CLINICAL DECISIONS

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

一名女性新冠肺炎患者

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.

患者入院已经一周，计划近期出院。康复期间，患者准备回家与年逾65岁的父母共同居住。她对于将SARS-CoV-2传染给父母表示担心。父亲近期接受了肾脏移植，目前正在服用免疫抑制药物。患者要求重复鼻咽拭子核酸检测。PCR结果显示为阳性。

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.

你需要根据新冠肺炎症状出现时间以及重复PCR检测的阳性结果，对患者将病毒传染给父母的风险提出建议。

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.

你会给出以下哪种建议？根据文献、你自己的经验、发表的指南以及其他信息来源，做出你的选择

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.

为帮助你的决策，上述两种选择分别由一名专家阐述理由。

Recommend Continued Isolation

建议继续隔离

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

随着对于SARS-CoV-2传播动力学的了解日益深入，对于新冠肺炎患者隔离时间的推荐意见也持续增加。新冠疫情早期，CDC的推荐意见包括临床情况改善且SARS-CoV-2分子检测结果阴性可以解除隔离。研究表明，没有活力的SARS-CoV-2病毒RNA在上呼吸道可以持续到病情恢复后数日甚至数周，因此这一推荐意见被基于时间（而非基于检测结果）的方式所取代。早期的小样本研究表明，起病10天后呼吸道标本中经PCR检测到的SARS-CoV-2并不能在细胞培养中繁殖，可能不具有传染性。然而，韩国CDC进行的基于人口的大样本研究提示，无论症状是否缓解，第一周后SARS-CoV-2的感染风险显著下降。

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.

对于这名患者，并不推荐重复PCR检测以确定隔离期长短。这是因为，正如前述，PCR结果阳性并不意味着患者具有传染性，而且临床实验室不能进行病毒的组织培养以确定病毒活力。重复PCR检测可以导致隔离时间不必要的延长，造成患者和医务人员的焦虑。对于新冠肺炎诊断方法的缺点以及排毒与活病毒之间的区别，公众的认知非常重要，只有这样，才能保证患者及医务人员了解我们现有的隔离措施。

Reassure the Patient of the Low Risk of Transmission

向患者说明传染风险很低

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?

病例描述的情况集中在这一问题，即新冠肺炎患者发病后多久还能传播病毒？在这一问题的背后，表明了目前检测方法的缺点。首先，rtPCR检测结果是否说明存在可以传播的病毒？其次，呼吸道标本分离到可以体外繁殖的病毒能否预测对人群的传染性？

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.

我对于前一个问题的回答是否定的，而对后一问题的回答是“有这种可能性”，尽管我们并不知道传染所需要的病毒感染剂量。

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.

起病后14天，一名没有基础疾病的24岁女性患者计划出院。尽管患者在ICU接受了数日治疗，但整个病程并不危重：患者一直没有发热，从未接受气管插管，胸片仅有中度改变。

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.

一些报告发现，老年、男性、肥胖、免疫功能抑制或病情严重的新冠肺炎患者排毒时间超过平均时长。这名患者不具备上述任何危险因素，预计其排毒时间不长。

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

在一项对90名确诊新冠肺炎患者（未描述严重程度）的回顾性交叉研究中，研究者将呼吸道标本置于非洲绿猴细胞系中。29%的病例观察到体外感染性，发病后每过1天，病毒繁殖的比数比下降37%。发病超过8天后采集的标本未发现病毒繁殖。

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

对于9例轻症新冠肺炎病例（中青年医务人员）进行了更为详细的病毒学分析，结果显示，血液、尿液或粪便的系列标本中均未分离到病毒。发病后1至5天，所有病例的口咽或鼻咽拭子均发现病毒繁殖。尽管第5天后仍有40%的患者检测到病毒RNA，甚至可以持续到28天，但8天后均未发现病毒繁殖。

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

2021年2月，CDC根据其未发表的资料以及其他研究结果声明，对于轻中度新冠肺炎患者，发病10天后未能分离到可以繁殖的活病毒。即使对于重症病例（收入ICU的绝大多数病例接受气管插管），15天后分离到病毒的概率仅为5%。

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.

总之，这名24岁中度新冠肺炎患者没有长期排毒的危险因素，尽管RNA检测结果仍为阳性，但可能并没有活病毒。她将病毒传染给免疫功能抑制的家人的风险很低。