严重急性呼吸综合征的病理改变

严重急性呼吸综合征(SARS)是一种新近定义的引起全球关注的传染病。自从2002年底在广东出现并流行,该传染病在中国内地及香港的感染人数已达到数千例。我们将香港的经验包括SARS的病理学表现等加以总结。 SARS在香港的爆发涉及的源头病患者(index patient)为一位来自广州的教授。他就诊于香港广华医院并死于该     

Pathology and pathogenesis of severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract. The pathogenesis of SARS is highly complex, with multiple factors leading to severe injury in the lungs and dissemination of the virus to several other organs. The SARS coronavirus targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Several organs/cell types may be infected in the course of the illness, including mucosal cells of the intestines, tubular epithelial cells of the kidneys, neurons of the brain, and several types of immune cells, and certain organs may suffer from indirect injury. Extensive studies have provided a basic understanding of the pathogenesis of this disease. In this review we describe the most significant pathological features of SARS, explore the etiological factors causing these pathological changes, and discuss the major pathogenetic mechanisms. The latter include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, down-regulation of lung protective angiotensin converting enzyme 2, autoimmunity, and genetic factors. It seems that both abnormal immune responses and injury to immune cells may be key factors in the pathogenesis of this new disease.     

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)-alpha, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10 concentrations from 5 to 8 days after treatment (all P < 0.001). Together, the elevation of Th1 cytokine IFN-gamma, inflammatory cytokines IL-1, IL-6 and IL-12 and chemokines IL-8, MCP-1 and IP-10 confirmed the activation of Th1 cell-mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.     

Influence of FcgammaRIIA and MBL polymorphisms on severe acute respiratory syndrome

Polymorphisms of human Fc gamma-receptor IIA (FcgammaRIIA) and mannose-binding lectin (MBL) genes have been associated with susceptibility to or severity of some infectious diseases. In order to investigate whether these genetic factors might influence susceptibility to infection with the severe acute respiratory syndrome-associated coronavirus (SARS-Cov) as well as the course and severity of the infection, we evaluated polymorphisms of FcgammaRIIA and MBL genes in DNA samples from a group of approximately 180 people from Hong Kong who were infected with SARS-Cov. These included 132 patients who had moderate course of SARS infection (home subgroup), 26 patients with a severe course requiring treatment in an intensive care ward (ICU subgroup) and a subgroup of 22 patients who died from SARS (deceased subgroup). A total of 200 normal blood donors from the same region were used as controls. A significant association was found between the FcgammaRIIA-R/R131 genotype and a severe course of SARS, with higher frequency of homozygosity for FcgammaRIIA-R/R131 in the ICU subgroup of SARS patients when compared with controls (P=0.03; odds ratio: 3.2; 95% confidence interval: 1.1-9.1). In comparison with controls, a significant difference in linear trend distribution of FcgammaRIIA genotypes was seen among the severe SARS patients (ICU and deceased subgroups) without co-morbidity, and the incidence of FcgammaRIIA-H/H131 was lower in these patients as well. There were no significant differences in MBL genotypes and allele frequencies among SARS patients and controls. The study reveals that in addition to age and co-morbidity, FcgammaRIIA polymorphism of individuals may also influence outcome after infection with the SARS-Cov.     

严重急性呼吸综合征病原体检测及临床病理学观察

目的 研究重症急性呼吸综合征(SARS)的临床病理学特点。方法 利用3例尸检材料为观察对象,全部材料经常规HE染色,肺组织部分标本经组织化学Macchiavello法(病毒包涵体染色)、网状纤维、PAS染色;免疫组织化学;超薄切片及染色;光镜及透射电镜观察。结果 3例均以高热为首发症状,继而出现进行性呼吸困难和肺部阴影;肺部病变：双肺广泛性实变;灶性出血,坏死,脱屑性肺泡炎及支气管炎,肺泡腔内充满增生脱落的肺泡上皮及渗出的蛋白、单核细胞、淋巴细胞和浆细胞,肺透明膜形成,部分肺泡腔内、渗出物机化呈肾小球样机化性肺炎改变,肺泡上皮细胞内可见病毒包涵体;免疫器官损伤：脾脏淋巴组织大片状坏死,淋巴结灶性坏死。骨髓造血组织抑制;全身小血管炎：心、肺、肝、肾、肾上腺、横纹肌间小静脉周围及血管壁水肿,灶性纤维素样坏死,单核细胞、淋巴细胞浸润,部分小静脉有血栓形成;全身中毒性改变：肺、肝、肾、心、肾上腺实质细胞变性,坏死。肺组织透射电镜观察发现群集的病毒颗粒。结论本病是一种全身多器官损伤性疾病,肺部及免疫系统是病毒主要作用的靶器官,肺部广泛性实变,大量透明膜形成,呼吸窘迫及免疫功能低下是本病死亡的主要原因。     

SARS患者血清细胞因子临床意义探讨

目的　探讨严重急性呼吸综合征 (SARS)患者病情进展的宿主免疫机制。方法　使用流式细胞仪检测急性SARS感染患者 5 0例和正常对照 2 0例的细胞因子 (IL 2、IL 4、IL 6、IL 10、IFN γ、TNF α)。按照疾病预后分成死亡组和治愈组 ,前瞻性设计分析细胞因子在 2组患者中的异同及对病情发展的影响。结果　治愈组与死亡组患者的细胞因子 (IL 2、IL 4、IL 6、IL 10、IFN γ、TNF α)均明显高于正常对照组 ,差异有显著性 (P <0 .0 5 )。治愈组和死亡组比较 :治愈组IFN γ高于死亡组 ,差异有显著性 (P <0 .0 5 ) ,死亡组IL 6、IL 10明显高于治愈组 ,差异有显著性 (P <0 .0 5 )。结论　SARS病毒感染确实引起机体的免疫系统紊乱。功能受损的程度与疾病的预后有一定相关性 ;TH2类细胞因子免疫反应过强 ,TH1类细胞因子免疫反应相对减弱 ,造成的机体免疫自稳平衡失调可能是SARS患者死亡的因素之一     

严重急性呼吸综合征T细胞亚群Meta分析

目的：研究严重急性呼吸综合症（SAPS）患者T细胞亚群变化。方法：检索2003年2月-2004年1月有关SAPS患者T细胞亚群计数研究的论文，汇合成大样本资料，借助先进的RevMan4．2分析软件对这些资料进行二次分析以探讨该病患者T细胞亚群变化。结果：SAPS病程〈14天期间，患者与正常对照比较，CD3^＋细胞、CD4^＋细胞、CD8^＋细胞均显著降低（均P〈0．01）。其中，重症病人（包括重型和极重型）比非重症病人（包括轻型和普通型）降低更显著（均P〈0．01）。病程〉14天恢复期病人与病程〈14天病人比较，CD3^＋细胞虽然有了上升，但无显著差异（Z=1．56，P=0．12）。CD4^＋细胞、CD8^＋细胞均恢复性上升，差异显著（均P〈0．01）。病程〉14天恢复期病人与正常对照比较，CD3^＋细胞、CD4^＋细胞仍然显著降低（均P〈0．01）。两者的CD8^＋细胞有差异（Z=2．28，P=0．02）。结论：①SAPS患者整个病程中都存在CD3^＋细胞、CD4^＋细胞、CD8^＋细胞数量暂时性、严重性、可逆性降低；②患者T细胞亚群数量的下降以重症病人为甚；③这种降低是可逆性的，随着病程进入恢复期，患者T细胞亚群开始恢复性上升。     

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection

The outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.     

9例严重急性呼吸综合征死亡病例分析

了解严重急性呼吸综合征死亡患者的危险因素。回顾性分析9例死亡患者的临床资料。6男，3女，大于65岁的6例，平均年龄61．66岁，从发病到死亡平均10．78天。5例患者有基础疾病其中2例为晚期肿瘤，1例糖尿病，1例高血压，1例慢支。8例患者有发热、咳嗽、全身不适，腹泻1例，8例淋巴细胞计数低于正常，5例患者血氧分压在入院时低于60mmHg，死亡前有肝功能异常和血小板降低分别有4例和5例。2例死于恶性肿瘤，3例突然死亡，4例死于呼吸衰竭。因此，年龄大于60岁，伴有基础疾病者死亡率较高；加强基础疾病治疗和护理以及强调卧床休息可能降低死亡率。     

严重急性呼吸综合征冠状病毒IgG抗体动态变化的初步观察

目的：探讨严重急性呼吸综合征(Severe Acute Respiratory Syndrome，SARS)冠状病毒抗体IgG的变化规律。方法：采用间接酶联免疫(ELISA)法，对534例发病后1—153天的SARS患者的血清特异性抗体IgG进行检测，并设置对照组进行比较。结果：SARS患者血清IgG抗体阳性率为58．1％，对照组为0．5％，两者具有显著性差异(P=0．000)。SARS患者中，临床症状出现后1—10天、11—30天、31—60天、61—90天、91—120天、≥121天组冠状病毒抗体IgG的阳性率分别为18．8％(3/16例)、63．8％(37／58例)、55．6％(30／54例)、51．4％(71/138例)、62．1％(159／256例)、83．3％(10／12例)。结论：SARS患者发病初期IgG抗体阳性率低，第11天后迅速上升，第4、5个月时持续存在，但持续多长时间尚需进一步观察。     

Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein

Severe acute respiratory syndrome (SARS) coronavirus (CoV) envelope (E) protein is a transmembrane protein. Several subcellular locations and topological conformations of E protein have been proposed. To identify the correct ones, polyclonal and monoclonal antibodies specific for the amino or the carboxy terminus of E protein, respectively, were generated. E protein was mainly found in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) of cells transfected with a plasmid encoding E protein or infected with SARS-CoV. No evidence of E protein presence in the plasma membrane was found by using immunofluorescence, immunoelectron microscopy and cell surface protein labeling. In addition, measurement of plasma membrane voltage gated ion channel activity by whole-cell patch clamp suggested that E protein was not present in the plasma membrane. A topological conformation in which SARS-CoV E protein amino terminus is oriented towards the lumen of intracellular membranes and carboxy terminus faces cell cytoplasm is proposed.     

从SARS患者肺部病变的病理特点探讨SARS的损伤机理

目的 根据严重急性呼吸道综合征(severe acute respiratory syndrome，SARS)患者肺部病变的病理特点探讨SARS的损伤机理。方法 在3500例尸体解剖材料中，找出死亡时有肺部炎症的共842例。对其中病毒性肺炎16例、Good-Pasture综合征2例、自身免疫疾病2例、SARS1例，共21例进行肺部病变的病理组织学的比较观察。结果 病毒性肺炎的肺部病变主要的病理变化表现为间质性肺炎；自身免疫性疾病病人的肺部病理变化有肺泡表面透明膜形成，肺泡腔内脱落的细胞团，肺泡腔内机化等；SARS病人尸体解剖的肺部病变主要为肺泡腔内细颗粒样或泡状肺水肿，脱屑性肺炎以及机化性肺炎的表现。同时，肺间质内的小动脉出现明显的结构改变，形态学上与自身免疫性疾病的肺损伤相似。结论 机体的变态反应可能是SARS的损伤机理之一。     

Assessment of synthetic peptides of severe acute respiratory syndrome coronavirus recognized by long-lasting immunity

In order to determine highly immunogenic severe acute respiratory syndrome coronavirus (SARS-CoV) epitope peptides capable of inducing long-lasting immunity, we first screened immunoglobulin-G (IgG) antibodies reactive to 197 different overlapping 15-mers from the SARS-CoV proteins in the sera of three infected patients. Forty-two peptides among them were reactive to the sera from all three patients. Consequently, we tested for the reactivity of these 42 peptides to patients' sera (n = 45) at 6-month post-infection. The significantly higher levels of IgG antibodies specific to three (S791, M207 and N161) of 42 peptides were detectable in the post-infection sera from 23 (51%), 27 (60%) and 19 (42%) of 45 patients, respectively. These three peptides, recognized by their long-lasting immunity, may provide a better understanding of the immunogenicity of SARS-CoV.     

Serum neopterin for early assessment of severity of severe acute respiratory syndrome

Neopterin and C-reactive protein (CRP) concentrations were determined in serum samples from 129 severe acute respiratory syndrome (SARS) patients and 156 healthy blood donors. In the patients with confirmed SARS, an early neopterin elevation was detected already at the day of onset of symptoms and rose to a maximum level of 45.0 nmol/L 3 days after the onset. All SARS patients had elevated neopterin concentrations (>10 nmol/L) within 9 days after the onset. The mean neopterin concentrations were 34.2 nmol/L in acute sera of SARS patients, 5.1 nmol/L in convalescent sera, and 6.7 nmol/L in healthy controls. In contrast, the mean CRP concentrations in both acute and convalescent sera of SARS patients were in the normal range (<10 mg/L). Serum neopterin level in SARS patients was associated with fever period and thus the clinical progression of the disease, while there was no significant correlation between the CRP level and the fever period. Serum neopterin may allow early assessment of the severity of SARS. The decrease of neopterin level was found after steroid treatment, which indicates that blood samples should be collected before steroid treatment for the neopterin measurement.     

The placentas of patients with severe acute respiratory syndrome: a pathophysiological evaluation

AIMS: The pathology of the placentas delivered from pregnant women who had severe acute respiratory syndrome (SARS) in Hong Kong was studied. METHODS: The pathology of the placentas was retrospectively studied in detail and compared with control sets. The clinical data of the women and neonates were also reviewed. RESULTS: A total of seven placentas were studied. The placentas from two women convalescent from SARS in the first trimester were normal. In three placentas delivered in the acute stage of SARS, there were increases in intervillous or subchorionic fibrin which might be related to disturbances in maternal placental blood flow due to the hypoxic respiratory disease. Extensive fetal thrombotic vasculopathy (FTV) with sharply demarcated zones of avascular fibrotic villi was noted in the placentas of two patients convalescent from SARS in the third trimester. Both pregnancies had intrauterine growth retardation, oligohydramnios and newborns small for gestation. The aetiology of the FTV might be related to thrombotic tendency due to SARS or placental hypoxia. CONCLUSIONS: This report highlights placental pathology that was probably the result of pathophysiological alteration of the maternal fetal unit during SARS. Further studies are required to delineate the relationship between severe maternal respiratory disease, placental pathology and pregnancy outcome.     

Pathological changes in masked palm civets experimentally infected by severe acute respiratory syndrome (SARS) coronavirus

Masked palm civets are highly susceptible to infection with the severe acute respiratory syndrome coronavirus (SARS-CoV). Infected animals become less aggressive and develop pyrexia, lethargy and diarrhoea. The present study describes the spectrum of histopathological changes in the lung, spleen, lymph node, liver, small intestine, kidney and cerebrum of civets infected experimentally with SARS-CoV. In-situ hybridization (ISH) with probes specific for the RNA polymerase gene demonstrated viral RNA in the lung, small intestine and cerebrum only. In-situ labelling was employed in order to demonstrate cellular apoptosis in the cerebrum, but there was no evidence of apoptosis within the myocardium. These results indicate that SARS-CoV causes multi-organ pathology in civets, similar to that observed in human SARS patients. These parallels suggest that civets may be used as an animal model of this infection to gain insight into the pathogenesis of SARS and for evaluation of candidate vaccines and antiviral drugs.     

The role of immunoinformatics in analysis of immune response against severe acute respiratory syndrome （SARS） coronavirus

Severe Acute Respiratory Syndrome (SARS) is asevere infectious disease with a 25 %incidence ofprogressionto acute lung injury/acute respiratorydistress syndrome (ARDS) and its mortality ex-ceeding10 %[1] . During the first out break ofSARS,in 2003 ,8450 persons were infected and810 diedincluding some workers serviced in hos-pitals .Duetothe unknowntransmissionroute andunsatisfactory treatment , immunological researchwith SARS coronavirus (SARS-CoV) is forbiddeninlabs except whichreac…