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[NEJM临床决策]: 医生,我应当隔离多久?
2021年03月20日 临床话题, 模拟诊室 暂无评论


Doctor, How Long Should I Isolate?

Siri R. Kadire, Valeria Fabre, and Richard P. Wenzel

N Engl J Med March 10, 2021
DOI: 10.1056/NEJMclde2100910

Case Vignette 病例介绍

A Woman with Covid-19


Siri R. Kadire, M.D.

A 24-year-old woman with no relevant medical history presented to the emergency department with a 1-week history of cough and shortness of breath. She stated that she had not had any contact with people who were sick but had recently attended a small event. She reported no fever, diarrhea, or loss of taste or smell. On physical examination, she was found to have hypoxemia, with an oxygen saturation of 88%, and crackles were heard on lung auscultation. A chest radiograph showed bilateral interstitial opacities, and a polymerase-chain-reaction (PCR) assay was positive for SARS-CoV-2. She was given supplemental oxygen, delivered by nasal cannula at 2 liters per minute, and was placed in an isolation observation unit overnight for monitoring. The next day, she continued to require oxygen and was admitted to a ward bed. Her oxygen requirements increased, and she was given supplemental oxygen at a rate of 15 liters per minute through a nonrebreather mask and was admitted to the intensive care unit (ICU). Her condition improved over the course of the week, and her need for supplemental oxygen decreased. The remainder of her course was uneventful, and she was transferred back to a ward bed.

一名24岁女性患者既往无特殊病史,因咳嗽和呼吸困难一周到急诊就诊。患者主诉没有与其他病人的接触史,但近期曾参加小型聚会。患者没有发热,腹泻,也没有味觉或嗅觉消失。体格检查发现,患者有低氧血症,氧饱和度88%,且肺部听诊可闻及啰音。胸片显示双侧间质病变,PCR检查提示SARS-CoV-2阳性。患者接受氧疗,鼻导管2 lpm,并收入隔离病房进行监测。第二天,患者仍需氧疗,遂入院接受治疗。期间,患者氧需求增加,使用非重复吸入面罩吸氧15 lpm,并收入ICU。此后一周,患者病情改善,氧需求降低。患者恢复良好,转入普通病房。

It has now been 1 week since her admission to the hospital, and discharge planning has started. The patient plans to go home to stay with her parents, both of whom are over the age of 65 years, while she recuperates. She is concerned about the risk of transmission of SARS-CoV-2 to her parents. Her father is taking immunosuppressive medication after recent kidney transplantation. She has requested that PCR testing be performed again on a repeat nasopharyngeal swab. The PCR test is performed, and the result is positive.


You must advise the patient about the risk of transmitting the virus to her parents, given the time since the onset of Covid-19 symptoms and the positive repeat PCR test.


Treatment Options 治疗选择

Which one of the following approaches would you take? Base your choice on the literature, your own experience, published guidelines, and other information sources.


  1. Recommend continued isolation. 建议继续隔离
  2. Reassure the patient of the low risk of transmission. 向患者说明传染风险很低

To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field.


Recommend Continued Isolation


Valeria Fabre, M.D.

Recommendations on the duration of isolation for patients with Covid-19 continue to evolve with increased understanding of SARS-CoV-2 transmission dynamics. Early in the Covid-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included discontinuing isolation when there was clinical improvement and a negative molecular SARS-CoV-2 test. This recommendation was replaced by a time-based approach (rather than a test-based one) when it became apparent that shedding of nonviable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from illness.1 Early, albeit small studies showed that SARS-CoV-2 detected by PCR in respiratory specimens beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible.2,3Large population-based studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 declines after the first week following symptom onset, irrespective of resolution of symptoms.4


However, a few studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory specimens obtained after the first week following the initial positive PCR test; one patient was never hospitalized, and one had been hospitalized with mild symptoms.5 Complete viral genome sequencing indicated that these cases represented the same infection rather than reinfection. Age, immunocompromised status, and severe illness have been associated with prolonged SARS-CoV-2 RNA shedding1; however, data are insufficient regarding factors associated with prolonged shedding of viable SARS-CoV-2. One recent study showed that some patients with immunosuppression after treatment for cancer could shed viable SARS-CoV-2 for at least 2 months.6 A study of 129 severe cases of Covid-19 showed that the probability of detecting viable virus beyond day 15 after symptom onset was 5% or less.7The CDC currently recommends isolation precautions for 10 days after symptom onset (with fever resolution lasting at least 24 hours without the use of fever-reducing medications), with extension to 20 days for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization severity scale and CDC criteria; thus, continuing isolation for a total of 20 days seems reasonable and in accordance with current evidence. No studies to date have reported person-to-person transmission occurring from the observed late shedding of viable SAR-CoV-2; thus, it may be reasonable to customize decisions regarding duration of isolation on the basis of individual circumstances. In the current case, a household member is a kidney transplant recipient, a condition in which Covid-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.

然而,近期的部分研究对上述观点提出了挑战。一项研究显示,在最初PCR检测结果呈阳性的第一周后,29名患者上呼吸道标本SARS-CoV-2 PCR检测持续阳性,其中14% (4/29)的患者可以分离到能够在体外细胞培养中繁殖的活病毒;其中1名患者从未住院,另1名住院患者症状轻微。全病毒基因组测序结果提示,这些病例并非再次感染。年龄,免疫抑制状态以及病情严重伴随SARS-CoV-2排毒时间延长;然而,有关长期排活病毒的危险因素的数据并不充分。近期一项研究显示,接受肿瘤治疗的部分免疫功能抑制患者其排活病毒时间可能至少2个月。对于129例危重新冠肺炎患者的一项研究表明,起病15天后检测到活病毒的概率低于5%。目前CDC建议采取隔离措施至起病后10天(未使用退热药物的情况下,发热持续缓解至少24小时)。根据WHO的病情分级以及CDC的标准,上述病例为重症感染;因此,继续隔离至20天是合理的选择,并符合现有证据。至今没有研究报告因晚期排活病毒导致人与人之间的传染;因此,根据个人情况对隔离时间进行决策是合理的。就目前这个病例,家人之一为肾脏移植后患者,一旦发生新冠感染,伴随罹患率及病死率增加,这也支持采取20天的隔离期。

Repeat SARS-CoV-2 PCR testing to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious, and viral tissue culture is not available to assess for viable virus in clinical laboratories. Repeat PCR testing can result in unnecessarily prolonged isolation and anxiety for patients and medical teams. Public awareness of the shortcomings of Covid-19 diagnostic tests and the distinction between shedding of viral RNA and viable virus is essential to ensure that patients and health care workers are comfortable with our current approach to isolation precautions for patients with Covid-19.


Reassure the Patient of the Low Risk of Transmission


Richard P. Wenzel, M.D.

The scenario in the vignette focuses on the question of how long after symptom onset a patient with Covid-19 can transmit the virus, SARS-CoV-2. Behind that question are additional questions that highlight current shortcomings in testing. First, is a reverse-transcriptase PCR test result a valid surrogate for the presence of transmissible virus? Second, does in vitro growth of virus from respiratory specimens predict transmissibility to people?


I’ll argue that the answer to the first question is “no” and to the latter “probably,” though we don’t know the infecting dose for transmission.


Fourteen days after the onset of symptoms, a 24-year-old woman with no underlying coexisting conditions is undergoing discharge planning. Though she spent several days in the ICU, her course was moderate, not severe: she was persistently afebrile, was never intubated, and had only moderate changes on chest radiography.


Some reports suggest that patients with Covid-19 who are older, male, or obese, who are immunosuppressed, or who have severe disease have longer-than-average periods of shedding virus. This patient has none of the above characteristics and would not be expected to have prolonged viral shedding.


In a retrospective, cross-sectional study of 90 patients with confirmed Covid-19 (severity not described), the investigators placed respiratory specimens on African green monkey (Vero) cell lines. In vitro infectivity was observed in 29%, and the odds ratio for viral growth decreased by 37% for each additional day after the onset of symptoms. No growth was detected in samples collected more than 8 days after the onset of symptoms.8


A detailed virologic analysis of nine cases of mild Covid-19 in young and middle-aged professionals showed no virus isolation in serial samples of blood, urine, or stool. Viral growth was found from oral–pharyngeal or nasopharyngeal swabs in all the patients from days 1 through 5 after symptom onset. Although viral RNA was detected in 40% of the patients after day 5, and was even detected up to 28 days, viral growth was not detected after day 8.2


Cheng and colleagues prospectively enrolled 100 patients with confirmed Covid-19 and 2761 contacts. The attack rate for 1818 contacts who were exposed within 5 days after symptom onset in the primary pool of patients was 1% (95% confidence interval [CI], 0.6 to 1.6), yet the attack rate among 852 contacts exposed later was 0% (95% CI, 0.0 to 0.4).9

Cheng及其同时前瞻性入选100名确诊病例及2761名密切接触者。在患者发病5天内与其接触的1818名密切接触者发病率为1%(95% 可信区间 [CI], 0.6 to 1.6)。而晚期暴露的852名密切接触者发病率为 0% (95% CI, 0.0 to 0.4)。

A systematic review and meta-analysis of SARS-CoV-2 case series, cohort studies, and randomized trials showed RNA shedding for 17 days after symptom onset (95% CI, 15.5 to 18.6) in upper respiratory samples among a total of 3229 participants in 43 studies and for 14.6 days (95% CI, 14.4 to 20.1) in lower respiratory tract samples among a total of 260 participants in 7 studies. Although RNA could be detected up to 83 days and 59 days in upper and lower respiratory samples, respectively, no study detected live virus beyond day 9 of illness.1

对于SARS-CoV-2病例的系统回顾与meta分析,以及随机临床试验显示,43项研究共计3229名患者起病17天(95% CI, 15.5 to 18.6)后,其上呼吸道仍可检测到病毒RNA,7项研究共计260名患者发病14.6天(95% CI, 14.4 to 20.1后,下呼吸道标本可检测到病毒RNA。尽管上下呼吸道标本检测到RNA可分别持续到发病后83天和59天,但没有研究在发病9天后检测到活病毒。

In February 2021, the CDC, citing their own unpublished data and those from other sources, stated that in patients with mild or moderate Covid-19, replication-competent virus hasn’t been recovered after 10 days following symptom onset. Even in severe illness (the vast of majority of patients admitted to the ICU had been intubated), the probability of virus isolation after 15 days was 5%.10


In summary, a 24-year-old woman with moderate Covid-19 infection and no markers for extended viral shedding has positive RNA detection yet probably has no replication-competent virus. She has little probability of transmitting SARS-CoV-2 to an immunosuppressed family member at home.


Given your knowledge of the issue and the points made by the experts, which approach would you choose? 基于你的知识以及专家意见,你会选择哪项措施?

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