相关感染的风险性,使用无菌技术插入,并保持导管密闭通畅排水。其他膀胱感染的倾向会在家庭中蔓延。其他危险因素包括糖尿病,未受割礼,有巨大前列腺。 复杂的因素是相当模糊的,包括解剖学上的,功能的或代谢异常的脆弱性。复杂的尿道感染治疗是比较困难的,通常需要更进取性的评估,治疗和后续工作。儿童尿道感染与膀胱输尿管回流相关(尿液从膀胱进入输尿管或肾脏的异常运动)和便秘。脊髓损伤者尿道感染的风险增加,部分原因是由于长期使用导尿管,部分原因是排尿功能障碍,在这一人群中,这是最常见的感染原因,以及最常见的住院治疗原因。另外,使用蔓越橘及其果汁似乎对这一人群预防和治疗都无效。发病机制引起尿道感染的细菌通常经尿道进入膀胱。但是,感染也可能通过血液或淋巴发生。人们相信,细菌常常从肠道传送到尿道,女性的风险更大,由于其解剖结构。进入到膀胱后,大肠杆菌能够附着在膀胱壁上,形成生物膜,抵抗人体的免疫反应。预防许多措施(没有被证实)会影响UTI的频率,包括:使用避孕药或避孕套,性交后立即排尿,内衣的类型,在排尿或大便后的个人卫生方法,通常是洗或淋浴。还有憋尿、卫生棉条使用、灌洗,同样缺乏证据。频繁的尿道感染者使用杀精剂作为避孕方法,建议他们使用替代方法。蔓月橘(果汁或胶囊)可能会降低频繁感染的发病率,但长期耐受性是一个问题,蔓月橘引起肠胃不适发生率在30%以上,每日两次使用可能优于每日一次使用。截至2011年,阴道益生菌是否有益还需要进一步研究。没有杀精剂安全套的使用或使用避孕药片不会增加简单的尿道感染的风险。药物对于反复感染者,每天抗生素长程使用是有效的,经常使用的药物包括呋喃妥因、甲氧嘧啶/磺胺甲基异恶唑。乌洛托品(六亚甲基四胺)是另一个常用于此目的药剂,在膀胱,酸度低,该药产生甲醛,(细菌)无法抵抗。在一些情况下,感染与性交有关,之后服用抗生素可能是有用的。在绝经后的妇女,局部阴道内雌激素已被发现,可减少复发。相对于局部药膏,使用子宫压定器阴道雌激素,不是和低剂量的抗生素一样的有用。截止到2011年,许多疫苗在开发中。儿童证据表明,在儿童中,预防性抗生素不能减少尿道感染。复发性尿道感染罕是进一步肾脏问题的原因,如果没有潜在的肾脏异常,导致不到三分之一个百分点(0.33%)的成人慢性肾脏病。诊断简单的案例,仅仅基于症状而不需要进一步的实验室确认,便可诊断并给于治疗。在复杂的或有疑问的情况下,通过验尿以确认诊断也许有用,寻找尿亚硝酸盐,白血细胞(白血球) ,或白细胞酯酶的存在。另一个试验中,尿显微镜,看红血细胞,白血细胞,或细菌的存在。尿培养,如果它示出菌落计数大于或等于103/ml活菌计数的典型尿道感染微生物,即被视为阳性。抗生素的敏感性以这些培养也可以进行测试,用于选择抗生素治疗。然而,细菌培养阴性的妇女经抗生素治疗仍可好转。在老年人中,由于症状可能是模糊的,以及对尿道感染没有可靠的测试,诊断可能是困难的。分类尿道感染可能只涉及下泌尿道,这种情况下被称为膀胱感染。或者,它可能涉及上尿道,称为肾盂肾炎。如果尿液中含有意义的细菌,但没有任何症状,称为无症状性菌尿。如果是尿道感染包括上尿道,是糖尿病的人,或者孕妇,或是男性,或免疫功能低下者,则被认为是复杂的。否则,如果女性为健康者、绝经期前,就被认为是非复杂的。在孩子中,当尿道感染与发烧关联,则被视为是上尿道感染。儿童为了诊断儿童尿道感染,积极尿培养是必需的。污染造成频繁的挑战,这取决于所用的尿液收集方法,因而105CFU/mL 为准用于净集中段尿样品, 104 CFU / mL用于导尿管得到的样品,和102CFU / ML是用于耻骨上经膀胱穿刺样品(直接用针从膀胱抽吸的样本) 。世界卫生组织不提倡尿培养使用“尿袋”收集样本,因为污染率很高,导尿首选于没有如厕训练者。有些人,如美国儿科学会建议肾脏超声检查和排尿性尿道膀胱摄影(看一个人排尿时的尿道和膀胱的实时X射线)用于所有小于2岁的有尿道感染儿童。然而,即使发现了问题,也缺乏有效的治疗方法,所以其他人,如英国国立临床疗效研究所建议在不到6个月大的或有异常结果者中常规成像检查。鉴别诊断在女性宫颈炎(宫颈炎症)或阴道炎(阴道炎症)和有尿道感染的症状的年轻男性中,沙眼衣原体或淋病奈瑟氏淋病感染可能是病因。阴道炎也可能是由于酵母菌感染,间质性膀胱炎(膀胱慢性疼痛)被认为是经历多次泌尿道感染症状的发作,但尿液细菌培养阴性,用抗生素不能改善者原因。前列腺炎(前列腺发炎)在鉴别诊断中也应考虑到。治疗治疗的主要支柱是抗生素。在最初的几天,除了抗生素外,偶尔处方会开出非那吡啶,以帮助膀胱感染患者有时的烧灼感和急迫感。然而该药不常规推荐使用,因为其使用存在安全问题。尤其高铁血红蛋白血症(血液中的高铁血红蛋白高于正常水平)风险很高。对乙酰氨基酚(扑热息痛)可用于发热。复发性单纯尿路感染的妇女,只有在初始治疗失败,当症状发生、医疗跟进时,可能会受益于自我治疗。可以将抗生素处方电话交付给药剂师取药。不复杂的非复杂性感染仅凭症状即可诊断和治疗。口服抗生素如甲氧苄啶/磺胺甲恶唑( TMP / SMX),头孢菌素类,呋喃妥因,或氟喹诺酮类,同样有效,大大缩短恢复的时间。为期三天的治疗,甲氧苄啶, TMP / SMX,或氟喹诺酮类药物,通常是足够的,而呋喃妥因需要5-7天。经过治疗,症状应在36小时内改善,大约50%的人都会痊愈,而不需要数天或数周治疗。美国感染病学会不建议氟喹诺酮类药物作为第一治疗药物,是由于对本类药物产生耐药的关注。尽管有此预防措施,但由于广泛使用这些药物,一些耐药已经发生。在一些国家,甲氧苄氨嘧啶被视为等同于TMP / SMX。简单的尿路感染,孩子往往用3天疗程的抗生素既有所反应。肾盂肾炎治疗肾盂肾炎比一个简单的膀胱感染要更积极。要么需要较长时间口服抗生素,要么静脉给药。若本地的耐药率小于10%,通常使用七天的口服氟喹诺酮类药物环丙沙星,若本地的耐药率大于10%,常予静脉注射头孢三嗪。在那些表现出更严重的症状者,必需入院做更进一步的抗生素治疗。经过两或三天的治疗,症状没有改善,可能会考虑是否有并发症,如肾结石尿路梗阻。流行病学尿路感染是妇女中最常见的细菌感染。最经常发生的年龄在16至35岁之间,10 %的妇女每年感染,60%的妇女在她们一生中的某些时候有感染。复发是常见的,初发者中将近一半的人在一年之内第二次感染。尿道感染发生率女性4倍于男性,肾盂肾炎发生率在20-30倍之间。他们是医院获得性感染最常见的原因,占约40% 。无症状性菌尿率随着年龄而增长,从育龄妇女中2%到7%,到在护理院的老年妇女中高达50%。无症状性菌尿在超过75岁男性中占7-10%。尿道感染在童年可能会影响10%人群。儿童尿道感染最常见于未受割礼的不到3个月的男孩,其次小于1岁的女孩。儿童之间的尿道感染频率估计很宽泛。在有发烧症状的儿童中,年龄从出生到两岁之间,2至20 %被诊断出患有尿道感染。社会文化在美国,办公室访问了近700万尿道感染者,一百万人急诊科就诊,并每年十万人住院治疗。在损失工作中的时间和在医疗服务的费用两方面,这些感染的成本相当大。在美国,直接治疗费用估计为每年16亿美元。历史在写就于公元前1550年的亚伯斯古医籍中,首次描述到尿道感染。它被埃及人描述为“从膀胱发出的热量”。直到在上世纪30年代,抗生素开发与运用前,没有有效的治疗。这之前,只有药材,放血和休息这样的手段。孕妇更多关注于孕妇尿道感染,是由于增加肾脏感染的危险性。在怀孕期间,孕激素水平升高使输尿管和膀胱肌张力降低的风险加大,导致回流的可能性更大,尿液流从输尿管回流到肾脏。孕妇没有无症状性菌尿增加的危险性,倘若菌尿存在,有25-40%肾脏感染的风险。 因此,如果尿液测试到感染迹象,即使是在没有症状,也要建议治疗。通常使用头孢氨苄或呋喃妥因,因为普遍被认为孕妇使用是安全的。在怀孕期间肾脏感染可能会导致早产或先兆子痫(在怀孕期间高血压,肾功能不全,可呈突发状态)。
真菌(霉菌)性肺炎真菌性肺炎即真菌所致的肺部感染。起因于地方性真菌或机会性真菌或两者兼有。免疫功能正常的患者普遍对抗真菌治疗反应良好,但在免疫功能低下的病人中,真菌性肺炎的病死率可高达90%。病因明确的带有肺部受累的真菌感染的实例:·组织胞浆菌病,原发性肺损伤和血源性传播。·球孢子菌病,通常始于自限性呼吸相关性感染(也称为“山谷热”或“圣华金热”)。·肺芽生菌病·肺囊虫肺炎,这通常发生在免疫功能低下的人,尤其是艾滋病。·孢子丝菌病 - 主要是淋巴皮肤孢子丝菌病,但也会使肺受累。·隐球菌病 - 通过吸入酵母污染的尘土感染,它可以表现为肺部感染和传播性隐球菌病。·曲霉菌病,导致侵袭性肺曲菌病·念珠菌病,很少,免疫功能低下患者中,有肺部表现。病理生理学随着真菌孢子被吸入,真菌就进入了呼吸者的肺脏。它们也可以通过其它身体部位的感染血行播散到达肺部。此外,潜伏感染的再激活也可以引起真菌性肺炎。一旦进入肺泡,真菌游荡于细胞间隙,并通过肺泡连接孔进入相邻的肺泡里。真菌的入侵触发免疫系统,发送白血细胞去攻击已到了肺部的微生物(中性白细胞)。中性粒细胞吞噬和杀死侵犯的微生物,并释放细胞因子,而细胞因子引起免疫系统的全面激活,直接导致发热,寒战和疲劳——细菌和真菌性肺炎中的普遍症状。中性粒细胞和肺泡周围血管漏出的液体弥漫肺泡,导致氧运输受损。诊断真菌性肺炎的诊断,可以通过多种方法得出。最简单和最廉价的方法是取病人的呼吸道体液培养真菌。然而这种测试不仅不敏感,而且费时——这是一个很大的弊端,因为有研究表明,真菌性肺炎的诊断延迟与高死亡率相关。显微镜是另一种方法,但慢而不精确。弥补这些经典方法的,是抗原检测。此技术极其明显快得多,但比起经典方法可能也欠缺敏感与特异。还可使用基于实时PCR技术的分子检测,它源于Myconostica。(英国著名分子诊断公司Myconostica有限公司 ——译注)。这项检测依靠DNA技术,对真菌检测最为敏感和特异,但目前仅限于检测卡氏肺囊虫和曲霉菌。真菌性肺炎在一些地方也可能会人传人,如宿舍。通过胸部X射线检查不能检测到真菌性肺炎。患者必要时需住院治疗。治疗抗真菌药物用以治疗真菌性肺炎,有时需要外科清创手术。抗真菌的药物抗真菌药物是一种药物,用于治疗真菌感染,如脚气,癣,念珠菌病(鹅口疮) ,严重的全身性感染,如隐球菌性脑膜炎和其他。这类药物通常通过医生的处方或药店得到。不良反应除了肝功能损害等副作用或影响雌激素的水平,许多人使用抗真菌药物可引起过敏反应。例如,已知的唑基药物引起过敏性反应。还有许多药物的相互作用。患者必须详细阅读药品随附的说明书。例如,唑类抗真菌药物,如酮康唑或伊曲康唑,可以是P-糖蛋白的底物和抑制剂, P-糖蛋白(其它功能之一)分泌毒素和药物进入肠道。唑类抗真菌药物也是细胞色素P450家族CYP3A4的底物和抑制剂, 用药时导致彼物质浓度增加,例如,钙通道阻滞剂,免疫抑制剂,化疗药物,苯二氮卓类药物,三环类抗抑郁药,大环内酯类与SSRIs类药物分类1、多烯类抗真菌药物多烯是具有多个共轭双键的分子。多烯类抗真菌药是大环多烯,有大量羟基化的部分,分部在共轭体系对面的环上。这使得多烯类抗真菌药物呈两性分子。在真菌的细胞膜里,多烯类抗真菌药结合甾醇类物质,主要是麦角固醇。这会改变真菌细胞膜的转变温度(Tg ),从而使得细胞膜处在较少的液体氛围,更多结晶状态。其结果是,细胞的内容物,包括一价离子(+和Na+,H+和Cl-)和小的有机分子的渗漏,这被视为细胞死亡的一个主要方式。动物细胞含有胆固醇,而不是麦角甾醇,它们不太容易受到影响。然而,一些两性霉素B,在治疗剂量,可以结合动物细胞膜胆固醇,从而增加人体毒性风险。两性霉素B 静脉给药时有肾毒性。当多烯的疏水链缩短,其与胆固醇结合活性增加。因此,疏水链的进一步减少可能导致它与胆固醇结合,对动物产生毒性。§两性霉素B§克念菌素§非律平- 35碳质物,结合胆固醇(有毒)§ 哈霉素§那他霉素 – 33碳质物,充分结合麦角甾醇§制霉菌素§(龟)裂霉素2、咪唑,三唑,噻唑抗真菌药唑类抗真菌药物抑制酶的羊毛甾醇14α-脱甲基酶,这种酶是羊毛甾醇转化为麦角固醇所必需的。唑类抗真菌药物耗竭真菌细胞膜中麦角固醇,破坏了真菌细胞膜的结构和细胞膜的多种功能,从而抑制真菌的生长。咪唑§联苯苄唑§布康唑§克霉唑§益康唑§芬替康唑§异康唑§酮康唑§霉康唑§双醚康唑§奥昔康唑§丝他康唑§硫康唑§噻康唑三唑§ 白康唑§氟康唑§ Isavuconazole(抗真菌新药——译注)§伊曲康唑§泊沙康唑§ Ravuconazole(抗真菌新药——译注)§特康唑§伏立康唑噻唑§ 艾博芬净3、烯丙胺烯丙胺抑制角鲨烯环氧酶,另一个麦角固醇合成所需的酶:§ 阿莫罗芬§布替萘芬§萘替芬§特比萘芬4、棘白菌素棘白菌素可用于免疫功能低下的病人全身性真菌感染,它们通过1,3 - β葡聚糖合酶抑制细胞壁内的葡聚糖合成:§阿尼芬净§卡泊芬净§米卡芬净棘白菌素口服吸收差。通过注射给药时,它们有足够的浓度达到大多数组织和器官,治疗局部和全身的真菌感染。5、其他§苯甲酸 - 具有抗真菌的性质,但必须结合角质层分离剂,如聚乙二醇膏。§环吡酮 - (环吡酮胺) - 是一种羟基吡啶酮的抗真菌剂,干扰膜主动运输、细胞膜的完整性和真菌呼吸过程。它对花斑癣最有用。§氟胞嘧啶或5 - 氟胞嘧啶 - 抗代谢物的嘧啶类似物。§灰黄霉素 – 结合聚合微管,抑制真菌的有丝分裂。§ 卤普罗近 -随着更多的副作用较少的现代抗真菌药物的出现而停用。 § 蓼二醛- 体外抗白色念珠菌活动强大而快效。§托萘酯 - 硫代氨基甲酸酯杀真菌剂,能抑制真菌的角鲨烯环氧酶(与烯丙胺类特比萘芬有类似的机制)。§十一碳烯酸 - 来自天然蓖麻油的不饱和脂肪酸,抑真菌,抗细菌,抗病毒,抑制假丝酵母的形态。§结晶紫 - 三芳基甲烷染料,它具有抗菌,抗真菌和驱虫的性能,是从前很重要的局部杀菌剂 。备选在1996年进行的研究表明,下列物质或香精油有抗真菌特性:§大蒜素 – 来自粉碎大蒜。§香茅油 – 取自不同品种的香茅(柠檬草)的茎和叶。§椰子油 - 油中的甘油三酯中链,具有抗真菌活性。§碘酒 – 卢戈尔碘。§柠檬香桃木§楝树种子油§橄榄叶§橙油§玫瑰草油§广藿香§硒 - 在膳食补充物或天然的食物来源中,特别是巴西坚果。§茶树油 - ISO 4730 (“互叶白千层油,松油烯-4 - 醇型” )§锌 – 在膳食补充物或天然的食物来源中,包括南瓜种子,鹰嘴豆。在2009年,特拉维夫大学植物科学系的研究人员发表的一个研究表明,食肉植物,如捕蝇草含有的化合物,可用以为人类提供一个新种类的抗真菌的药物,以应对真菌感染目前的抗药性。作用机理抗真菌药起效,是靠充分利用哺乳动物和真菌细胞之间的差异去杀死真菌,而又不能危害宿主。与细菌不同,真菌和人类是真核生物。因此,真菌和人类细胞在分子水平上是相似的。这使得找到或设计既杀死真菌而又不影响人体细胞的药物非常困难。其结果是,许多抗真菌药物产生副作用。如果不能正确使用这些药物.,这些副作用会危及生命。抗头屑洗发香波经常发现在去头屑洗发水中有抗真菌剂(如酮康唑) 。抗真菌的药物抑制了发酵的马拉色菌藻助长脂溢性皮炎和花斑癣。下面表格所述为国外商品,略去不译。References^Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E (July 2007)."Invasive aspergillosis in the intensive care unit".Clin. Infect. Dis.45(2): 205–16.doi:10.1086/518852.PMID17578780.^Bulpa P, Dive A, Sibille Y (October 2007)."Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease".Eur. Respir. J.30(4): 782–800.doi:10.1183/09031936.00062206.PMID17906086.^Morrell M, Fraser VJ, Kollef MH (September 2005)."Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality".Antimicrob. Agents Chemother.49(9): 3640–5.doi:10.1128/AAC.49.9.3640-3645.2005.PMC1195428.PMID16127033.^Denning, D (September 2008)."Webinar on fungal diagnostics"(PDF).^, Philippe Hauser, Lagrou K, Cui X, PerlinD S, Park S, Harrison E, Meerssman W, Hughes M J, Bowyer P, Denning DW, Bille J, Lass-Flor C, Maertens J. Clinical performance of FXG: RESP (Asp +) assay forAspergillusspp. andPneumocystis jiroveciion respiratory specimens. Unpublished Data.^abdoctorfungus > Antifungal Drug InteractionsContent Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010^[Baginski M, Czub B. Amphotericin B and its new derivatives. Current Drug Metabolism. 2009 Jun;10(5): 459-69]^> Sheehan D., Hitchcock C, Sibley C. Current and Emerging Azole Antifungal Agents^Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)^Wilson, Gisvold, Block, Beale (2004).Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia, Pa.: Lippincott Williams & Wilkins.ISBN0-7817-3481-9.^"antifung".Archivedfrom the original on 17 June 2008. Retrieved 2008-07-09.^accessdate = 2007-02-17 "Haloprogin".DrugBank. University of Alberta. November 6, 2006.^abMcCallion R F, Cole A L J, Walker J R L, Blunt J W, Monro M H G. (1982) Antibiotic Substances from New Zealand Plants, Planta Medica, vol 44, pp134-138^Lee S H, Lee J R, Lunde C S, Kubo I. (1999). In Vitro Antifungal Susceptibilities of Candida albicans and other Fungal Pathogens to Polygodial, a Sesquiterpene Dialdehyde, Planta Medica, vol 65, pp205-208^Docampo, R.; Moreno, S.N. (1990), "The metabolism and mode of action of gentian violet",Drug Metab. Rev.22(2–3): 161–178,doi:10.3109/03602539009041083,PMID2272286^Pattnaik S, Subramanyam VR, Kole C (1996)."Antibacterial and antifungal activity of ten essential oils in vitro".Microbios86(349): 237–46.PMID8893526.^Eilenberg, Haviva; Smadar Pnini-Cohen, Yocheved Rahamim, Edward Sionov, Esther Segal, Shmuel Carmeli and Aviah Zilberstein (December 2009)."Inducedproduction of antifungal naphthoquinones in the pitchers of the carnivorous plantNepenthes khasiana".Journal of Experimental Botany(Oxford University Press)61(3): 911–922.doi:10.1093/jxb/erp359.PMC2814117.PMID20018905.Archivedfrom the original on 12 April 2010. Retrieved 2010-04-22.^"Carnivorous plants may save people".Israel 21c Innovation News Service. April 11, 2010.Archivedfrom the original on 27 April 2010. Retrieved 2010-04-13.^"From carnivorous plants to the medicine cabinet". physorg.com. February 18, 2010. Retrieved 2010-04-13.^McGrath J, Murphy GM (1991). "The control of seborrhoeic dermatitis and dandruff by antipityrosporal drugs".Drugs41(2): 178–84.doi:10.2165/00003495-199141020-00003.PMID1709848.^Ketoconazole Shampoo: Effect of Long-Term Use in Androgenic Alopecia^Dubini F, Bellotti MG, Frangi A, Monti D, Saccomani L (2005). "In vitro antimycotic activity and nail permeation models of a piroctone olamine (octopirox) containing transungual water soluble technology".Arzneimittel-Forschung55(8): 478–83.PMID16149717.^NIVEA^Warner RR, Schwartz JR, Boissy Y, Dawson TL (2001)."Dandruff has an altered stratum corneum ultrastructure that is improved with zinc pyrithione shampoo".J. Am. Acad. Dermatol.45(6): 897–903.doi:10.1067/mjd.2001.117849.PMID11712036.^Piérard-Franchimont C, Piérard GE, Vroome V, Lin GC, Appa Y (2000). "Comparative anti-dandruff efficacy between a tar and a non-tar shampoo".Dermatology (Basel)200(2): 181–4.doi:10.1159/000018362.PMID10773717.^Prensner R (2003)."Does 5% tea tree oil shampoo reduce dandruff?".The Journal of family practice52(4): 285–6.PMID12681088.
风湿热风湿热是在化脓性链球菌感染后(诸如链球菌咽炎或猩红热)发生的一种炎症性疾病,是由抗体交叉反应引起,使心脏,关节,皮肤和大脑受累, 该病通常显现于链球菌感染后的两到三个星期。急性风湿热通常出现在6至15岁之间的儿童中,成人的初发患病率只有20%。 这种疾病之所以如此命名是因为其表现形式与风湿症相似。诊断T. Duckett Jones博士于1944年首次公开发表了修正的琼斯标准,此后美国心脏协会与其他团体合作,定期地对标准进行修订。根据经修订的Jones标准,诊断为风湿热需具备两个主要标准;或一个主要标准,加上两个次要标准;同时具备链球菌感染的表现:升高的或上升的链球菌溶血素O滴度或DNA酶。要除外舞蹈病和慢性心脏炎,这两者各自本身就可以表明风湿热。主要标准·多发性关节炎:大关节的炎症短时间迁移,通常开始于腿并向上移动。·心脏炎:心脏肌肉的炎症(心肌炎) ,它可以表现为伴有呼吸急促的充血性心脏衰竭;带有刮擦样杂音或有一个新发心脏杂音的心包炎。·皮下结节:无痛,在骨或肌腱上的聚集的胶原纤维物,紧张而固定。它们通常出现在手腕背面上,肘部外面,和膝盖前面。·边缘性红斑:一种持久的、平于皮肤的斑块样淡红色皮疹,始于躯干或手臂,向外扩散,斑块中间形成清晰的环状,继续外向展开,合并其他环斑,最终形成蛇一样的外观。这种皮疹通常不出现在脸上,并且会由于发热变得更加严重。·西登哈姆氏舞蹈病(圣维图什舞) :面部和手臂一系列特征性的快速无目的的运动。它可能发生的很晚,可能受感染侵袭至少3个月后发生。次要标准·发热38.2-38.9 °C( 101-102° F)·关节痛:关节疼痛,不肿胀(如果多发性关节炎作为主要症状出现,这一点将不被包括)·升高的红细胞沉降率或C反应蛋白·白细胞增多·心电图显示心脏传导阻滞,如PR间期延长(如果心脏炎作为主要症状出现,这一点将不被包括)·之前风湿热或风湿性心脏疾病处于非活动状态其他症状和体征·腹部疼痛·鼻出血·先前的链球菌感染:最近的猩红热,升高的抗链球菌溶血素O或其它链球菌抗体滴度,或咽拭子培养阳性病理生理学风湿热是一种全身性疾病,影响周围小动脉的结缔组织,在A组β溶血性链球菌咽部感染而未经治疗后可出现。它被认为是由抗体的交叉反应性引起的。这种交叉反应是一种II型超敏反应,称为分子拟态。通常,如果没有T细胞共刺激,自身反应性B细胞在外周无应激反应。链球菌感染期间,提供诸如B细胞这类细胞的成熟的抗原,提供细菌抗原给 CD4 + T细胞,后者分化成辅助性T2细胞。辅助性T2细胞随后激活B细胞成为浆细胞并促使针对链球菌细胞壁的抗体的产生。然而,抗体也可能对心肌和关节反应,产生风湿热的症状。A组化脓性链球菌具有支化聚合物组成的细胞壁,支化聚合物有时含有M蛋白,具有高度抗原性。免疫系统产生的应激M蛋白的抗体,会与心脏肌纤维蛋白的肌球蛋白、心脏肌糖原和动脉的平滑肌细胞交叉反应,诱导细胞因子的释放和组织破坏。然而,目前只有与血管周围的结缔组织的交叉反应得到证实。这种炎症的发生需要直接附着的补体和结晶段受体介导的中性粒细胞、巨噬细胞的补充。特征性的的阿孝夫氏小体在光学显微镜下就能看到,它由淋巴细胞和巨噬细胞包围的肿胀嗜酸性胶原组成。较大的巨噬细胞可成为阿孝夫氏巨大细胞。急性风湿性心脏瓣膜损伤可能会涉及一种细胞介导的免疫反应,这些损伤主要在辅助性T细胞和巨噬细胞。在急性风湿热,这些病变可见于心脏各层,因此被称为全心炎 。炎症可能会造成一种浆液纤维素性的心包渗出液,被描述为“面包与黄油”的心包炎,通常可以得到解决,没有后遗症。病变牵涉到心内膜会导致沿左侧的心脏瓣膜的封闭口边缘出现典型地纤维蛋白样坏死和疣状物形成。形成的沉积物量的不同,导致心内膜下可能会引起不规则的加厚的齿菌斑——麦卡勒姆斑块。慢性风湿性心脏瓣膜病的特点是反复发作的带有纤维素析像的炎症。瓣膜的主要解剖学的变化包括瓣叶增厚,合缝处的粘连融合,瓣膜腱索缩短和增厚。预防防止病情反复发作要靠通过消除急性感染和使用抗生素预防。美国心脏协会建议,每天或每月的预防,长期维持,也许终生。治疗治疗急性风湿热,就是以诸如阿司匹林或糖皮质激素类药减少炎症。链球菌培养阳性喉炎的患者还应以抗生素治疗。阿司匹林是可供选择药物,应给予高剂量为100毫克/公斤/天。患者应注意药物副作用,如胃炎和水杨酸中毒。在儿童和青少年中,使用阿司匹林和包含有阿司匹林的药品可能与Reye氏综合征有关,这是一种严重和具有潜在致命性的病症。因此,使用阿司匹林和包含有阿司匹林的药品时,风险和利益必须都要考虑到。风湿热研究表明,布洛芬针对疼痛和不适,皮质类固醇激素缓解严重的炎症反应,在儿童和青少年患者中,应予考虑。有证据显示心脏受累时,类固醇类药物使用应有保留。使用类固醇可能会阻止组织疤痕进一步的痊愈,可能会妨碍后遗症,如二尖瓣狭窄的改善。遭受过一次风湿热打击的患者,应每月注射长效青霉素,为期五年。如果有心脏炎的证据,疗程可长达40年。治疗风湿热的另一个重要基石包括持续使用低剂量的抗生素(如青霉素,磺胺嘧啶,或红霉素)来阻止复发。疫苗目前没有疫苗来防止感染化脓性链球菌,虽然一直在研究。开发一种疫苗的困难包括在环境中存在的各种化脓性链球菌的菌株,大量的时间以及需要人来试验疫苗的安全性和有效性。感染化脓性链球菌培养阳性的患者,只要青霉素不过敏,应及时予青霉素治疗。这种治疗不会改变急性疾病的过程。牛津临床医学手册表述对风湿热最适当的治疗——苄星青霉素。炎症显著症状的患者可能需要糖皮质激素。水杨酸盐对疼痛有用。心脏衰竭一些患者出现显着的心脏炎,表现为充血性心脏衰竭。这通常需要治疗心脏衰竭:血管紧张素转换酶抑制剂,利尿剂, β受体阻滞剂,地高辛。与一般心脏衰竭不同,风湿性心脏衰竭对皮质类固醇激素反应良好。流行病学风湿热在全世界很普遍,并造成心脏瓣膜受损。在西方国家, 20世纪60年代以来,它变得相当罕见,可能是由于广泛使用抗生素来治疗链球菌感染。在美国,虽然自20世纪初以来很不常见,但80年代以来有过几次爆发。虽然本病很少发生,该病是严重的,病死率为2-5%。风湿热主要影响5岁至17岁之间的青少年,约链球菌咽喉炎后20天发病。在多达三分之一的链球菌感染者可能没有引起任何症状。未经治疗的链球菌感染者约有3%发展为风湿热。复发感染而又无后续治疗者发展为风湿热者比例非常大(约50% ) 。而那些接受抗生素治疗的个体发展为风湿热比例要远低得多。患过风湿热的病人若有反复的链球菌感染,有突发加重的倾向。那些没有维持低剂量的抗生素治疗的风湿热患者,复发是相当常见的,特别是在第一次风湿热感染后的三到五年。心脏并发症可能是长期和严重的,尤其当心脏瓣膜受累时。风湿热的幸存者常常不得不用青霉素预防链球菌感染,不然,病例证明,链球菌的感染是致命的。References^ a b c Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 403-406 ISBN 978-1-4160-2973-1^ "rheumatic fever" at Dorland's Medical Dictionary^ Jones TD (1944). "The diagnosis of rheumatic fever".JAMA 126 (8): 481–4.doi:10.1001/jama.1944.02850430015005.^ Ferrieri P; Jones Criteria Working, Group (2002)."Proceedings of the Jones Criteria workshop".Circulation 106 (19): 2521–3.doi:10.1161/01.CIR.0000037745.65929.FA. PMID 12417554.^ Steven J Parrillo, DO, FACOEP, FACEP. "eMedicine — Rheumatic Fever". Retrieved 2007-07-14.^ "Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association". JAMA 268 (15): 2069–73. 1992. doi:10.1001/jama.268.15.2069.PMID 1404745.^ Saxena, Anita (2000). "Diagnosis of rheumatic fever: Current status of Jones criteria and role of echocardiography". Indian Journal of Pediatrics 67 (4): 283–6. doi:10.1007/BF02758174. PMID 11129913.^ Aly, Ashraf (2008). "Rheumatic Fever". Core Concepts of Pediatrics. University of Texas. Retrieved 2011-08-06.^ a b Ed Boon, Davidson's General Practice of Medicine, 20th edition. P. 617.^ Abbas, Abul K.; Lichtman, Andrew H.; Baker, David L.; et al (2004). Basic immunology: functions and disorders of the immune system (2 ed.). Philadelphia, Pennsylvania: Elsevier Saunders. ISBN 978-1-4160-2403-3.^ Faé KC, da Silva DD, Oshiro SE, et al. (May 2006)."Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease". J. Immunol. 176 (9): 5662–70.PMID 16622036.^ a b Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005).Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. ISBN 0-7216-0187-1.^ "Rheumatic Heart Disease/Rheumatic Fever". American Heart Association. Retrieved 2008-02-17.^ "Initiative for Vaccine Research (IVR) - Group A Streptococcus". World Health Organization. Retrieved 15 June 2012.^ "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved Nov. 11, 2009.^ NLM/NIH: Medline Plus Medical Encyclopedia: Rheumatic fever^ Porth, Carol (2007). Essentials of pathophysiology: concepts of altered health states. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7087-4.
Fever of unknown origin (FUO) 不明原因发热(英语)pyrexia of unknown origin (PUO) 不明原因发热(拉丁-希腊语)febris e causa ignota (febris E.C.I.) 不明原因发热(拉丁语)是指病人体温升高,虽经检查未能确诊的状态,即使做出诊断,也通常是一个排除性诊断,即,消除所有可能性直到仅存一种解释而得出的诊断。定义1961年Petersdorf和Beeson提出了以下标准:·体温多次高于38.3 °C (101° F)上·至少3个星期无法确诊·至少在医院1周的检查一个新的FUO定义,其中门诊病人(这反映了当前的医疗行为)更受到重视,规定:· 3次门诊随访或·3天在医院治疗没有确定病因,或·1周的“智能有创的”门诊检查后未果。目前FUO病例被分四类1、传统的FUO这是指最早由Petersdorf和Beeson提出的分类:·感染(例如脓肿,感染性心内膜炎,结核和复杂性尿路感染) ,·肿瘤(如淋巴瘤,白血病) ,·结缔组织疾病(如颞动脉炎和风湿性多肌痛, Still病,系统性红斑狼疮,类风湿关节炎) ,·杂类疾病(例如,酒精性肝炎,肉芽肿状态) ,和·未确诊状况2、医院发生的医院发生的FUO是指入院接受治疗至少24小时的患者的发热。这通常与医院相关因素有关,如手术,使用的导尿管,血管内装置(即“点滴” ,肺动脉导管) ,药物(抗生素诱发难辨梭状芽孢杆菌性结肠炎,药物热) ,固定(褥疮) 。在重症监护病房中的与鼻胃管和经口-气管管道有关的鼻窦炎,还应考虑下肢深静脉血栓性静脉炎,肺栓塞,输血反应,非结石性胆囊炎,甲状腺炎,酒精/毒品戒断,肾上腺功能不全,胰腺炎。3、免疫缺陷的免疫缺陷存在于接受化疗的患者,或患有血液系统恶性肿瘤患者。发烧常伴随嗜中性白血球减少症(中性粒细胞< 500/uL ) 或受损的细胞介导的免疫。免疫反应缺失掩盖了一个有潜在危险性的过程。感染是最常见的原因。艾滋病毒感染者是免疫缺陷FUO的一个子群,经常有发热。初期阶段,它有一种传染性单核细胞增多症样疾病,有发热表现。在晚期的感染发热大多是叠加感染的结果。 4、一些重要的原因肺外结核是不明原因发热最常见的原因。药源性高热,作为药物不良反应唯一的症状,应要考虑到。FUO还与肺结核,组织胞浆菌病,球孢子菌病,芽生菌,结节病等传播性肉芽肿病有关 。在成年人中,淋巴瘤是最常见的FUO病因。血栓栓塞性疾病(即肺栓塞,深静脉血栓形成) ,偶尔发烧。虽然不常见,但这些疾病潜在的致命性不容忽视。感染性心内膜炎,虽然罕见,确是另一个要考虑的重要病因。人为的发热是一个被低估的原因。患者经常是在医疗领域工作或工作过的妇女,有复杂的病历。诊断全面细致的病史(即家庭成员的疾病,最近访问的热带地区,药物) ,重复体检(即皮疹,焦痂,淋巴结肿大,心脏杂音) ,以及数量巨大的实验室检查(血清,血培养,免疫学)是找到病因的基本。其他检查也是必要的。超声检查可显示胆囊结石,超声心动图,用以诊断感染性心内膜炎,CT扫描可显示内脏器官的感染或恶性肿瘤。另一种技术是核医镓67扫描,这似乎对可视化慢性感染更有效。明确诊断可能还需要有创技术(活检和开腹手术的病理学和细菌学检查)。有报告,使用放射性标记的氟脱氧葡萄糖(FDG)正电子发射断层扫描来锁定不明发热的源头,敏感性84%,特异性为86%。尽管有这一切,诊断也往往被治疗结果所提示。病人在停止用药后恢复,那可能是药物热,抗生素或抗真菌药起效时,那可能是感染。其他的检查技术都无法确诊时,可用经验性治疗尝试。治疗除非患者是急重病,确诊前不应治疗。因为非针对性治疗很少是有效的,大多还会延误诊断。一个例外是中性粒细胞减少患者,延迟治疗可能会导致严重的并发症。采血培养后,立刻用强力广谱抗生素积极治疗,后依血培养结果调整抗生素。艾滋病病毒感染者带有发热和缺氧时,将启动针对可能感染卡氏肺囊虫的药物治疗。 诊断一经判定,治疗紧随变动。预后因为与FUO相关的条件宽泛,预后取决于特定的病因。如果6个月至12个月后仍无诊断,那么诊断将会越来越难以明确。然而这种情形下,预后是良好的。Reference1. Mandell's Principles and Practices of Infection Diseases 6th Edition by Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin MD, ISBN 0-443-06643-4 · Hardback · 4016 Pages Churchill Livingstone2. Harrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Companies, ISBN 0-07-140235-73. The Oxford Textbook of Medicine Edited by David A. Warrell, Timothy M. Cox and John D. Firth with Edward J. Benz, Fourth Edition , Oxford University Press, ISBN 0-19-262922-04. Cecil Textbook of Medicine by Lee Goldman, Dennis Ausiello, 22nd Edition , W.B. Saunders Company, ISBN 0-7216-9652-X5. Irwin and Rippe's Intensive Care Medicine by Irwin and Rippe, Fifth Edition , Lippincott Williams & Wilkins, ISBN 0-7817-3548-36. Fever of Unknown Origin at Mount Sinai Hospital7. Meller J, Altenvoerde G, Munzel U, Jauho A, Behe M, Gratz S, Luig H, Becker W . "Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET.". Eur J Nucl Med. 27 (11): 1617–25. doi:10.1007/s002590000341. PMID 11105817.
干扰素治疗慢性乙型肝炎的作用机制干扰素是人体受到病毒感染时产生的一种多功能蛋白质(生物学上叫细胞因子)。我们都得过流行性感冒,当你发热、全身肌肉、关节酸痛、全身无力时,你就感受到了干扰素的存在。当然也还有其它细胞因子的参与,但干扰素是病毒感染时产生的最主要的细胞因子之一。如果您曾经注射过干扰素,医生会告诉你打干扰素后会出现“流感样症状”,这是因为流感时的症状其实也是干扰素引起的。 干扰素是个多功能的蛋白质,属于人体天然免疫的重要组成部分。总的来说,干扰素具有以下几个重要作用:1、抗病毒作用。当我们的机体感染病毒时,体内会产生大量的干扰素。2、抗增生作用。这是干扰素能用于治疗多种肿瘤的原因。3、免疫调节作用。干扰素是天然免疫的一部分,但干扰素也参与多种特异性的细胞免疫,如增强感染的肝细胞表达被T淋巴细胞识别的蛋白质,帮助T细胞识别病毒感染的细胞等。4、抗纤维化作用。这是为什么干扰素治疗的病人肝纤维化会明显好转。 此外,干扰素还有抗新血管增生、促进细胞凋亡等多种功能。但在治疗慢性乙肝方面,抗病毒作用和免疫调节作用,以及抗纤维化作用可能是主要的。 那干扰素是怎样起作用的呢?干扰素需要“攻破肝细胞膜吗”? 干扰素根本不需要攻破肝细胞,干扰素必须通过与细胞表面的干扰素受体结合才能发挥其生物学作用。 干扰素有抗病毒、免疫调节、抗纤维化作用,但这些作用的实现并不是靠干扰素本身直接作用实现的,而是通过与细胞表面的受体结合,把“信号”从细胞表面传入细胞核,在那里激活一系列基因,表达出发挥干扰素作用的一系列蛋白质,干扰素激活产生的这些蛋白质来完成干扰素的功能。 干扰素与位于细胞表面的干扰素受体结合后,把干扰素的信号传到细胞核,激活干扰素要激活的基因,从而表达出实现干扰素功能的一系列蛋白质。其中最重要的标志性的两种蛋白质就是PKR和25OAS。这两种蛋白质再去激活其它一些特殊功能的蛋白质产生,达到抗病毒或免疫增强的作用。如通过PKR,干扰素可以刺激细胞产生一种RNA酶,这种RNA酶在细胞内产生后,可以直接水解病毒的RNA或单链DNA,直接降低病毒的产生。干扰素激活的蛋白还可以干扰病毒在细胞内的组装,使病毒量下降。更重要的是,干扰素可以刺激感染的细胞在细胞表面产生标记蛋白质,有利于免疫细胞识别感染的肝细胞,当进入免疫清除期后,将有助于细胞毒性的T淋巴细胞将感染的肝细胞清除,同时一起将cccDNA清除。这种通过加强免疫达到清除病毒的作用是干扰素有别于核苷类似物的根本所在。干扰素还能通过其激活的一系列蛋白质,促进感染的肝细胞发生凋亡等等。此外,到目前为止,对干扰素还有许多没研究清楚的方面,有待进一步明确。 综上所述,干扰素与细胞表面的干扰素受体结合是干扰素发挥其生物作用的关键。当有活性的干扰素与干扰素受体结合后,通过激活一系列蛋白质,发挥抗病毒和增强抗病毒免疫的作用。干扰素可以刺激细胞产生多种直接抗病毒蛋白,直接灭活或水解病毒。更重要的是增强抗病毒的免疫功能,达到持久抑制病毒的目的。 但是,如果病人自身的免疫没有激活,没有进入免疫清除期,干扰素也无能为力。它必须在人体针对乙肝病毒的细胞免疫激活后,才能充分发挥它的作用。打个形象的比喻,“星星之火,可以燎原”,这星星之火要靠病人自己来点燃,一旦有了星星之火,干扰素可以帮助燎原。又好比汽车要跑起来必须要先打火,打火后再加油车就跑起来了。“打火”要靠病人自己,干扰素可以起到加油的作用。 与核苷类似物相比,干扰素最大的作用是借助病人自身免疫的激活,经过有限疗程的治疗,达到停药后的持久应答。少数病人更可以表面抗原转阴,表面抗体转阳,达到最终治愈的目的。
慢性乙肝治疗的初次治疗的两种策略 第一种策略:以免疫为基础的干扰素alfa治疗,经过有限的疗程(6-12个月,少数可用到18个月),达到停药后的持久应答,HBeAg消失,同时Anti-HBe转阳的持久血清学转换;少数病人还有可能获得HBsAg消失,Anti-HBs转阳的真正治愈,这虽然要靠些运气,不能做为主要目标,但有少数人的确可以达到。 第二种策略:用核苷类似物,长期服药,达到用药期间的维持应答(这意味着核苷类似物一旦开始就不能轻易停药,更不能没有经过医生的允许私自停药,否则有肝功能恶化的危险。核苷类似物一旦开始,就要无限期的应用下去,停药后多数会复发。HBV DNA反弹到比治疗前还要高的水平)。但长期用药又带来另外一个严重的问题,就是病毒的变异。目前,有越来越多的临床研究表明,病毒变异后,肝脏炎症和纤维化重新活动,少数病人甚至出现肝功能恶化。 除非有干扰素的禁忌症,不能使用干扰素。如精神病史或家族精神病史、严重的抑郁症、对干扰素或干扰素中的某种成份过敏、怀孕、严重的自身免疫性疾病、肝硬化失代偿(即出现肝硬化的症状如腹水等)、白细胞或血小板太低等。否则,只要病人ALT升高、HBV DNA阳性,没有黄疸,已经进入免疫清除期,就应该首先考虑干扰素alfa治疗。这是目前国内占绝对多数的乙肝专家的观点,是中国的肝病学家经过多年的经验和教训得出来的结论,是在总结拉米夫定多年滥用后,从很多失败、甚至死亡的病例中总结出来的结论。 早在1998年,拉米夫定上市时,由于其口服方便,血清HBV DNA降低快的特点,国内的医生和病人对它没有经验,缺乏足够的认识,一时间拉米夫定卖疯了。甚至一些大小药店都在卖这种本该在医院才可以的处方药。更有基层的小医院,连脂肪肝、丙肝等毫不相干的肝病都用上了拉米夫定。好象拉米夫定就是治疗肝病的神药一样。可见当时拉米夫定的滥用情况有多么严重。 时间到了2000年,香港的Nance Leung报道了拉米夫定停药后肝功恶化,肝坏死,病人死亡的病例。此后,在国内出现多例由于拉米夫定停药不当致肝坏死和肝功能恶化的报道。到这时,肝病医生们才明白这是个什么药,并不象他们想象的那么神奇。这种药不仅不能治愈乙肝,反而带来长期用药后各种麻烦。病毒变异的发生率不断出现,停药后病情加重的病人越来越多。成都、上海、杭州等地相继出现病人由于停用拉米夫定后致人死亡状告葛兰素公司的案件。在经过了近8年以后,中国的肝病医生终于明白,不能再滥用核苷类似物类药物。不仅仅是拉米夫定,所有的核苷类似物都要慎用。不管新的核苷类似物药的降低HBV DNA的能力多强,血清HBV DNA转阴的速度多快,停药后多数还是要复发。而长期用药多数将在不同的时间出现变异和耐药。 中国人慢性乙肝的治疗具有长期性、艰巨性和复杂性的特点。这主要是由于多数中国人慢性乙肝是母婴垂直传播,病人在出生或者很小的时候就感染了,处在非常强的免疫耐受状态,在10-20年,甚至更长的时间里,病人都处在免疫耐受期,自身的免疫系统对乙肝病毒没有免疫反应。对于在体内生存了个么久的乙肝病毒,机体对它又没有免疫识别和清除,很难想象我们能通过什么神奇的方法,在短期内将病毒全部歼灭,全部从体内清除。必须有长期与病毒做战的思想准备,绝不能急于求成。这正发我们平常经常说的一句话,冰冻三尺非一日之寒,而解冻冻久的坚冰也不能一蹴而就。 中国人乙肝治疗困难的另一个原因是中国的乙肝以C型乙肝为主,在上海可能占到70%左右,根据目前在全球范围内对乙肝的认识,C型和D型乙肝治疗要比B型和A型困难得多。 乙肝治疗的长期性和艰巨性决定了无论是肝病医生,还是乙肝病人自己都要认真地对待,一定要有策略上的思考,然后再做决定。因为,一个决定做出后,这个决定所带来的结果不是一天、两天就能看到,而是要一年、两年甚至更长时间才能看到。这样漫长、耗时、耗力、耗财的“任务”,怎能轻易下决定!这就是为什么乙肝专家们在决定选择哪种药物时提出了乙肝治疗的两种策略。这不是我的创造,而是国内知名的学者和专家们多年结验的总结,国内最主流专家学者们的共识。 这里要说明一下,上面的两种策略主要针开始治疗阶段,在初始治疗时,如果能用干扰素,就尽量不用核苷类似物。但从总体抗病毒上,两种策略不是对立和矛盾的,临床上如果应用得好,应该是互补的。毕竟还有很多干扰素治疗也无效的病人。 干扰素与核苷类似物有着本质的区别,作用的原理完全不同。有时医生会根据病人的不同情况,采取干扰素与核苷类似物的不同的组合方式,以达到最大程度地控制病毒。但对于如何进行组合就更加复杂,每个人都可能有不同的观点,这就是为什么病人从一家医院到另一家医院,从一个医生换另一个医生,会有完全不同的治疗方案,甚至完全相反的方案。经常弄得乙肝病人摸不着头脑。 为什么现在用核苷类似物的病人这么多呢? 一个最主要的原因是核苷类似物,如拉米夫定、阿德福韦、恩替卡韦等通过口服给药,服药期间副作用比干扰素少。 第二个原因是核苷类似物除拉米夫定外,多数是新药,医生和病人都比较有兴趣,容易引起医生和病人的注意力。 还有一个更重要的原因,是核苷类似物降低血清的HBV DNA的速度快,病人用药后很快血清里面的HBV DNA就转阴了。这种HBV DNA暂时、快速转阴,对医生和病人都有很强的吸引力。 最后,就是核苷类似物一年的药费相对干扰素,尤其是进口的干扰素要便宜。由于这些原因,很多不明真相的病人轻易就做出了首先选择核苷类似物的决定,而没有考虑到一年、二年、三年以后会怎么样。没有考虑一旦用上核苷类似物是不能轻易停药的,否则可能带来严重后果。没有考虑长期用核苷类似物的变异和停药后的复发问题。如果医生没有耐心或没有很多时间向病人解释,病人很难区分这两种药物到底应该首选哪一个? 干扰素是人体内针对病毒感染产生的多功能的蛋白质,具有抗病毒、增强乙肝特异性免疫和抗纤维化等多种功能。虽然干扰素的直接抗病毒力较弱,但其提高机体识别乙肝病毒,增强针对乙肝病毒的特异性免疫功能对达到停药后的持久应答致关重要。相比这下,核苷类似物只能暂时抑制细胞浆内的HBV DNA的合成,不是通过免疫起作用,所以,无论它对血清的HBV DNA降得多快,都不能从根本上长期控制病毒,必须长期服药,达到服药期间的维持应答,停药后多数要复发,前功尽弃。但长期用药的最大问题是病毒的变异和耐药。 明白两种药物的作用机理后,就不难明白为什么能用干扰素一定要首选选择干扰素,只有干扰素不能用,或者多次治疗失败后再考虑核苷类似物。核苷类似物虽然可以取得暂时的HBV DNA下降快或者消失,而且新的恩替卡韦降病毒的速度比拉米夫定快得多,但本质上,无论降的速度多快,最终结果不大同小异。因为它们的作用原理是一样的。虽然HBV DNA下降快,但治疗一年的血清转换率与拉米夫定没有大的区别。 干扰素alfa除了直接抗病毒的作用外,最主要的作用是可以加强人体免疫对乙肝病毒的识别,加强淋巴细胞对感染肝细胞的清除。一种叫做CD8+的淋巴细胞激活后,识别感染的肝细胞,将其溶解破坏,将CCC-DNA一起清除。这种通过免疫激活所获得的应答,停药后多较持久。 核苷类似物只抑制细胞将内的HBV DNA合成,对人体免疫没有作用,不能通过激活免疫功能清除CCC DNA,这种只抑制细胞浆内病毒,停药后多数复发,必须长期用药,不能间断。
NorovirusNorovirusesarea genetically diverse group of single-stranded RNA, non-envelopedvirusesin theCaliciviridaefamily.[1]Theviruses are transmitted byfecally-contaminatedfood or water; by person-to-person contact;[2]andviaaerosolizationof the virus and subsequentcontamination of surfaces.[3]Noroviruses are the most common causeof viralgastroenteritisin humans,[4]andaffect people of all ages.[4]Norovirus infection is characterized bynausea, forceful vomiting, watery diarrhea, and abdominal pain, and in somecases, loss of taste. General lethargy, weakness, muscle aches, headache,coughs, and low-grade fever may occur. The disease is usually self-limiting,and severe illness is rare. A small number of people die, mostly the veryyoung, the elderly, and persons with weakened immune systems.Winter vomiting bugis acommon term for noroviruses in the UK, because the virus tends to causevomiting and to spread more easily in winter, when people tend to spend moretime indoors and near to each other.[5]Afterinfection,immunityto norovirus is usually incomplete andtemporary.[6]Outbreaksof norovirus infection often occur in closed or semiclosed communities, such aslong-term care facilities, overnight camps, hospitals, prisons, dormitories,and cruise ships, where the infection spreads very rapidly either byperson-to-person transmission or through contaminated food.[7]Manynorovirus outbreaks have been traced to food that was handled by one infectedperson.[8]Norovirus is rapidly inactivated by eithersufficient heating or bychlorine-based disinfectants,but the virus is less susceptible to alcohols and detergents, as it does nothave alipidenvelope.[9]The genus nameNorovirusis derived from Norwalk virus, whichcauses approximately 90% ofepidemicnonbacterial outbreaks ofgastroenteritisaround the world,[10]andmay be responsible for 50% of all foodborne outbreaks of gastroenteritis in theUnited States.[11][12]DiagnosisSpecific diagnosis of norovirus is routinelymade bypolymerase chainreaction(PCR)assaysorreal-timePCRassays, which giveresults within a few hours. These assays are very sensitive and can detect asfew as 10 virus particles.[13]Tests such asELISAthat useantibodiesagainsta mixture of norovirus strains are available commercially, but lackspecificityandsensitivity.[14]VirologyTransmissionNoroviruses are transmitted directly fromperson to person and indirectly via contaminated water and food. They arehighly contagious, and fewer than twenty virus particles can cause aninfection.[4]Transmissionoccurs through ingesting contaminated food and water and by person-to-personspread. Transmission through fecal-oral can beaerosolizedwhenthose stricken with the illness vomit, and can be aerosolized by a toilet flushwhen vomit or diarrhea is present; infection can follow eating food orbreathing air near an episode of vomiting, even if cleaned up.[15]Theviruses continue to be shed after symptoms have subsided and shedding can stillbe detected many weeks after infection.[16]Vomiting, in particular, transmits infectioneffectively. In one incident, a person who vomited spread infection rightacross a restaurant, suggesting that many unexplained cases of food poisoningmay have their source in vomit. 126 people were dining at six tables inDecember 1998; one woman vomited. Staff quickly cleaned up, and peoplecontinued eating. Three days later others started falling ill; 52 peoplereported a range of symptoms, from fever and nausea to vomiting and diarrhoea.The cause was not immediately identified. Researchers plotted the seatingarrangement: more than 90% of the people at the same table as the sick womanlater reported becoming ill. There was a direct correlation between the risk ofinfection of people at other tables and how close they were to the sick woman.More than 70% of the diners at an adjacent table fell ill; at a table on theother side of the restaurant, the rate was still 25%. The outbreak is beingblamed on a Norwalk-like virus (norovirus). Other cases of transmission byvomit were later identified.In one outbreak at an international scoutjamboree in the Netherlands, each person with gastroenteritis infected anaverage of 14 people before increased hygiene measures were put in place. Evenafter these new measures were enacted, an ill person still infected an averageof 2.1 other people.[17]ACDCstudy of 11 outbreaks inNew York Statelists the suspectedmode oftransmissionasperson-to-person in seven outbreaks, foodborne in two, waterborne in one, andone unknown. The source of waterborne outbreaks may include water frommunicipal supplies, wells, recreational lakes, swimming pools and ice machines.[18]Shellfishandsalad ingredients are the foods most often implicated in norovirus outbreaks.Ingestion of shellfish that have not been sufficiently heated poses a high riskfor norovirus infection.[19]Foodsother than shellfish may be contaminated by infected food handlers.[20]ClassificationNoroviruses (NoV) are a genetically diversegroup of single-stranded RNA, non-envelopedvirusesbelonging to theCaliciviridaefamily.[21]Accordingto the International Committee on Taxonomy of Viruses, thegenusNorovirushas one species, whichis calledNorwalk virus.[1]Serotypes,strains and isolates include:[22]·Norwalk virus;·Hawaii virus;·Snow Mountain virus;·Mexico virus;·Desert Shield virus;·Southampton virus;·Lordsdale virus;·Wilkinson Virus.[23]Noroviruses commonly isolated in cases ofacute gastroenteritis belong to two genogroups: genogroup I (GI) includesNorwalk virus, Desert Shield virus and Southampton virus; and II (GII), whichincludes Bristol virus, Lordsdale virus, Toronto virus, Mexico virus, Hawaiivirus and Snow Mountain virus.[21]Noroviruses can genetically be classifiedinto five different genogroups (GI, GII, GIII, GIV, and GV), which can befurther divided into different genetic clusters orgenotypes. For example, genogroup II, the mostprevalent human genogroup, presently contains 19 genotypes. Genogroups I, IIand IV infect humans, whereas genogroup III infectsbovine species, and genogroup V has recentlybeen isolated in mice.[23]Most noroviruses that infect humans belong togenogroups GI and GII.[24]Norovirusesfrom Genogroup II, genotype 4 (abbreviated as GII.4) account for the majorityof adult outbreaks ofgastroenteritisand often sweep across the globe.[25]Recentexamples include US95/96-US strain, associated with global outbreaks in themid- to late-1990s;Farmington Hillsvirus associated with outbreaks inEuropeandthe United States in 2002 and in 2004; and Hunter virus which was associatedwith outbreaks in Europe, Japan and Australasia. In 2006, there was anotherlarge increase in NoV infection around the globe.[26]Reportshave shown a link between the expression of human histo-blood group antigens(HBGAs) and the susceptibility to norovirus infection. Studies have suggestedthe viral capsid of noroviruses may have evolved from selective pressure ofhuman HBGAs.[27]A 2008 study suggests the proteinMDA-5may be the primary immune sensor thatdetects the presence of noroviruses in the body.[28]Interestingly,some people have common variations of the MDA-5 gene that could make them moresusceptible to norovirus infection.[29]A 2010 study suggested a specific geneticversion of norovirus (which would not be distinguishable from other types ofthe virus using standard viral antibody tests) interacts with a specificmutation in theATG16L1geneto help trigger symptomaticCrohn's diseasein mice that have been subjected to achemical that causes intestinal injury similar to the process in humans (thereare other similar ways for such diseases to happen like this, and this study initself does not prove norovirus causes Crohn's in humans).StructureNoroviruses contain apositive-senseRNAgenomeofapproximately 7.5kbp, encoding a majorstructuralprotein(VP1) of about 58~60kDaand a minorcapsidprotein(VP2).[30]Thevirus particles demonstrate an amorphous surface structure when visualizedusingelectron microscopyand are between 27-38nmin size.[31]Themost variable region of the viral capsid is the P2 domain, which containsantigen-presenting sites and carbohydrate-receptor binding regions.[32][33][34]The estimated mutation rate (1.21 x 102to 1.41 x 102substitutions per site per year) inthis virus is high even compared with other RNA viruses.[35]PathophysiologyWhen a person becomes infected with norovirus,the virus begins toreplicatewithinthesmall intestine. After approximately one totwo days, norovirus symptoms can appear. The principal symptom is acutegastroenteritisthat develops between 24 and 48 hoursafter exposure, and lasts for 24–60 hours.[12]Thedisease is usuallyself-limiting,and characterized by nausea, forceful vomiting, waterydiarrhea, and abdominal pain, and in somecases, loss of taste. General lethargy, weakness, muscle aches, headache,coughs, and low-grade fever may occur.Severe illness is rare: although people arefrequently treated at the emergency ward, they are rarely admitted to thehospital. The number of deaths from norovirusin the United States is estimated to be around 300 each year, with most ofthese occurring in the very young, the elderly, and persons with weakenedimmune systems. Symptoms may become life-threatening in these groups ifdehydrationisignored or not treated.[2]PreventionHand washing with soap and water is aneffective method for reducing the transmission of noroviruspathogens. Alcohol rubs (≥62% ethanol) may be used as an adjunct, but are less effective thanhand-washing, as norovirus lacks alipidviral envelope. Surfaces where norovirusparticles may be present can be sanitised with a solution of 1.5% to 7.5% ofhousehold bleach in water, or other disinfectant effective against norovirus.[36][37][38]In health-care environments, the preventionofnosocomial infectionsinvolves routine andterminal cleaning.Nonflammablealcohol vapor in CO2systems are used in health careenvironments where medical electronics would be adversely affected byaerosolized chlorine or other caustic compounds.[39]Ligocyte announced in 2007 that it wasworking on a vaccine and had started phase 1 trials.[40]Asof 2011a monovalent nasalvaccine had completed phase I/II trials, while bivalent intramuscular and nasalvaccines were at earlier stages of development.[41]PersistenceThe norovirus can survive for long periodsoutside a human host depending on the surface and temperature conditions: 12hours on hard surfaces, and up to 12 days on contaminated fabrics,[42]andit can survive for months, maybe even years in contaminated still water.[43]Astudy done in 2006 found the virus on several surfaces used for foodpreparation 7 days after contamination.[44]Detection in foodsRoutine protocols to detect norovirus(norovirus RNA) in clams and oysters byreverse transcription polymerase chain reactionare being employed by governmentallaboratories such as the FDA in the USA.[45]EpidemiologyEpidemiological data from developingcountries about the importance of norovirus in pediatric diarrhea are limited.Recently, in Nicaragua, it has been observed that norovirus is responsible for11% of the diarrhea cases occurring in children less than five years of age atcommunity level and 15% of the moderate to severe cases requiring intravenousrehydration.[47]In theGuangdongprovinceof the People's Republic of China, the Provincial Health Department said onDecember 17, 2010, that it had confirmed 429 cases of norovirus infection inthe November 2010 outbreak inConghua,Guangzhou, but no one died from it.[48]Human geneticsA non functionalfucosyltransferaseFUT2 provides high protection from themost common norovirus GII.4.[49]Functional FUT2 fucosyltransferasetransfers a fucose sugar to the end of the Histo-blood groupABO(H)precursor in gastrointestinal cells and saliva glands. The ABH antigen producedis thought to act as receptors for human norovirus. Homozygous carriers of anynonsense mutation in the FUT2 gene are called non-secretors, as no ABH antigenis produced. Approximately 20% of Caucasians are non-secretors due to the G428Aand C571T nonsense mutations in FUT2 and therefore have strong although notabsolute protection from the norovirus GII.4.[50]Non-secretorscan still produce ABH antigens in erythrocytes, as the precursor is formed byFUT1.[51]Somenorovirus genotypes (GI.3) can infect non-secretors.[52]Of individuals who are secretor positive,those with blood type O were more likely to be infected and B less likely.[53][54][55]HistoryThe norovirus was originally named the"Norwalk agent" afterNorwalk, Ohio, in the United States, where anoutbreak of acute gastroenteritis occurred among children at BronsonElementary Schoolin November 1968. In 1972, electronmicroscopy on storedhuman stoolsamplesidentified a virus, which was given the name "Norwalk virus." Numerous outbreaks withsimilar symptoms have been reported since. Thecloningandsequencingofthe Norwalk virus genome showed that these viruses have a genomic organizationconsistent with viruses belonging to the familyCaliciviridae.[56]Thename was shortened to "norovirus" after being identified in anumber of outbreaks oncruise shipsandreceiving attention throughout the United States. The name"norovirus" (Norovirusforthe genus) was approved by theInternationalCommittee on Taxonomy of Viruses(ICTV)in 2002.[57]In2011, however, a press release and a newsletter[58]werepublished by ICTV, which strongly encourage the media, national healthauthorities and the scientific community to use the virus nameNorwalk virus, rather than the genus nameNorovirus, when referring to outbreaks of the disease. This is also a publicstatement of ICTV to the request from an individual in Japan to rename thegenus Norovirus because of the possibility of negative associations for peoplein Japan and elsewhere who have the family name "Noro". Before thisposition of ICTV was made public, ICTV consulted widely with members of theCaliciviridae Study Group and carefully discussed the case.In addition to "Norwalk agent" and"Norwalk virus," the virus previously has been called"Norwalk-like virus," "small, round-structured viruses"(SRSVs), and "Snow Mountain virus."[59]Commonnames of the illness caused by noroviruses still in use include "wintervomiting disease,"[60]"wintervomiting bug,"[61][62]"viralgastroenteritis," and "acute nonbacterial gastroenteritis."[2]Italso colloquially is known as "stomach flu," but this actually is abroad name that refers to gastric inflammation caused by a range of viruses andbacteria.
The 2009 flu pandemic or swine flu was an influenza pandemic, and the second of the two pandemics involving H1N1 influenza virus (the first of them was the 1918 flu pandemic), albeit in a new version. First described in April 2009, the virus appeared to be a new strain of H1N1 which resulted when a previous triplereassortment of bird, swine and human flu viruses further combined with a Eurasian pig flu virus,[2] leading to the term "swine flu" to be used for this pandemic.[3] Unlike most strains of influenza, H1N1 does not disproportionately infect adults older than 60 years; this was an unusual and characteristic feature of the H1N1 pandemic.[4] Even in the case of previously very healthy persons, a small percentage will developpneumonia or acute respiratory distress syndrome (ARDS). This manifests itself as increased breathing difficulty and typically occurs 3–6 days after initial onset of flu symptoms.[5][6] The pneumonia caused by flu can be either direct viral pneumonia or a secondary bacterial pneumonia. In fact, a November 2009 New England Journal of Medicine article recommends that flu patients whose chest X-ray indicates pneumonia receive both antivirals and antibiotics.[7] In particular, it is a warning sign if a child (and presumably an adult) seems to be getting better and then relapses with high fever, as this relapse may be bacterial pneumonia.[8]Initially coined an "outbreak", the stint began in the state of Veracruz, Mexico, with evidence that there had been an ongoing epidemic for months before it was officially recognized as such.[9] The Mexican government closed most of Mexico City's public and private facilities in an attempt to contain the spread of the virus; however, it continued to spread globally, and clinics in some areas were overwhelmed by infected people. In June, the World Health Organization (WHO) and the U.S. CDC stopped counting cases and declared the outbreak a pandemic.[10]Despite being informally called "swine flu", the H1N1 flu virus cannot be spread by eating pork or pork products;[11][12] similar to other influenza viruses, it is typically contracted by person to person transmission through respiratory droplets.[13] Symptoms usually last 4–6 days.[14] Antivirals (oseltamivir orzanamivir) were recommended for those with more severe symptoms or those in an at-risk group.[15]The pandemic began to taper off in November 2009,[16] and by May 2010, the number of cases was in steep decline.[17][18][19][20] On 10 August 2010, the Director-General of the World Health Organization, Margaret Chan, announced the end of the H1N1 pandemic,[21] and announced that the H1N1 influenza event has moved into the post-pandemic period.[22]According to the latest WHO statistics (July 2010), the virus has killed more than 18,000 people since it appeared in April 2009, however they state that the total mortality (including deaths unconfirmed or unreported) from the H1N1 strain is "unquestionably higher".[17][23] Critics claimed the WHO had exaggerated the danger, spreading "fear and confusion" rather than "immediate information".[24] The WHO began an investigation to determine[25] whether it had "frightened people unnecessarily".[26] A flu followup study done in September 2010, found that "the risk of most serious complications was not elevated in adults or children."[27] In an 5 August 2011 PLoS ONE article, researchers estimated that the 2009 H1N1 global infection rate was 11% to 21%, lower than what was previously expected.[28] However, by 2012, a study showed that as many as 579,000 people could have been killed by the disease, as only those fatalities confirmed by laboratory testing were included in the original number, and meant that many of those without access to health facilities went uncounted. The majority of these deaths occurred in Africa and Southeast Asia. Experts agreed that an estimated 294,500 people were killed by the disease.[29][30] The World Health Organization also said that the initial death toll could be much higher.[31]ClassificationThe initial outbreak was called the "H1N1 influenza", or "Swine Flu" by American media. It is called pandemic H1N1/09 virus by the World Health Organization,[32] while the U.S. Centers for Disease Control and Prevention refer to it as "novel influenza A (H1N1)" or "2009 H1N1 flu".[33] In theNetherlands, it was originally called "Pig Flu", but is now called "New Influenza A (H1N1)" by the national health institute, although the media and general population use the name "Mexican Flu". South Korea and Israel briefly considered calling it the "Mexican virus".[34] Later, the South Korean press used "SI", short for "swine influenza". Taiwan suggested the names "H1N1 flu" or "new flu", which most local media adopted.[35] The World Organization for Animal Health proposed the name "North American influenza".[36] The European Commission adopted the term "novel flu virus".[37]Signs and symptomsThe symptoms of H1N1 flu are similar to those of other influenzas, and may include fever, cough (typically a "dry cough"), headache, muscle or jointpain, sore throat, chills, fatigue, and runny nose. Diarrhea, vomiting, and neurological problems have also been reported in some cases.[38][39]People at higher risk of serious complications include those aged over 65, children younger than 5, children with neurodevelopmental conditions, pregnant women (especially during the third trimester),[5][40] and those of any age with underlying medical conditions, such as asthma, diabetes, obesity, heart disease, or a weakened immune system (e.g., taking immunosuppressive medications or infected with HIV).[41] More than 70% of hospitalizations in the U.S. have been people with such underlying conditions, according to the CDC.[42]In September 2009, the CDC reported that the H1N1 flu "seems to be taking a heavier toll among chronically ill children than the seasonal flu usually does."[8] Through 8 August 2009, the CDC had received 36 reports of paediatric deaths with associated influenza symptoms and laboratory-confirmed pandemic H1N1 from state and local health authorities within the United States, with 22 of these children having neurodevelopmental conditions such as cerebral palsy, muscular dystrophy, or developmental delays.[43] "Children with nerve and muscle problems may be at especially high risk for complications because they cannot cough hard enough to clear their airways".[8] From 26 April 2009, to 13 February 2010, the CDC had received reports of the deaths of 277 children with laboratory-confirmed 2009 influenza A (H1N1) within the United States.[44]Symptoms in severe casesThe World Health Organization reports that the clinical picture in severe cases is strikingly different from the disease pattern seen during epidemics of seasonal influenza. While people with certain underlying medical conditions are known to be at increased risk, many severe cases occur in previously healthy people. In severe cases, patients generally begin to deteriorate around three to five days after symptom onset. Deterioration is rapid, with many patients progressing to respiratory failure within 24 hours, requiring immediate admission to an intensive care unit. Upon admission, most patients need immediate respiratory support with mechanical ventilation.[45]A November 2009 CDC recommendation stated that the following constitute "emergency warning signs" and advised seeking immediate care if a person experiences any one of these signs:[46]In adults:· Difficulty breathing or shortness of breath· Pain or pressure in the chest or abdomen· Sudden dizziness· Confusion· Severe or persistent vomiting· Low temperatureIn children:· Fast breathing or working hard to breathe· Bluish skin color· Not drinking enough fluids· Not waking up or not interacting· Being so irritable that the child does not want to be held· Flu-like symptoms which improve but then return with fever and worse cough· Fever with a rash· Being unable to eat· Having no tears when cryingResearch later indicated that the severe flu effects in healthy young and middle-aged adults are caused by an excessive immune response.[47]ComplicationsMost complications have occurred among previously healthy individuals, with obesity and respiratory disease as the strongest risk factors. Pulmonarycomplications are common. Primary influenza pneumonia occurs most commonly in adults and may progress rapidly to acute lung injury requiringmechanical ventilation. Secondary bacterial infection is more common in children. Staphylococcus aureus, including methicillin-resistant strains, is an important cause of secondary bacterial pneumonia with a high mortality rate. Neuromuscular and cardiac complications are unusual but may occur.[48]A United Kingdom investigation of risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza looked at 631 patients from 55 hospitals admitted with confirmed infection from May through September 2009. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged ≥65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically confirmed pneumonia and a raised C-reactive protein (CRP) level (≥100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people.[49]Fulminant (sudden-onset) myocarditis has been linked to infection with H1N1, with at least four cases of myocarditis confirmed in patients also infected with A/H1N1. Three out of the four cases of H1N1-associated myocarditis were classified as fulminant, and one of the patients died.[50]Also, there appears to be a link between severe A/H1N1 influenza infection and pulmonary embolism. In one report, five out of 14 patients admitted to the intensive care unit with severe A/H1N1 infection were found to have pulmonary emboli.[51]An article published in JAMA in September 2010[52] challenged previous reports and stated that children infected in the 2009 flu pandemic were no more likely to be hospitalised with complications or get pneumonia than those who catch seasonal strains. Researchers found that about 1.5% of children with the H1N1 swine flu strain were hospitalised within 30 days, compared with 3.7% of those sick with a seasonal strain of H1N1 and 3.1% with an H3N2 virus.[27]DiagnosisConfirmed diagnosis of pandemic H1N1 flu requires testing of a nasopharyngeal, nasal or oropharyngeal tissue swab from the patient.[53] Real-time RT-PCR is the recommended test as others are unable to differentiate between pandemic H1N1 and regular seasonal flu.[53] However, most people with flu symptoms do not need a test for pandemic H1N1 flu specifically, because the test results usually do not affect the recommended course of treatment.[54] The U.S. CDC recommend testing only for people who are hospitalised with suspected flu, pregnant women and people with weakened immune systems.[54] For the mere diagnosis of influenza and not pandemic H1N1 flu specifically, more widely available tests include rapid influenza diagnostic tests (RIDT), which yield results in about 30 minutes, and direct and indirect immunofluorescence assays (DFA and IFA), which take 2–4 hours.[55] Due to the high rate of RIDT false negatives, the CDC advises that patients with illnesses compatible with novel influenza A (H1N1) virus infection but with negative RIDT results should be treated empirically based on the level of clinical suspicion, underlying medical conditions, severity of illness and risk for complications, and if a more definitive determination of infection with influenza virus is required, testing with rRT-PCR or virus isolation should be performed.[56] Dr. Rhonda Medows of the Georgia Department of Community Health states that the rapid tests are incorrect anywhere from 30% to 90% of the time and warns doctors in her state not to use them because they are wrong so often.[57] The use of RIDTs has also been questioned by researcher Paul Schreckenberger of the Loyola University Health System, who suggests that rapid tests may actually pose a dangerous public health risk.[58] Dr. Nikki Shindo of the WHO has expressed regret at reports of treatment being delayed by waiting for H1N1 test results and suggests, "[D]octors should not wait for the laboratory confirmation but make diagnosis based on clinical and epidemiological backgrounds and start treatment early".[59]On 22 June 2010, the CDC announced a new test called the "CDC Influenza 2009 A (H1N1)pdm Real-Time RT-PCR Panel (IVD)". It uses a molecular biology technique to detect influenza A viruses and specifically the 2009 H1N1 virus. The new test will replace the previous real-time RT-PCR diagnostic test used during the 2009 H1N1 pandemic, which received an emergency use authorisation from the U.S. Food and Drug Administration in April 2009. Tests results are available in four hours and are 96% accurate.[60]TransmissionSpread of the H1N1 virus is thought to occur in the same way that seasonal flu spreads. Flu viruses are spread mainly from person to person through coughing or sneezing by people with influenza. Sometimes people may become infected by touching something – such as a surface or object – with flu viruses on it and then touching their face. "Avoid touching your eyes, nose or mouth. Germs spread this way".[11]The basic reproduction number (the average number of other individuals whom each infected individual will infect, in a population which has no immunity to the disease) for the 2009 novel H1N1 is estimated to be 1.75.[69] A December 2009 study found that the transmissibility of the H1N1 influenza virus in households is lower than that seen in past pandemics. Most transmissions occur soon before or after the onset of symptoms.[70]The H1N1 virus has been transmitted to animals, including swine, turkeys, ferrets, household cats, at least one dog and a cheetah.[71][72][73][74]PreventionThe H1N1 vaccine was initially in short supply and in the U.S., the CDC recommended that initial doses should go to priority groups such as pregnant women, people who live with or care for babies under six months old, children six months to four years old and health-care workers.[75] In the UK, the NHS recommended vaccine priority go to people over six months old who were clinically at risk for seasonal flu, pregnant women and households of people with compromised immunity.[76]Although it was initially thought that two injections would be required, clinical trials showed that the new vaccine protected adults "with only one dose instead of two", and so the limited vaccine supplies would go twice as far as had been predicted.[77][78] Health officials worldwide were also concerned because the virus was new and could easily mutate and become more virulent, even though most flu symptoms were mild and lasted only a few days without treatment. Officials also urged communities, businesses and individuals to make contingency plans for possible school closures, multiple employee absences for illness, surges of patients in hospitals and other effects of potentially widespread outbreaks.[79]In February 2010, the CDC's Advisory Committee on Immunization Practices voted for "universal" flu vaccination in the U.S. to include all people over six months of age. The 2010–2011 vaccine will protect against the 2009 H1N1 pandemic virus and two other flu viruses.[80]VaccinesAs of 19 November 2009, over 65 million doses of vaccine had been administered in over 16 countries; the vaccine seems safe and effective, producing a strong immune response that should protect against infection.[88] Whereas the 2009 trivalent seasonal influenza vaccine neither increases nor decreases the risk of infection with H1N1, the vaccines rushed to combat the new strain are effective against H1N1,[89][90] although they are manufactured similarly. Overall the safety profile of the new H1N1 vaccine is similar to that of the seasonal flu vaccine, and as of November 2009 fewer than a dozen cases of Guillain-Barre syndrome had been reported post-vaccination.[91]Only a few of these were suspected to be actually related to the H1N1 vaccination, and only temporary illness had been observed.[91] This is in strong contrast to the 1976 swine flu outbreak, when mass vaccinations in the United States caused over 500 cases of Guillain-Barre syndrome and led to 25 deaths.[92] Although the vaccines were effective, many industrialised nations were giving away, selling, canceling orders for and destroying excess doses of the vaccine.[93][94]There are safety concerns for people who are allergic to eggs because the viruses for the vaccine are grown in chicken-egg-based cultures. People with egg allergies may be able to receive the vaccine, after consultation with their physician, in graded doses in a careful and controlled environment.[95] A vaccine manufactured by Baxter is made without using eggs, but requires two doses three weeks apart to produce immunity.[96]As of late November 2009, in Canada there had been 24 confirmed cases of anaphylactic shock following vaccination, including one death. The estimated rate is one anaphylactic reaction per 312,000 persons receiving the vaccine; however, six persons had suffered anaphylaxis out of 157,000 doses given from one batch of vaccine. Dr. David Butler-Jones, Canada's chief public health officer, stated that even though this was an adjuvantedvaccine, that did not appear to be the cause of this severe allergic reaction in these six patients.[97][98]Infection controlTravel precautionsOn 7 May 2009, the WHO stated that containment was not feasible and that countries should focus on mitigating the effect of the virus. They did not recommend closing borders or restricting travel.[107] On 26 April 2009, theChinese government announced that visitors returning from flu-affected areas who experienced flu-like symptoms within two weeks would be quarantined.[108]U.S. airlines had made no major changes as of the beginning of June 2009, but continued standing practices which include looking for passengers with symptoms of flu, measles or other infections, and relying on in-flight air filters to ensure that aircraft were sanitised.[109] Masks were not generally provided by airlines and the CDC did not recommend that airline crews wear them.[109] Some non-U.S. airlines, mostly Asian, including Singapore Airlines, China Eastern Airlines, China Southern Airlines, Cathay Pacific and Mexicana Airlines, took measures such as stepping up cabin cleaning, installing state-of-the-art air filters and allowing in-flight staff to wear face masks.[109]SchoolsU.S. government officials have been especially concerned about schools because the H1N1 flu virus appears to disproportionately affect young and school-age people, between six months and 24 years of age.[110] The H1N1 outbreak led to numerous precautionary school closures in some areas. Rather than closing schools, the CDC recommended that students and school workers with flu symptoms should stay home for either seven days total, or until 24 hours after symptoms subsided, whichever was longer.[111] The CDC also recommended that colleges should consider suspending fall 2009 classes if the virus began to cause severe illness in a significantly larger share of students than the previous spring. They also urged schools to suspend rules, such as penalties for late papers or missed classes or requirements for a doctor's note, to enforce "self-isolation" and prevent students from venturing out while ill;[112] schools were advised to set aside a room for people developing flu-like symptoms while they waited to go home and to have ill students or staff and those caring for them use face masks.[113]In California, school districts and universities were on alert and working with health officials to launch education campaigns. Many planned to stockpile medical supplies and discuss worst-case scenarios, including plans to provide lessons and meals for low-income children in case elementary and secondary schools closed.[114]University of California campuses stockpiled supplies, from paper masks and hand sanitizer to food and water.[114] To help prepare for contingencies, University of Maryland School of Medicine professor of pediatricsJames C. King Jr. suggested that every county should create an "influenza action team" to be run by the localhealth department, parents and school administrators.[115] As of 28 October 2009, about 600 schools in the United States had been temporarily closed, affecting over 126,000 students in 19 states.[116]WorkplaceFearing a worst-case scenario, the U.S. Department of Health and Human Services (HHS), the Centers for Disease Control and Prevention and theDepartment of Homeland Security (DHS) developed updated guidance[117] and a video for employers to use as they developed plans to respond to the H1N1 outbreak. The guidance suggested that employers consider and communicate their objectives, such as reducing transmission among staff, protecting people who are at increased risk of influenza-related complications from becoming infected, maintaining business operations, and minimising adverse effects on other entities in their supply chains.[117]The CDC estimated that as much as 40% of the workforce might be unable to work at the peak of the pandemic due to the need for many healthy adults to stay home and care for an ill family member,[118] and advised that individuals should have steps in place should a workplace close down or a situation arise that requires working from home.[119] The CDC further advised that persons in the workplace should stay home sick for seven days after getting the flu, or 24 hours after symptoms end, whichever is longer.[111]In the UK, the Health and Safety Executive (HSE) also issued general guidance for employers.[120]Facial masksThe U.S. CDC does not recommend use of face masks or respirators in non-health care settings, such as schools, workplaces, or public places, with a few exceptions: people who are ill with the virus when around other people, and people who are at risk for severe illness while caring for someone with the flu.[121] There has been some disagreement about the value of wearing facial masks, some experts fearing that masks may give people a false sense of security and should not replace other standard precautions.[122] Masks may benefit people in close contact with infected persons, but it is unknown whether they prevent H1N1 flu infection.[122] Yukihiro Nishiyama, professor of virology at Nagoya University's School of Medicine, commented that the masks are "better than nothing, but it's hard to completely block out an airborne virus since it can easily slip through the gaps".[123]According to mask manufacturer 3M, masks will filter out particles in industrial settings, but "there are no established exposure limits for biological agents such as swine flu virus".[122] However, despite the lack of evidence of effectiveness, the use of such masks is common in Asia.[123][124] They are particularly popular in Japan, where cleanliness and hygiene are highly valued and where etiquette obligates those who are sick to wear masks to avoid spreading disease.[123]Pigs and food safetyThe pandemic virus is a type of swine influenza, derived originally from a strain which lived in pigs, and this origin gave rise to the common name of "swine flu". This term is widely used by mass media. The virus has been found in American hogs,[133] and Canadian[134] as well as in hogs in Northern Ireland, Argentina, and Norway.[135] Leading health agencies and the United States Secretary of Agriculture have stressed that eating properly cooked pork or other food products derived from pigs will not cause flu.[136][137] Nevertheless, on 27 April, Azerbaijan imposed a ban on the importation of animal husbandry products from America.[138] The Indonesian government also halted the importation of pigs and initiated the examination of 9 million pigs in Indonesia.[139] The Egyptian government ordered the slaughter of all pigs in Egypt on 29 April 2009.[140]TreatmentFurther information: Influenza treatmentA number of methods have been recommended to help ease symptoms, including adequate liquid intake and rest.[141] Over-the-counter pain medications such as acetaminophen and ibuprofen do not kill the virus; however, they may be useful to reduce symptoms.[142] Aspirin and other salicylate products should not be used by people under 19 with any flu-type symptoms because of the risk of developing Reye's Syndrome.[143]If the fever is mild and there are no other complications, fever medication is not recommended.[142] Most people recover without medical attention, although those with pre-existing or underlying medical conditions are more prone to complications and may benefit from further treatments.[46]People in at-risk groups should be treated with antivirals (oseltamivir or zanamivir) as soon as possible when they first experience flu symptoms. The at-risk groups include pregnant and post partum women, children under two years old, and people with underlying conditions such as respiratory problems.[15] People who are not in an at-risk group who have persistent or rapidly worsening symptoms should also be treated with antivirals. People who have developed pneumonia should be given both antivirals and antibiotics, as in many severe cases of H1N1-caused illness, bacterial infection develops.[59] Antivirals are most useful if given within 48 hours of the start of symptoms and may improve outcomes in hospitalised patients.[144] In those beyond 48 hours who are moderately or severely ill, antivirals may still be beneficial.[13] If oseltamivir (Tamiflu) is unavailable or cannot be used, zanamivir (Relenza) is recommended as a substitute.[15][145] Peramivir is an experimental antiviral drug approved for hospitalised patients in cases where the other available methods of treatment are ineffective or unavailable.[146]To help avoid shortages of these drugs, the U.S. CDC recommended oseltamivir treatment primarily for people hospitalised with pandemic flu; people at risk of serious flu complications due to underlying medical conditions; and patients at risk of serious flu complications. The CDC warned that the indiscriminate use of antiviral medications to prevent and treat influenza could ease the way for drug-resistant strains to emerge, which would make the fight against the pandemic that much harder. In addition, a British report found that people often failed to complete a full course of the drug or took the medication when not needed.[147]Side effectsBoth medications have known side effects, including lightheadedness, chills, nausea, vomiting, loss of appetite and trouble breathing. Children were reported to be at increased risk of self-injury and confusion after taking oseltamivir.[141] The WHO warn against buying antiviral medications from online sources, and estimate that half the drugs sold by online pharmacies without a physical address are counterfeit.[148]ResistanceAs of December 2010, the World Health Organization (WHO) reported 314 samples of the 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir (Tamiflu).[149] This is not totally unexpected as 99.6% of the seasonal H1N1 flu strains tested have developed resistance to oseltamivir.[150] No circulating flu has yet shown any resistance to zanamivir (Relenza), the other available anti-viral.[151]Effectiveness of antivirals questionedOn 8 December 2009, the Cochrane Collaboration, which reviews medical evidence, announced in a review published in BMJ that it had reversed its previous findings that the antiviral drugs oseltamivir (Tamiflu) and zanamivir (Relenza) can ward off pneumonia and other serious conditions linked to influenza. They reported that an analysis of 20 studies showed oseltamivir offered mild benefits for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.[152][153] Their published finding relates only to its use in healthy adults with influenza; they say nothing about its use in patients judged to be at high risk of complications (pregnant women, children under five and those with underlying medical conditions), and uncertainty over its role in reducing complications in healthy adults may still leave it as a useful drug for reducing the duration of symptoms. The drugs might eventually be demonstrated to be effective against flu-related complications; in general, the Cochrane Collaboration concluded "Paucity of good data".[153][154]Some specific results from the BMJ article include: "The efficacy of oral oseltamivir against symptomatic laboratory confirmed influenza was 61% (risk ratio 0.39, 95% confidence interval 0.18 to 0.85) at 75 mg daily ... The remaining evidence suggests oseltamivir did not reduce influenza related lower respiratory tract complications (risk ratio 0.55, 95% confidence interval 0.22 to 1.35)".[153] Notice especially the wide range for this second result.
发热发烧(也被称为热病)是最常见的医学体征之一,其特征是体温升高超过正常范围36.5-37.5 ℃(98-100°F),是由于体温调节设定点的提高所致。体温调节设定点触发点的提高增加了肌肉紧张度并且(颤抖)寒战。温度的升高,一般而言,会有一种寒冷的感觉,尽管体温是升高了。一旦达到新的温度,会有一种热的感觉。从发烧的开始,到有潜在危险性的发烧,发烧会由许许多多不同的条件引起。发烧是否有用,这个问题存在争议,有赞成的,也有反对的。除了非常高的温度,降温治疗常常是不必要的。然而,解热药物可以有效地降低温度,可能会改善受影响的人的舒适度。发热不同于不受控制的高烧,高烧是由于过度产热和/或体温调节的不足,体温升高超过人体的体温调节设定点。定义人们已经发现了一个宽泛的正常温度范围。如果升高的体温由抬高的设定点所致,便常被认定存在发热,且肛温(直肠/直肠的)处于或超过37.5-38.3°C(99.5-100.9°F)口温(口部的)处于或超过37.7 ℃(99.9°F)臂下温度(腋窝的)或耳内(耳部的)温度处于或超过37.2 ℃(99.0°F)在健康的成年男性和女性中,正常的,健康的口腔温度温度范围为33.2-38.2 °C (91.8-100.8°F),直肠为34.4-37.8°C(93.9-100°F),鼓膜(耳鼓)是35.4-37.8℃(95.7-100°F),腋温(腋下)是35.5-37.0℃(95.9-98.6°F)。哈里森内科教科书定义发烧为,早晨温度大于37.2 °C(98.9°F)或晚上温度> 37.7°C(99.9°F),而一般的日常温度变化一般为0.5°C(0.9°F)。正常的身体温度变化取决于许多因素,包括年龄,性别,一天中的时间,环境温度,活动水平,和更多。体温升高并不总是发烧。例如,一个健康的人,当他或她锻炼时,温度上升,但这不被认为是发烧,因为(体温)设定点是正常的。另一方面,可能一个“正常”的温度或许就是发热——如果一个温度对一个人而言,异乎寻常的高。例如,年老体弱者产生身体热量能力下降,所以“正常”的温度37.3°C(99.1°F)可能对他们而言就是一种临床上显著的发热。类型温度的变化模式可能暗示诊断:持续发热:温度一整天持续高于正常,24小时波动不超过1°C,例如:大叶性肺炎,伤寒,泌尿道感染,布氏杆菌病,或斑疹伤寒。伤寒热可以表现出一种特殊的发热模式(伤寒热文德利希曲线),温度缓慢逐级上升达到与一个高温的稳定阶段。(退烧药所致降温除外)。间歇性发热:只有在某一段时间表现出温度升高,之后回于正常,如疟疾,黑热病,脓血症,败血症等。以下是它的类型:——每日热,24小时的周期性的,典型的恶性疟原虫或诺尔斯疟原虫。——间日热(48小时周期),典型的间日(单细胞动物)疟原虫和卵形疟原虫疟疾。——四日热(72小时周期),典型的三日疟原虫疟疾。时好时坏发热(驰张热):温度一整天都高于正常,24小时内波动超过1 °C,如感染性心内膜炎。佩-埃热:与霍奇金淋巴瘤有关的一种特殊类型的发热,表现为一个星期的发烧,下一个星期体温降下,等等。然而,这种模式是否真的存在存有争议。中性粒细胞减少性发热,也被称为发热性中性粒细胞减少,是一种缺乏正常免疫系统功能的发热。由于缺乏抗感染中性粒细胞,细菌感染可迅速蔓延,这种发热,通常认为需要紧急就医。与正常人相比,这种发热更常见于接受免疫抑制化疗的人。轻热病是指低热的一个古老词汇,尤其是病因不明,没有表现出其他症状,病人不到一个星期就完全恢复。高热高热是体温极度升高大于或等于41.5°C(106.7°F)。如此高的温度被认为是医疗紧急情况,因为它可能表明有严重的、潜在的情况,或有重大的副作用。最常见的原因是颅内出血。 其他可能的原因包括败血症,川崎综合征,抗精神病药物恶性综合征,药物作用,五羟色胺(血清素)综合征,甲状腺危象。感染是最常见的发烧原因,然而随着温度的升高,其他原因变得更常见。感染通常与高烧相关,包括:红疹(玫瑰疹),麻疹,肠病毒感染。立即积极降温到低于38.9 °C(102.0 °F )已被发现可以提高存活率。高热不同于过高热,在于高热时身体的温度调节机制设置体温高于正常的温度,之后产生热量以达到此温度,而过高热是因外源性因素使身体体温升高超过体温设定点。(如中暑等)。过高热过高热是高温一个例子,它不是发烧。它有许多原因,包括中暑,抗精神病药物恶性症候群,恶性高热,兴奋剂如安非他明和可卡因,特异的药物反应,和五羟色胺综合征。征象发烧通常伴有病态的行为,包括倦怠,抑郁,厌食,嗜睡,痛觉过敏,注意力不集中。鉴别诊断发热是许多身体疾病的常见症状:感染性疾病,如流感,HIV,疟疾,传染性单核细胞增多症,或肠胃炎各种皮肤炎症,如疖,或脓肿免疫学疾病,例如红斑狼疮,结节病,炎症性肠疾病,川崎病组织破坏,可发生溶血,手术,血栓形成,挤压综合征,横纹肌溶解症,脑出血等。不兼容的血液制品反应癌症,最常见于肾癌和白血病和淋巴瘤代谢性疾病,如痛风或卟啉症血栓栓塞的过程,例如,肺栓塞或深静脉血栓形成经过反复常规的临床查询后无法解释的持续发热,被称为不明原因发热病理生理学体温最终在下丘脑调节。发烧的起因,即致热原,导致前列腺素E2 (PGE2)的释放。 PGE2之后反作用于下丘脑,后者产生全身反应返回到身体其他部位,造成产热效果以配合新的体温水平。在许多方面,下丘脑起着恒温器的作用。当设定点升高,人体通过主动产生热量和保持热量,增加其温度。血管收缩,能减少热量通过皮肤损失,也造成人感到寒冷。如果这些措施不足以令大脑中的血液温度适应下丘脑新的设定,便开始寒战,以使肌肉运动,产生更多的热量。发烧停止时,下丘脑的体温设定点设置较低,与发热过程相反(血管舒张,寒战和非寒战产热的结束)和出汗,使得体温冷却到新的、较低的体温设定。而过高热,正常体温设定没有变化,身体过热是由于多余热量或过量产热令人厌烦地保留。过高热通常是极度热环境(中暑)或药物不良反应的结果。通过周围的境况以及对解热药物的反应,能够鉴别发热与过高热。热原质热原质是引起发热的一种物质,可以是身体内部的(内生的、内源性)亦或外部的(外生的、外源性)。细菌物质脂多糖(LPS),存在于一些细菌的细胞壁中,是外源性热原质的一个例子。热原能够变化:在极端的例子中,一些细菌致热原,被称作超抗原,会导致快速而危险的发烧。去热源法,可以通过过滤,蒸馏,色谱法,钝化(失活)这些方法实现。内生的在本质上,所有的内源性热原都是细胞因子,分子学是先天免疫系统的一部分,由吞噬细胞产生,导致下丘脑的体温调节设定点的升高。主要内源性热原质是白细胞介素1(α和β),白细胞介素6(IL-6),肿瘤坏死因子-α。次要的内源性热原包括白细胞介素8 ,肿瘤坏死因子-α ,肿瘤坏死因子-β ,巨噬细胞炎性蛋白-α,巨噬细胞炎性蛋白-β ,以及干扰素-α,干扰素-β ,和γ-干扰素。这些细胞因子被释放到全身循环中,并迁移到更易吸收它们的脑室周围结构,因为血-脑屏障在那里减少了过滤。细胞因子然后与血管壁的内皮细胞上的受体结合,或与该处的小胶质细胞相互作用。当这些细胞因子结合时,花生四烯酸途径随即得到激活。外生的外源性热原引起发烧的机制的一个类型包括脂多糖(LPS),是革兰阴性细菌的细胞壁成分。免疫蛋白结合LPS 被称为脂多糖结合蛋白(LBP)。之后,LBP-LPS复合物结合邻近巨噬细胞的CD14受体。这种结合导致各种内源性细胞因子,如白细胞介素1(IL-1),白细胞介素6(IL-6),和肿瘤坏死因子-α的合成与释放。换句话说,外源性因素引起内源性因素释放,这反过来,激活花生四烯酸途径。释放前列腺素E2PGE2释放来自花生四烯酸途径。这条通路(它涉及到发热),由磷脂酶A2(PLA2),环氧合酶-2(COX-2)和前列腺素E2合成酶介导。最终这些酶介导前列腺素E2(PGE2)的合成和释放。PGE2是发热反应最终的调解物质。身体的设定点温度将继续升高直到PGE2不再存在。 PGE2通过前列腺素E受体3(EP3)作用于视前区(POA)的神经元。 EP3表达POA的神经元刺激下丘脑背内侧核(DMH),延髓头端中缝苍白核(rRPa),下丘脑室旁核(PVN)。发烧信号发送到DMH和rRPa,刺激交感神经输出系统,它唤起非颤抖生热作用产生体热,和皮肤血管收缩,以减少从身体表面的热损失。据推测,从POA到PVN的神经分布,通过垂体和各种内分泌器官途径,介导神经内分泌影响的发热。下丘脑通过自主(植物性)神经系统,大脑最终编排热效应机制。这些可能是:靠肌张力增高,颤抖(寒战)和如肾上腺素的激素增加产热防止热损失,如血管收缩在婴幼儿,自主(植物性)神经系统也可以激活褐色脂肪组织产生热量(非运动相关的生热,也被称为非颤抖性产热)。发热时增加心率和血管收缩,导致血压增高。有用性发烧是否有用,这个问题存在争议,有赞成的,也有反对的。一些提议说,发热使人从感染或危重病中恢复得更快,后有使用热血脊椎动物和人类的活体研究。芬兰的一项研究表明出现发热降低了细菌感染的死亡率。从理论上讲,发热可以帮助宿主的防御。一定是有一些重要的免疫反应由于发热而加快, 有严格的温度偏好的一些病原体受到干扰。研究表明,发热有助于愈合过程的几个重要方面:增加粒细胞流动性增强粒细胞的吞噬作用内毒素影响的减少增加T细胞的增殖管理发烧不一定要治疗。大多数人未经特殊的医药治疗而痊愈。虽然它不太舒服,发热很少上升到一个危险水平,即时未经治疗。对大脑的损害一般不会发生,除非温度达到42 °C (107.6 °F),但未经治疗的发烧超过41°C(105°F)是及其罕见的。一些有限的证据支持给发烧的孩子用温水擦身或洗浴。使用风扇或空调可能会有所降低温度和增加舒适度。如果温度达到非常高的高烧,需要积极的降温。在一般情况下,建议应保持充足的水分。是否增加液体的摄入量改善症状,或是缩短呼吸系统疾病,如普通感冒病程,目前尚不清楚。药物降温的药物被称为退热药。退热药布洛芬在儿童中用于降温是有效的,它比对乙酰氨基酚(扑热息痛)更有效。布洛芬和对乙酰氨基酚都可安全地用于孩子发烧。对乙酰氨基酚单独用于孩子发烧受到质疑。对于孩子发烧,布洛芬是优于阿司匹林。此外,阿司匹林不建议在儿童和青壮年(16岁或19岁以下,因国家而异)使用,因有瑞氏综合征的风险。流行病学看急诊的人中,大约有5%发烧。历史到希波克拉底时代,人们已经认识到了发热的几种模式:包括间日热(每48小时)和四日热(每72小时)是由疟疾引起的发烧。在随后的几个世纪中形成普遍共识:发烧怎样形成,发烧作为一个症状和发烧作为一种疾病的差别,多种类型发热的详尽的分类方案,发热原因的假设,诊断和治疗发烧的不同的方法。在10世纪,波斯医生Akhawaynī创造发烧曲线的概念——发热对应时间,作为诊断的辅助手段。社会文化发热恐怖症发烧恐惧症是医学专家针对患儿家长对发烧的误解给出的名称。其中,很多家长错误地认为,发热是一种疾病,而不知道它是一个医学体征,认为低烧是有害的,还认为即使是短时间略高于很简单的温度计上标记的“正常”的数字,是临床上显着的发热。他们也害怕无害的副作用,如热病猝发和夸张性高估典型的发烧所致的长期损害的可能性。儿科教授Barton D. Schmitt 指出,根本的问题,是“作为父母,我们往往怀疑我们的孩子的大脑可能会熔化。“由于这些误解的结果,父母都急迫地给孩子退烧药物,即时当温度在技术上是正常或仅轻度增高,并且为让孩子保持正常睡眠,给孩子更多的药品。词源发热源自希腊PYR,是火的意思。发热词源拉丁词febris,意思是发烧,古体被称为疟疾。其他动物的发热发烧是驯养动物疾病诊断中的一个重要特征。动物的体温,采于直肠,物种间是不同的。例如,据说马发烧是体温超过101.0°F(38.3°C)。允许身体有一个宽范围“正常”温度的物种,如骆驼,有时是难以确定发热阶段。