戊型肝炎(HEV)的前世今生
1978-1979 年在印度 Kashmir 肝炎流行期间,共累计发生黄疸型肝炎约52000人,其中死亡1700 人,人们对这种既不是甲型又不是乙型的肝炎首次有所认识[1],接着不久,Wong 等对病毒性肝炎流行做回顾性调查时发现,印度新德里早在1955-1956 年发大洪水期间,新德里各大医院挤满了此肝炎患者约97000人[2]。
1983 年,前苏联病毒学家Balayan 等发现此肝炎的病原为一种无包膜的单股正链RNA病毒,该病毒颗粒在环境中相对比较稳定,可在生活污水样本中被检出来并通过水源传播给人类[3]。
1989年此“非甲非乙型肝炎”被命名为戊型肝炎病毒,1990年,戊肝病毒基因组测序完成。继后的20余年时间,人类逐步揭开其病原学及流行病学的面纱,中国的科学家成功研发并上市了全球首款戊型肝炎疫苗。
但是对于许多临床、疾控以及接种单位的医务人员,对于戊肝及其疫苗认识上还有许多迷雾,本文将逐一驱散拨开。
迷“戊”之一
我国戊肝真实发病率知多少?
01
据WHO网站的数据,全球每年约2000万人感染,造成约330万人出现症状,2015年估计导致4.4万人死亡。
我国是戊肝高流行区,目前以散发为主,但戊肝突发公共卫生事件时有发生,戊肝报告发病率呈逐渐上升趋势。
2012年以来,在经肠道传播的肝炎中,戊肝报告发病率持续超过甲型肝炎,居急性病毒性肝炎之首,2018年发病人数是甲肝的1.8倍。
由于戊肝发现较迟,临床医生对其了解不多,加之多数基层医院尚未开展戊肝实验室的检测,导致误诊漏报较高。
为了解真实戊肝发病率,2006-2007年,江苏省疾控中心联合厦门大学在盐城东台市开展基于近31万人的社区戊肝主动监测,社区医疗机构一旦接诊到乏力、食欲不振大于3天的患者,即进行转氨酶的检测,如转氨酶大于40单位,即进行甲、乙、丙、戊型肝炎感染指标的检测,结果急性肝炎发病率为 10. 76/ 万人年, 戊肝发病率为 2. 98/ 万人年[5], 而同期该地区传染病网络报告系统报告急性肝炎和确诊戊肝发病率分别仅为2.38/ 万人年、0. 28/ 万人年。
迷“戊”之二
戊肝疾病负担及病死率高吗?
02
戊肝基因1~4型与人类疾病关系最为密切。基因1、2型只感染人,常因水源被污染而造成大规模流行,历史上曾发生数以千计甚至万计的患者,病死率为0.2%~0.4%,孕妇的病死率可高达20%~50%[13]。
20世纪80年代末,在我国新疆南部地区曾发生戊肝流行,发病119280例,死亡707人,其中414名孕妇[14]。发达国家以人兽共患的HEV基因3、4型引起的散发病例为主,多由摄入未煮熟的被HEV感染的动物肉类引起。
既往研究认为,戊肝是一种急性自限性疾病,但自2008年法国学者Kamar等[6]首次报道器官移植患者发生慢性HEV感染以来,相继报道了在免疫缺陷人群中,如艾滋病[7]、肿瘤患者[8]发生HEV慢性感染。
此外,慢性肝病患者重叠感染HEV,则会引起更加严重的疾病,如肝衰竭,严重加速疾病进程和影响生命质量[9]。近年来还发现,HEV感染可引发一系列肝外疾病,最常见的如神经系统疾病[10]、肾脏病变[11]和血液系统病变[12]等。
有基础慢性肝病者感染HEV后,通常预后较差,易发展为重症肝炎。系统综述结果显示[15],在我国慢性乙型肝炎(CHB)住院患者中HEV重叠感染率为13.6%,HEV重叠感染的CHB住院患者中肝衰竭发生率为34.7%,病死率为13.8%,其肝衰竭和病死风险均显著高于单纯CHB患者、单纯戊肝患者以及HAV重叠感染的CHB住院患者。
迷“戊”之三
戊肝的传播危险因素有哪些?
03
戊肝主要是通过粪口途径传播,但也可以经输血传播。Hewitt 等[16]调查英国东南地区225 000份献血样本,发现79例HEV基因3型核酸阳性。
追踪其中43例受血者,18例(42%,18/43)发生输血后HEV感染,提示HEV可经输血和血液制品传播。我国近几年研究也在血制品中发现HEV RNA,提示潜在的输血传播风险[17]。
目前,欧洲数个国家已将或拟将HEV核酸筛查纳入常规血制品筛查项目中 [18]。
戊肝的传染源除了戊肝病人及隐性感染者外,猪、牛、羊及海产品是重要传染源。根据对我国20个省、市、自治区的120个养猪场的8626只成年猪进行了HEV血清学调查显示,发现HEV感染率高达83.4%,调查的每个猪场的商品猪中均发现了HEV感染[19]。
迄今为止,已有诸多研究证实,摄入生的或未煮熟的贝类是戊肝病毒感染的危险因素。我国对渤海海域的HEV监测发现:HEV在毛蚶中更普遍(28.2%),其次是泥蚶(14.3%)和砂蛤(11.5%)。
在渤海湾沿岸受污染的贝类中检测出13株不同4型基因亚型HEV。因此,渤海水域使用者和贝类消费者可能存在感染HEV的风险[20]。
迷“戊”之四
我国研发的戊肝疫苗有多“牛”?
04
我国自主研发的全球唯一戊肝疫苗,从1998年发现戊肝疫苗的侯选物,到2012年成功上市,历时14年,累计投入5亿元。
核心技术上的突破是打破了国际医药界的结论性看法,采用大肠杆菌作为表达系统,独创出与酵母、昆虫细胞、哺乳动物细胞并行的第四种基因工程疫苗的研发路径。
该疫苗安全性良好,临床研究及上市后的监测均未收集到严重或罕见不良反应的报告;在江苏盐城东台市开展的世界上最大规模的(11.26万人)Ⅲ期临床研究表明,疫苗组于接种3针戊肝疫苗后12个月内未发生一例戊肝患者,保护率为100%,Ⅲ期临床试验的延续监测研究结果显示,疫苗接种4.5年后保护率为86.8%[21];65岁以上老人接种第3针戊肝疫苗后1个月时,其抗-HEV IgG阳转率 (96.2%,76/79) 及不良事件发生率 (40.0%,80/200) 与18-65岁组 (100.0%, 116/116和42.3%,85/2001) 无显著差异[22]。
美国疾病预防控制中心肝炎室主任Holmberg博士称赞道:“该疫苗的成功是戊型肝炎预防控制的一个重大突破……这些数据令人信服的证明了疫苗的有效性和安全性……这一疫苗是在世界各地控制戊型肝炎的最好的新方法。”
迷“戊”之五
推荐何人群接种戊肝疫苗呢?
05
戊肝的诊断主要包括病原学检查以及肝功能的评估,根据病原学的检测、肝脏功能的评估,结合患者的症状,可对戊肝病人进行临床诊断。
戊肝病原学的检查包括戊肝的抗体检查以及戊肝病毒的 RNA 检查。
- 血清戊肝病毒 IGM 抗体阳性或者戊肝病毒的 IGG 抗体 4 倍增高都可诊断为戊肝病毒感染
- 血清以及粪便中的戊肝病毒 RNA 阳性也可以诊断戊肝病毒感染
肝功能的检查主要包括转氨酶、胆红素、白蛋白以及凝血酶原时间。
- 在戊肝感染患者,出现转氨酶异
- 如果患者胆红素增高时间超过 3 周以上,并出现皮肤瘙痒,大便颜色变浅等症状,就需要考虑诊断为淤胆型肝炎
- 如患者黄疸急剧加深,大于正常 10 倍,常,胆红素增高以及乏力纳差等消化道症状,就可以诊断为急性戊型肝炎了
- 凝血功能延长,高于正常 2 倍以上,并出现极度乏力以及明显食欲不振,厌油,恶心呕吐等严重的消化道症状就需要诊断肝功能衰竭了
以下内容来源于新英格兰医学杂志。
Presentation of Case
Differential Diagnosis
Movement Disorders
Seizures
Functional Movement Disorder
Dyskinesia
Limb-Shaking TIAs
Clinical Impression and Initial Management
Clinical Diagnosis
Dr. Albert Y. Hung’s Diagnosis
Pathological Discussion
Pathological Diagnosis
Additional Management
Final Diagnosis
以下内容来源于新英格兰医学杂志。
Presentation of Case
Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.
Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.
A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.
The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.
Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.
On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.
The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.
The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.
Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.
Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B12 were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.
Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.
On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.
Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.
Dr. Parsons: Diagnostic tests were performed, and management decisions were made.
Differential Diagnosis
Cancer
Infectious Disease
Autoimmune Disease
Hypocomplementemia
Dr. Beth L. Jonas’s Diagnosis
Pathological Discussion
Pathological Diagnosis
Discussion of Management
Follow-up
Final Diagnosis
Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.
以下内容来源于PubMed。
Abstract
Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR+HER2- mBC from the EVER-132-002 study. Patients were randomized to SG (n = 166) or chemotherapy (n = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52-0.87; P = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47-0.88; P = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR+HER2- mBC (ClinicalTrials.gov identifier no. NCT04639986 ).
以下内容来源于PubMed。
Abstract
Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of Lactobacillus murinus in the gut. Lactobacillus murinus-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.
Keywords: AdorA2B; Lactobacillus murinus; irritable bowel syndrome with diarrhea; spermidine; stress; type I interferon; xanthine.
以下内容来源于PubMed。
Abstract
The severe bronchiolitis endotype characterized by a high abundance of H. influenzae, high proportion of RV-A and RV-C infections, and high asthma genetic risk had a significantly higher risk for developing asthma.
Background: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. However, little is known about its biologically distinct subgroups based on the integrated metagenome and asthma genetic risk signature and their longitudinal relationships with asthma development.
Methods: In a multi-center prospective cohort study of infants with severe bronchiolitis (i.e., bronchiolitis requiring hospitalization), we profiled nasopharyngeal airway metagenome and virus at hospitalization, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome-asthma genetic risk endotypes. We also examined their longitudinal association with the risk of developing asthma by age six years.
Results: Of 450 infants with bronchiolitis (median age, 3 months), we identified five distinct endotypes-characterized by their nasopharyngeal metagenome, virus, and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled "classic" bronchiolitis), endotype E infants (characterized by a high abundance of H. influenzae, high proportion of RV-A and RV-C infections, and high asthma genetic risk) had a significantly higher risk for developing asthma (35.9% versus 16.7%; ORadj, 2.24; 95%CI, 1.02-4.97; p=0.046). The pathway analysis showed that endotype E had enriched microbial pathways (e.g., glycolysis, L-lysine, arginine metabolism) and host pathways (e.g., IFNs, IL-6/JAK/STAT3, fatty acids, MHC, and immunoglobin-related) (FDR<0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR<0.05).
Conclusion: In this multi-center prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks for developing asthma.
以下内容来源于PubMed。
Summary
Background
Methods
Findings
Interpretation
Funding
Keywords
泌乳素轻度偏高与多种因素相关。
从生理因素来看,日常活动就有影响,像剧烈运动、体力劳动后,泌乳素会出现轻度上升。睡眠也对其有作用,睡眠不足或睡眠质量差可能导致泌乳素轻度升高,而在入睡后的一段时间内,泌乳素分泌会自然增加。另外,处于妊娠期和哺乳期的女性,身体需要为泌乳做准备和进行哺乳活动,泌乳素会升高,这是正常的生理反应。
精神因素也不容忽视。长期处于紧张、焦虑、压力大的精神状态下,比如工作压力巨大的上班族或临近重大考试的学生,会引起神经调节功能紊乱,从而导致泌乳素分泌轻度异常。
再者是饮食因素。如果经常食用一些含激素类食物,特别是含有较高雌激素的食物,可能会刺激垂体分泌泌乳素。同时,过度饮酒、高蛋白高脂肪饮食也可能和泌乳素轻度偏高有一定关联。
某些药物也会造成泌乳素升高。常见的如抗精神病药物、抗抑郁药物、降压药等,这些药物在治疗疾病的同时,可能会对内分泌系统产生副作用,使泌乳素水平轻度上升。
最后是疾病因素。一些下丘脑疾病、垂体微腺瘤等会影响泌乳素的正常分泌,但在疾病初期,可能仅表现为泌乳素轻度偏高,还可能有甲状腺功能减退症,因为甲状腺激素分泌不足会反馈影响下丘脑 - 垂体轴,从而导致泌乳素升高。
男性泌乳素轻度偏高与多种因素有关。
在生理方面,首先是性生活因素。性生活不规律或过度手淫,可能引起短暂的泌乳素升高。此外,男性乳头受到刺激,比如摩擦、挤压或外伤等,会向大脑传递信号,使泌乳素分泌增加。年龄也是一个因素,随着男性年龄增长,身体机能变化,泌乳素水平可能出现一定程度的自然波动,有可能轻度偏高。
疾病因素也很关键。下丘脑 - 垂体疾病会对泌乳素的调控产生影响,垂体瘤是其中较为常见的原因。当垂体瘤存在时,可能压迫或刺激泌乳素细胞,使其分泌增加。另外,甲状腺功能减退症会引起甲状腺激素水平降低,通过下丘脑 - 垂体 - 甲状腺轴的反馈调节机制,促使下丘脑分泌更多的促甲状腺激素释放激素,而这种激素可能刺激垂体分泌泌乳素。慢性肾功能不全也会导致泌乳素升高,因为肾功能异常时,身体对泌乳素的代谢和排泄能力下降,使体内泌乳素水平上升。
药物的副作用也不容忽视。多巴胺受体拮抗剂,如抗精神病药物中的氯丙嗪、奋乃静等,通过阻断多巴胺受体,抑制多巴胺对泌乳素分泌的抑制作用,从而导致泌乳素升高。某些降压药,如利血平,会干扰多巴胺的储存和释放,也可能引起泌乳素轻度偏高。
最后,精神和生活习惯也会影响泌乳素水平。长期的精神紧张、焦虑、抑郁等精神状态,会干扰下丘脑的神经调节功能,引起泌乳素分泌异常。不良的生活习惯,如长期熬夜、过度饮酒、暴饮暴食等,可能通过影响身体的内分泌和代谢功能,间接导致泌乳素轻度偏高。
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