Adverse events associated with high-dose ribavirin: evidence from the Toronto outbreak of severe acute respiratory syndrome

STUDY OBJECTIVES: To distinguish adverse events related to ribavirin therapy from those attributable to severe acute respiratory syndrome (SARS), and to determine the rate of potential ribavirin-related adverse events. DESIGN: Retrospective cohort study. SETTING: Hospitals in Toronto, Ontario, Canada. PATIENTS: A cohort of 306 patients with confirmed or probable SARS, 183 of whom received ribavirin and 123 of whom did not, between February 23, 2003, and July 1, 2003. Of the 183 treated patients, 155 (85%) received very high-dose ribavirin; the other 28 treated patients received lower-dose regimens. MEASUREMENTS AND MAIN RESULTS: Data on all patients with SARS admitted to hospitals in Toronto were abstracted from charts and electronic databases onto a standardized form by trained research nurses. Logistic regression was used to evaluate the association between ribavirin use and each adverse event (progressive anemia, hypomagnesemia, hypocalcemia, bradycardia, transaminitis, and hyperamylasemia) after adjusting for SARS-related prognostic factors and corticosteroid use. In the primary logistic regression analysis, ribavirin use was strongly associated with anemia (odds ratio [OR] 3.0, 99% confidence interval [CI] 1.5-6.1, p<0.0001), hypomagnesemia (OR 21, 99% CI 5.8-73, p<0.0001), and bradycardia (OR 2.3, 99% CI 1.0-5.1, p=0.007). Hypocalcemia, transaminitis, and hyperamylasemia were not associated with ribavirin use. The risk of anemia, hypomagnesemia, and bradycardia attributable to ribavirin use was 27%, 45%, and 17%, respectively. CONCLUSIONS: High-dose ribavirin is associated with a high rate of adverse events. The use of high-dose ribavirin is appropriate only for the treatment of infectious diseases for which ribavirin has proven clinical efficacy, or in the context of a clinical trial. Ribavirin should not be used empirically for the treatment of viral syndromes of unknown origin.     

利巴韦林治疗与SARS患者心率减慢的关系

目的:分析应用利巴韦林治疗与严重急性呼吸综合征(SARS)患者心率减慢的关系,探讨利巴韦林少见的不良反应,为临床合理用药提供参考.方法:采用药物流行病学病例对照研究的方法,回顾分析181例SARS患者的住院病历,应用利巴韦林的患者135例为试验组,未用的46例为对照组,分析使用利巴韦林治疗SARS与心率减慢的关系.结果:使用利巴韦林治疗的SARS患者,其心率减慢,与对照组比较P＜0.05,引起心率减慢的危险性为不使用利巴韦林治疗的4.1倍,这种危险性的可信范围为1.59～10.55.结论:使用利巴韦林治疗有致SARS患者心率减慢的不良反应.     

Advancements in the battle against severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Respiratory failure is the major complication of SARS and approximately 20% of patients may progress to acute respiratory distress syndrome requiring invasive mechanical ventilatory support. However, the severity is much milder in infected young children. Treatment of SARS was empirical in 2003 due to our limited understanding of this new disease. Protease inhibitors (lopinavir/ritonavir) in combination with ribavirin may play a role as antiviral therapy in the early phase, whereas the role of IFN and systemic steroid in preventing immune-mediated lung injury deserves further investigation. Knowledge of the genomic sequence of the SARS coronavirus has facilitated the development of rapid diagnostic tests. In addition, other antiviral treatment, RNA interference, monoclonal antibody, synthetic peptides, and vaccines are being developed. This paper provides a review of the epidemiology, clinical features and possible treatment strategies of SARS.     

Advancements in the battle against severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Respiratory failure is the major complication of SARS and ～ 20% of patients may progress to acute respiratory distress syndrome requiring invasive mechanical ventilatory support. However, the severity is much milder in infected young children. Treatment of SARS was empirical in 2003 due to our limited understanding of this new disease. Protease inhibitors (lopinavir/ritonavir) in combination with ribavirin may play a role as antiviral therapy in the early phase, whereas the role of IFN and systemic steroid in preventing immune-mediated lung injury deserves further investigation. Knowledge of the genomic sequence of the SARS coronavirus has facilitated the development of rapid diagnostic tests. In addition, other antiviral treatment, RNA interference, monoclonal antibody, synthetic peptides, and vaccines are being developed. This paper provides a review of the epidemiology, clinical features and possible treatment strategies of SARS.     

Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin

Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1alpha, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.     

Development of antiviral therapy for severe acute respiratory syndrome

A new disease, the severe acute respiratory distress syndrome (SARS), caused by the SARS coronavirus (SARS-CoV), emerged at the beginning of 2003 and rapidly spread throughout the world. Although the disease had disappeared in June 2003 its re-emergence cannot be excluded. The development of vaccines against SARS-CoV may take years. Therefore, the availability of effective antiviral drugs against SARS-CoV may be crucial for the control of future SARS outbreaks. In this review, experimental and clinical data about potential anti-SARS drugs is summarised and discussed. Animal model studies will be needed to help to determine which interventions warrant controlled clinical testing.     

Recent patents on treatment of severe acute respiratory syndrome (SARS)

Severe acute respiratory syndrome (SARS) is an epidemic that spread worldwide in early 2003. The aetiological agent was originally defined as a novel coronavirus and later designated as the SARS coronavirus (SARS-CoV), which appears similar to other coronaviruses in both virion structure and genome organization with a single-stranded, plus-sense RNA. However, the epidemiology and pathogenesis of SARS remain poorly understood and there is currently no effective treatment. To date, considerable research has been done on detection, prevention and treatment of SARS. In this review, we mainly focus on the recent patents and research work on detecting, preventing and treating SARS.     

利巴韦林治疗新型冠状病毒肺炎可能性系统评价

目的系统评价利巴韦林治疗新型冠病毒肺炎的可能性。方法检索PubMed,Embase,The Cochrane Library,以及中国期刊全文数据库(CNKI)、万方数据库(WangFang DATA)、中国生物医学文献数据库(CBM)等有关利巴韦林治疗严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)的文献,同时回溯纳入文献的参考文献。应用世界卫生组织(WHO)推荐的快速系统评价方法,并对文献质量进行评价,评估利巴韦林治疗2019新型冠状病毒肺炎(COVID-19)的可能性。结果共检索到437篇文章,最终纳入18项研究。SARS疫情期间,我国大陆、香港以及加拿大等国家或地区都有应用高剂量利巴韦林联合干扰素、激素、洛匹那韦/利托那韦(LPV/r)治疗的经验,高剂量利巴韦林的不良反应有贫血、心动过缓、肌痛、低氧血症、电解质紊乱等,这些不良反应可能导致停止药物治疗或不良结局。结论利巴韦林可在联合应用干扰素、激素、LPV/r并严密监测相关不良反应的基础上尝试用于COVID-19的治疗,但其临床有效性还有待更多的随机对照试验来证实。     

利巴韦林用于病毒感染性疾病国内外文献分析

目的为新型冠状病毒肺炎(COVID-19)的治疗提供参考。方法计算机检索Ovid Medline,Ovid EMBase,Cochrane Central Register of Controlled Trials(CENTRAL),以及中国知识基础设施工程(CNKI)数据库,检索时限均为建库至2020年3月10日,对符合纳入标准的文献进行描述性分析,探讨利巴韦林用于感染性疾病的有效性和安全性。结果初筛文献392篇,筛选后最终纳入利巴韦林用于病毒感染性疾病文献99篇,其中关于流行性感冒37篇、获得性免疫缺陷综合征(HIV)9篇、严重急性呼吸综合征(SARS)8篇、中东呼吸综合征(MERS)13篇、COVID-191篇、寨卡病毒(ZIKV)3篇、登革热病毒(DENV)9篇、拉沙病毒(LV)8篇、汉坦病毒(HV)5篇、基孔肯尼亚病毒(CHIKV)6篇。流行性感冒治疗中,多采用利巴韦林与其他药物(多为奥司他韦)联合抗病毒治疗。体外试验显示,利巴韦林对HIV,SARS-CoV,MERS-CoV均有抑制作用,但临床研究效果不确切;DENV动物实验显示无效;ZIKV,HV,CHIKV体外试验显示有效;建议重新评估对LV的临床疗效。利巴韦林用于COVID-19的研究仅1篇。结论仍需开展更多规范的回顾性临床病例研究,验证利巴韦林治疗COVID-19的疗效。     

利巴韦林治疗SARS患者致心率减慢的病例对照研究

目的分析利巴韦林治疗SARS患者与心率减慢的关系,为临床合理用药提供参考。方法采用药物流行病学病例对照研究的方法,回顾分析我院181例SARS患者使用利巴韦林治疗与心率减慢的关系。结果本文研究发现,使用利巴韦林治疗SARS患者有减慢心率的作用,且多发生在用药后0～3d,并可能与剂量有关;其发生心率减慢/心动过缓的例数与对照组比较有显著性差异(P<0.05),引起心率减慢的危险性是对照组的4.1倍(1.59～10.55)。结论利巴韦林治疗SARS患者有致心率减慢的不良反应。     

无创正压通气对严重急性呼吸综合征患者的治疗价值

目的探讨无创正压通气(NIPPV)在救治严重急性呼吸综合征(severeacuterespiratorysyndrome,SARS)致呼吸衰竭患者中的治疗作用。方法采用临床观察研究的方法,对太原地区五所三级综合医院2003年3月至2003年5月所收治的临床确诊的304例SARS患者的临床资料及NIPPV治疗情况进行分析。结果304例SARS患者中接受NIPPV治疗的有44例(14.5%),男性25例,女性19例,年龄(46±14)岁。有基础疾病者11例(25%)。应用NIPPV的平均时间(20±5)d。其中34例(77%)患者成功撤机,康复出院;3例患者(7%)因病情加重转为有创机械通气治疗;7例(16%)患者死亡。死亡组患者与存活组患者相比,年龄较大、有基础疾病者和并发症人数的比例增高(P<0.05)。应用NIPPV通气治疗后,患者脉搏容积血氧饱和度(SpO2)、动脉血氧分压(PaO2)明显改善,呼吸频率(RR)、心率(HR)减慢,动脉血二氧化碳分压(PaCO2)回升,与通气前比较各指标的变化差异有显著性(P<0.05)。但pH值变化不明显。13例患者出现恐惧、配合差、鼻咽部干燥及胃胀气,未发现气压伤及医务人员在应用NIPPV过程中感染SARS。结论应用NIPPV辅助通气可明显改善SARS患者的呼吸困难症状、纠正低氧血症,显著降低对气管插管的需求。NIPPV应用的时机、患者的年龄、既往健康状况可能是影响NIPPV预后的主要危险因     

利巴韦林对57例SARS患者血红蛋白的影响

目的:了解利巴韦林(ribavirin,RBV)对严重急性呼吸综合征(SARS)患者血红蛋白的影响。方法:以57例使用了利巴韦林的SARS患者为观察对象,对治疗前后血红蛋白的变化与利巴韦林总用药时间、累积总量、日用药量的关系进行分析。结果:用药前、后血红蛋白水平相比差异显著(P<0.05)。血红蛋白下降的幅度与利巴韦林累积总量及总用药时间无关;而与该药的每日用量相关(P<0.01)。结论:利巴韦林每日用量对SARS患者血红蛋白影响大,推荐临床小剂量使用利巴韦林。     

Antiviral applications of RNAi for coronavirus

Until the appearance of severe acute respiratory syndrome (SARS), caused by the SARS coronavirus (SARS-CoV) in early 2003, coronavirus infection was not considered to be serious enough to be controlled by either vaccination or specific antiviral therapy. It is now believed that the availability of antiviral drugs effective against SARS-CoV will be crucial for the control of future SARS outbreaks. Recently, RNA interference has been successfully used as a more specific and efficient method for gene silencing. RNA interference induced by small interfering RNA can inhibit the expression of viral antigens and so provides a new approach to the therapy of pathogenic viruses. This review provides an overview of current information on coronavirus and the application of small interfering RNA in viral therapeutics, with particular reference to SARS-CoV.     

Clinical management and infection control of SARS: Lessons learned

The outbreak of severe acute respiratory syndrome (SARS) in 2003 was the first emergence of an important human pathogen in the 21st century. Responding to the epidemic provided clinicians with extensive experience in diagnosing and treating a novel respiratory viral disease. In this article, we review the experience of the SARS epidemic, focusing on measures taken to identify and isolate patients, prevent the transmission of infection to healthcare workers and develop effective therapies. Lessons learned from the SARS epidemic will be especially important in responding to the current emergence of another highly pathogenic human coronavirus, the agent of Middle East respiratory syndrome (MERS), and to the recently emerging H7N9 influenza A virus in China. This paper forms part of a symposium in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”     

Antiviral applications of RNAi for coronavirus

Until the appearance of severe acute respiratory syndrome (SARS), caused by the SARS coronavirus (SARS-CoV) in early 2003, coronavirus infection was not considered to be serious enough to be controlled by either vaccination or specific antiviral therapy. It is now believed that the availability of antiviral drugs effective against SARS-CoV will be crucial for the control of future SARS outbreaks. Recently, RNA interference has been successfully used as a more specific and efficient method for gene silencing. RNA interference induced by small interfering RNA can inhibit the expression of viral antigens and so provides a new approach to the therapy of pathogenic viruses. This review provides an overview of current information on coronavirus and the application of small interfering RNA in viral therapeutics, with particular reference to SARS-CoV.     

2种SARS冠状病毒分子生物学快速检测方法的建立

目的建立SARS冠状病毒NS、S基因的检测方法,为青岛市可能出现的SARS病毒流行提供一个标准的、可以确证为SARS病毒感染的实验室检测方法。方法分别根据SARS-CoVnsp11基因和S基因片段序列,建立了2种SARS-CoV基因检测方法,并对2003年4月20日～2003年9月20日期间收集的106份青岛市部分医院呼吸道门诊急性呼吸道感染者的血清样品进行了检测。结果106份急性呼吸道感染标本和健康对照人群的SARNS、S基因RT-PCR检测均为阴性。结论建立的2种SARS-CoV核酸RT-PCR检测的方法具有较高的特异性,可用于SARS感染的实验室检测。同期急性呼吸道感染人群中未发现SARS感染病例。     

发热门诊与SARS传染病流行的关系

目的：探讨发热门诊在SARS传染病流行中的作用。方法：总结天津市SARS流行期间，我院发热门诊的患者组成及特点，采用归一化方法对比同期我市SARS病例的分布及2002年同期我院呼吸道感染急诊患者分布。结果：今年近一个月我院发热门诊累积就诊患者429例，转诊(定点医院)4例，其中确诊或疑似患者各1例。初诊病例以社区获得性呼吸道感染为主，占78．1％。2002年同期我院急诊呼吸道感染患者443例。今年同期天津市每日新增SARS确诊病例累计175例，其中医务人员67例。与去年同期相比，今年每日新增发热患者波动大，并呈现与SARS疑似患者相似的消长趋势，与SARS确诊患者峰值出现时间亦相近。结论：SARS流行期间我院发热门诊以普通发热病人为主，SARS患者不多，这与本市SARS流行期间，SARS病例以医院感染为主的特点相一致。急性发热患者数波动高峰是否有轻型SARS感染患者的参与尚待日后进一步研究。     

Severe acute respiratory syndrome (SARS): the pharmacist's role

OBJECTIVES: After two outbreaks of severe acute respiratory syndrome (SARS) occurred in Toronto, Ontario, Canada, from March-June 2003, we reviewed the unexpected role and responsibilities of pharmacists during these two crises, and present strategies for better crisis preparedness. METHODS AND RESULTS: Pharmacists were actively involved in battling the SARS crises. After conducting extensive literature searches and evaluations, pharmacists prepared administration and dosing guidelines for the two investigational drugs, ribavirin and interferon alfacon-1, that were being used to treat the syndrome. They provided direct patient care under modified conditions. They revised drug distribution procedures and developed new ones to meet more stringent infection-control standards. Collaborative teamwork with key stakeholders was important in accomplishing tasks in an efficient and timely manner. Regular communication with health care staff took place internally and externally. Education and updated information for pharmacists was crucial. CONCLUSION: Pharmacists can play a vital role during crises in the areas of drug distribution, drug information, and direct patient care. Collaborative teamwork and close communication are keys to success. Pharmacists must be proactive and take a leadership role in assuming pharmacy-related responsibilities. By evaluating what worked and what didn't, pharmacists can develop procedures for future crises requiring pharmacy support.     

Treatment of respiratory syncytial virus pneumonia in a lung transplant recipient: case report and review of the literature

A 61-year-old woman who underwent lung transplantation developed severe respiratory syncytial virus (RSV) pneumonia and experienced respiratory failure requiring mechanical ventilation. She was treated initially with aerosolized ribavirin monotherapy; RSV hyperimmune globulin was later added to her regimen. Lung transplant recipients are acutely susceptible to respiratory infections, including community-acquired respiratory viruses. Respiratory syncytial virus is particularly difficult to treat in immunocompromised patients because of the lack of proved pharmaceutical agents and solid scientific evidence by which to guide therapy. The most important factor appears to be the early start of therapy; immunocompromised patients who develop RSV pneumonia and subsequent respiratory failure requiring mechanical ventilation have a mortality rate approaching 100%. This case report demonstrates the successful treatment of RSV pneumonia with the combination of aerosolized ribavirin and RSV hyperimmune globulin in a severely ill lung transplant recipient who required mechanical ventilation.     

重症严重急性呼吸综合征临床特点及其预警指标的分析

目的探讨重症严重急性呼吸综合征(SARS)患者的临床特点以及发生重症的预警指标,为SARS患者的病情估计、临床救治和预后提供资料。方法根据“重症SARS的诊断标准”将2003年3月至6月山西省太原市确诊的、临床资料完整的304例SARS患者分为非重症组和重症组,分析两组间临床及实验室指标的差异性,以及发生重症SARS可能的危险因素。结果①重症组患者平均年龄[(44±16)岁]大于非重症组[(33±12)岁],差异有统计学意义(P<0.01),重症组年龄>50岁患者比例(32.3%)及合并基础疾病者(15.0%)明显高于非重症组(10.7%、2.0%,P均<0.01)。②重症组入院后最高体温[(38.8±0.9)℃]、发热持续时间[(15±12)d]及胸片病变累及双肺者比例(58.6%)均高于非重症组[(38.3±1.0)℃、(10±8)d和40.5%],差异均有统计学意义(P均<0.01)。③重症组病程各期呼吸频率均高于非重症组,血氧饱和度和动脉血氧分压均低于非重症组,差异均有统计学意义(P均<0.01)。④重症组病程各期血白细胞总数均高于非重症组;而淋巴细胞绝对值均低于非重症组,差异均有统计学意义(P<0.05)。⑤年龄≥50岁、呼吸频率≥24次/min和经皮血氧饱和度≥90%时发生重症SARS的危险度分别为年龄<50岁、呼吸频率<24次/min和经皮血氧饱和度<90%的3.442、1.219和0.545倍,95%可信区间分别为1.391～8.518、1.067～1.393和0.451～0.659(P值分别为0.007,0.004和0.000)。结论重症SARS患者具有年龄大、合并基础疾病多、发热持续时间长、呼吸频率快、血氧饱和度低、白细胞总数高、淋巴细胞计数低及X线胸片病变累及双肺多等特点。因此年龄≥50岁、呼吸频率≥24次/min和经皮血氧饱和度<90%可作为发生重症SARS的预警指标。