《Implementing New Approaches to Tuberculosis Control》（采取新措施控制结核病）是The New England Journal of Medicine主编、哈佛大学公共卫生学院教授Eric J. Rubin和同事Kristine M. Guinn在2021年「世界结核病日」前夕，应邀为China CDC Weekly撰写的述评。

重点内容摘录

• 由于结核病的传染性，使得耐药很容易造成人群传播。
• 许多国家和地区几乎没有发现耐药性的能力。据世界卫生组织最新报告，全球1,000万例结核病患者中，约有46.5万例是耐多药的。尽管这个数字惊人，但肯定也是被低估了的。
• 随着耐多药和广谱耐药结核病越来越多，针对二、三线药物的传统药敏试验变得更加重要。
• 繁琐且长期的多药治疗过程是导致令人沮丧的高失败率的原因之一。
• 尤其是针对耐药性结核病，某些技术需要更加个性化。

以下为原文

尽管多年从事结核病研究，但也不得不承认长期以来结核病（TB）一直都不是医学上热点领域。现在全世界广泛使用的预防结核病的疫苗是在20世纪30年代研发的。治疗结核病的基础性临床研究是20世纪60年代在印度开展的。上一个治疗结核病的新药及推广使用也是30年前的事了。

这种缓慢发展所带来的重要结果就是在过去几十年里，公共卫生的重点已经从新疗法转变为如何实施我们已有的手段。包括大规模诊断、接触者追踪、药品供应以及患者长期治疗保障的基本公共卫生措施 ，这些都已成为有效控制结核病的主要内容。

但是，结核病干预所面临的挑战和机遇，已经在发生着翻天覆地的变化。应对结核病，在患者个体和未感染群体两个层面上，新的诊断方法、新的治疗方法以及可能的新的预防措施都有可能带来重大的改变。但是使用这些新工具需要在实施层面上进行创新。创新要应用到日渐严峻且日益增加的耐药性结核病上。因此，未来几年面临的挑战，不只是开发新工具，而且是如何应用新工具带来真正的改变。

耐药的问题

对于结核病来说，抗生素耐药不是新问题。使用链霉素不久就发现患者单药治疗无效。由于结核病的传染性，使得耐药很容易造成人群传播。使用联合疗法后，在一定程度上缓解了耐药性的问题。从理论上讲，联合用药的选择会使突变逃逸的可能性大大降低，从而限制新的耐药性产生。

但是，实践与理论是不同步的。当新的抗生素研制出来后，它会被应用到已经逐步获得了患者个体化的对已有药物耐药的突变的人群中。而且由于处方不当、药品不能连续供应以及患者依从性不佳的问题更加剧了耐药结核病患者的增加和后续的传播。更糟的是，许多国家和地区几乎没有发现耐药性的能力。据世界卫生组织最新报告，全球1,000万例结核病患者中，约有46.5万例是耐多药的。尽管这个数字惊人，但肯定也是被低估了的。由于发现耐药性的时间太晚或根本没有发现，许多患者得不到充分的治疗，导致较高的发病率和死亡率以及耐药菌株不可控制的传播。

更好的诊断

近一个世纪以来，我们一直沿用两种方法来确诊结核病。痰涂片快速但相对不敏感，痰培养敏感但太慢。幸运的是，近年来情况发生了很大变化。最引人注目的成果来自工程学、基因学和生物化学相结合的无需培养的方法，如GeneXpert MTB和TrueNat MTB设备。这些检测方法有两个明显的优势，一是快速而且直接用痰液出结果；二是不仅可以用于诊断，同时也可以预测耐药性。这些检测方法紧跟其他技术的进步，包括肉汤培养方法的使用可以加快细菌的生长。

当然，这些新技术只有应用了才有用。对于世界绝大多数流行地区，即使是有国际补助，新设备和耗材价格也贵得惊人。能够为结核病规划提供基于细菌培养开展质量控制的参比实验室也没有普及。随着耐多药和广谱耐药结核病越来越多，针对二、三线药物的传统药敏试验变得更加重要。然而，像中国疾病预防控制中心拥有的能够开展可靠的抗生素敏感性检测的优良的实验室，在全球很多地区尚未普及。当然，将实验室数据信息转化为实践仍然存在问题。

更有效的药物和治疗策略

现有结核病治疗策略一直相当有效。在可控的情况下，该策略至少对于药物敏感结核病，治愈率高达90％及以上。但不幸的是，真实世界的结果是每年死亡人数超过120万。究其原因，患者在“结核病关怀服务链”中不断丢失，其中很多是从未被诊断的，其他有些人诊断后从未接受关怀，有些人无法获得治疗药物，还有些人接受治疗但没有完成治疗。毫无疑问，繁琐且长期的多药治疗过程是导致令人沮丧的高失败率的原因之一。此外，耐药率的升高意味着很多接受标准化治疗的患者实际上未得到充分的治疗，失败率高。

当前的治疗方法存在双重问题。疗程长意味着必须建立起稳固的支持性体系来确保用药的依从性，但支持性体系很昂贵，而且从失败率上看，这种支持性体系也并非总是有用。我们对耐药结核病的治疗疗程更长，失败率更高。

我们在过去的几年中看到了真正的变化。几种新的抗生素已纳入了结核病治疗药品库。其中大多数由于之前没有发现耐药性，因此对耐药的结核分枝杆菌（Mtb）菌株有效。目前投入使用或很快就能投入使用的新型抗结核药物有三种。贝达喹啉（Bedaquiline）是结核分枝杆菌ATP合成酶的抑制剂，是一种强效药。尽管它与三线药氯法齐明（Clofazimine）有交叉耐药性，存在耐药的可能性，但是相对耐药性比较罕见。第二种是硝基咪唑类的德拉玛尼（Delamanid）和普托马尼（Pretomanid），它们作用机理几乎相同，即便有耐药也很罕见。第三种是恶唑烷酮类的利奈唑胺（Linezolid），不是新药，但已显示出对耐药性结核治疗有效，由于该药还未被广泛使用，因此其耐药性还不常见。这些药物与现有的二、三线药物联合使用可显著提高耐药结核病的治愈率。更值得注意的是，一项开放式临床试验表明，治疗失败或者不能耐受其他治疗方案的广泛耐药（XDR）或耐多药的（MDR）结核病患者，口服贝达喹啉、普托马尼和利奈唑胺三种药，6个月的治愈率很高。许多患者对此抱有很大的期待，其中很多都是之前无法医治的患者。

几年来的临床前动物实验表明，某些治疗方法可能缩短药物敏感性结核病的疗程。然而直到今年，临床试验还是令人失望。但是一项最近公布试验（截至撰写本文之日尚未发布）显示，在直接观察治疗下，用利福喷丁（Rifapentine）代替利福平(Rifampin)，联合莫西沙星(Moxifloxacin)的标准方案，4个月的疗效不输于原标准的6个月方案。动物实验也表明联合新药的实验疗程更短。根据最近公布的药物效力，甚至有可能实现 “通用治疗方案”，既能缩短疗程治疗，也能治疗所有患者，无论患者耐药与否。考虑到某些新药的毒性，尤其是利奈唑胺，我们还有很多的工作要做，但令人期待。

预防的可能性

包括中国在内的世界大多数国家都在接种卡介苗（BCG）。这一款20世纪30年代研发的疫苗，有效预防了儿童重症结核病带来的可怕后果，但在控制成人结核病方面效果甚微。研发一种可以为成人提供有效保护的疫苗已历经多年，但直到近期，试验结果仍令人失望。但在过去的两年中，有两项研究让我们看到了希望。其中一项表明，对青少年进行卡介苗（BCG）复种可能保护免受持续性Mtb感染，另一项则表明使用新的佐剂配伍两种Mtb蛋白抗原融合物，三年内预防从感染到发病的有效率达50％及以上。

上述策略还远未达到临床应用。但它们确实表明与卡介苗相比可以对成年人起到更好的保护作用。即使是部分有效的疫苗也可能改变结核病控制格局，尽管带来变化的大小很大程度上取决于实施的好坏。

实施面临的挑战

推广COVID-19疫苗接种的初步经验表明要快速控制疫情，疫苗与实施策略同等重要。这个经验同样适合结核病的控制。目前，尽管需要改进，我们是有良好的诊断手段和有效且廉价药物的。但是，因为世界各地的实施情况并不一致，产生了大量可预防的死亡。强大的结核病控制规划是最好的武器，既能确保个体得到合理治疗，也能保护公众健康，这是因为治疗是我们最好的预防方式。

但是，快速变化对于结核病规划来说是一个挑战，即便是最好的结核病规划也要面临这一挑战。毕竟，这些项目能成功的原因之一是标准化，确保为所有患者提供相同的治疗。然而，尤其是针对耐药性结核病，某些技术需要更加个性化。在大型官僚组织中，即便是更改标准化方法也可能非常困难。事实上，我们中的许多人都听说过规划实施者更倾向于因循守旧，即使新的干预措施明显优于旧的模式。

由于诊断和治疗出现许多新方法，现在是时候接受改变并整合到结核病控制中了。可能有帮助的措施包括：

▷ 适用于涵盖不同诊断速度和敏感性的新诊断工具的检测流程。如果任何一个国家同时在全国所有点上采用一种新的诊断方法，那就简单多了。不会发生这种情况，实际上结核病防治人员面对的情况是每个点上的每位患者不同类型的信息。他们需要帮助解读这些实验结果以及每个实验结果所对应的治疗及接触追踪措施。

▷ 快速识别耐药性。合理治疗越早，传播就越少。但在许多规划中，临床治疗失败后，才意识到耐药性的问题。发现耐药患者不仅有利于患者本人，同时也有利于公众健康。

▷ 快速整合治疗学改进的能力。世界卫生组织的指南更新很快，而且会加快。并非所有抗结核病药物在世界所有地区都能平等可及，但其中有些药物有望对个体和群体有效。结核病规划应该准备如何改变，而不是简单地应对新指南。

▷ 创建用于个体化治疗的支持基础。耐药结核病的识别和最优治疗药物需要在规划中设立专门的路径。最好的规划不仅能够及早诊断耐药性，还可以基于分离的特殊耐药株创建个性化的治疗方案。这可以通过专家对个体的指导来完成，或者更实际地，按照根据相关信息更新的流程来完成。实际上，大多数临床试验的患者，耐药程度是不同的，所以能够创建合适的流程。

▷ 与艾滋病治疗规划整合或至少协作。一旦被诊断为结核病，尤其是那些CD4计数低的患者，及早接受HIV治疗会受益。设一个最适合监控抗逆转录病毒药物和结核抗生素药物之间的相互作用的项目。

我们生活在令人鼓舞的结核病防治时代。经过数十年持续努力，我们在结核病的识别、治疗和预防方面已经取得了实质性的进展。但是只有当我们能够把这些措施应用并转化，努力从实验室应用到公共卫生规划，这些方法才会真正发挥作用。

英文版

标题：Commentary: Implementing New Approaches to Tuberculosis Control

正文：

As someone who has studied tuberculosis (TB) for many years, it is difficult for me to admit, but tuberculosis has not been the most exciting field in medicine for a long time. The vaccine that is used in much of the world was developed in the 1930’s. The foundational clinical research that defines how we treat TB was performed in India in the 1960’s. And the last new drug to enter the TB armamentarium was introduced in many countries almost 30 years ago.

This slow pace has had an important consequence. Over the last few decades the emphasis in public health has moved from new therapies to doing a better job of implementing what we already have. This means that basic public health measures, including large-scale diagnostics, contact tracing, drug supply logistics and ensuring that patients are able to complete long treatment courses, have become the leading edge in efforts to control TB.

But changes are on the horizon, with both challenges and opportunities emerging in TB intervention. New diagnostics, new treatments and, potentially, new ways to prevent TB have the potential of dramatically changing how we approach disease, both at the level of the individual patient and also for the uninfected public. But employing these new tools is going to require reinvention at the level of implementation. And they must be applied in a landscape of significant and increasing drug resistant disease. Thus, the challenge of the next several years is not only going to be in developing tools but also determining how we’re going to use them to produce real change.

THE PROBLEM OF DRUG RESISTANCE

Antibiotic resistance in TB is hardly a new problem. Very early after the introduction of streptomycin patients were seen to fail monotherapy. And, since the disease is transmissible, resistance could easily spread in the population. That problem could be mitigated, to some extent, using combination therapy. In theory, this could limit the evolution of new drug resistance as combinatorial selection makes escape mutations much less likely.

However, practice has not kept up with theory. As each new antibiotic was developed, it was introduced into populations that had already serially acquired individual resistance mutations to the existing drugs. This was exacerbated by inappropriate prescribing, inconsistent drug supply and imperfect patient compliance all leading to increased development and subsequent transmission of drug resistant TB. To make matters worse, many countries and localities have little ability to detect drug resistance. In the most recent WHO report (1), of 10 million worldwide incident TB cases, 465,000 are thought to be multidrug resistant. This is a frightening number but is also undoubtedly an underestimate. Because drug resistance is either detected late or not at all, many patients are being treated inadequately, resulting in greater morbidity and mortality and unchecked transmission of resistant strains.

BETTER DIAGNOSTICS

For close to a century we’ve relied on two approaches to definitively diagnose TB. Sputum smears are fast but relatively insensitive while culture is highly sensitive but extremely slow. Fortunately, this has changed dramatically in recent years. The most dramatic results have come from culture-independent methodologies that result from the combination of engineering, genetics, and biochemistry such as the GeneXpert MTB (2) and TrueNat MTB (3) devices. These have two substantial advantages. They are very rapid and can provide answers directly from sputum. And these tests can not only diagnose disease but can simultaneously predict drug resistance. These tests come on the heels of other technical improvements, including the growing use of broth culture methods which can also accelerate growth.

Of course, these new technologies are only useful if they are actually used. New devices and the supplies they require are prohibitively expensive for most endemic parts of the world even after international subsidies. Reference labs that perform reliable culture-based testing, which is essential for quality control in TB control programs, are not widely available. As multidrug- and extensively drug-resistant TB become more widespread, traditional drug susceptibility testing for second- and third-line drugs becomes even more important. Yet labs capable of reliably testing for these antibiotic susceptibilities, like the excellent lab at the Chinese CDC, are unavailable in most of the world. And, finally, how the information generated in the lab gets translated into practice remains problematic.

MORE EFFECTIVE THERAPIES AND TREATMENT STRATEGIES

The current therapeutic strategy for TB has served us fairly well for a long time. In controlled circumstances, cure rates are very high, 90%, at least for drug-susceptible disease. Unfortunately, real-world results still translate to an estimated >1.2 million annual deaths (1). There are many reasons for this. Patients are lost all along the “TB care cascade,” with many never diagnosed, others never getting connected to care following their diagnosis, others not having access to drugs, and still others starting but not completing therapy (4). There is no question that the cumbersome and extended multidrug course of therapy is a contributor to our frustratingly high failure rates. In addition, rising drug resistance rates mean that many patients receiving standard therapy are being inadequately treated with very high failure rates.

The problem with current therapy is two-fold. The length of therapy means that a substantial infrastructure needs to be built to ensure compliance — though infrastructure is expensive and, as shown by failure rates, doesn’t always work. And our treatments for drug resistant disease are typically even longer, with higher failure rates.

Over the past few years we have seen real changes, however. Several new antibiotics have entered the TB armamentarium. For most of these, there is no real pre-existing resistance, so they are active against circulating drug resistant Mycobacterium tuberculosis (Mtb) strains. Three novel classes of antituberculous drugs are now available and more are on the horizon. Bedaquiline (5), an inhibitor of the mycobacterial ATP synthase, is a very potent drug. Relative resistance is rare, though there is cross-resistance with the third-line agent clofazimine so that there is some pre-existing resistance (6). Two nitroimidazoles, delamanid (7) and pretomanid (8), have nearly identical mechanisms but pre-existing resistance is rare if it exists at all. And linezolid, an oxazolidinone drug, is not new but has been shown to be useful for drug-resistant disease (9). Because it is not widely used, pre-existing linezolid resistance is uncommon. Using these drugs in combination with existing second- and third-line agents has resulted in much higher cure rates for drug-resistant TB. And, most intriguingly, an open label clinical trial showed that using only three oral drugs, bedaquiline, pretomanid and linezolid, resulted in high cure rates within six months in patients with either extensively- (XDR) or multidrug-resistant (MDR) TB who had failed or could not tolerate other regimens (10). These regimens hold great promise for many patients, many of whom were previously untreatable.

For several years, preclinical animal studies have suggested that there might be treatments that could result in a shorter course of treatment for drug- susceptible disease. Until this year, however, clinical trials have been disappointing. But a recently announced trial (unpublished as of the date of writing) has shown that a standard regimen that includes rifapentine instead of the rifampin together with added moxifloxacin for four months with directly observed therapy is non-inferior to the standard six month regimen. And animal experiments that test combinations including new drugs could make that even shorter (11). Given the potency of the recently released agents, it might even be possible to arrive at a “universal regimen” that could simultaneously be shorter and be used to treat all patients regardless of drug resistance. Given the toxicity of some of the newer drugs, particularly linezolid, more work will have to be done before we get there, but it remains an aspirational goal.

THE POSSIBILITY OF PREVENTION

Most of the world, including China, administers the Mycobacterium bovis BCG (BCG) vaccine. This agent, developed in the 1930’s, helps to prevent the devastating consequences of childhood TB but has little efficacy in controlling TB in adults. There has been a long search for a better vaccine that could offer protection to adults but, until recently, trials have been disappointing. However, over the past two years, two studies have shown at least some promise. One suggested that revaccination of adolescents with BCG might protect against persistent Mtb infection (12). Another used a new adjuvant together with a fusion of two Mtb protein antigens, had efficacy of 50% in preventing progression of infection to disease over the course of three years (13).

These new strategies are still far from clinical application. But they do suggest that it is possible to achieve better protection in adults than is afforded by BCG. Having even a partially-effective vaccine could change the TB control landscape, though how much of a change it would bring about would entirely depend on its performance characteristics.

THE CHALLENGE OF IMPLEMENTATION

The early experience with rolling out vaccination against COVID-19 has brought one aspect of disease control into sharp relief — the vaccine is only as good as the implementation strategy that utilizes it. This lesson has long been clear in TB control. Right now, we have good diagnostics and effective and inexpensive drugs, even if they can be improved. But they are being implemented inconsistently around the world, resulting in a huge number of preventable deaths. Having a strong TB control program is the best weapon we have both to ensure proper treatment of individuals and also, because treatment is our best form of prevention, protecting public health.

But rapid change is a challenge to even the best TB control programs. After all, one of the reasons that that these programs can be successful is that they are standardized, ensuring the same care to all patients. However, some of the new technologies require much more individualization, particularly when it comes to drug-resistant disease. And changing even standardized approaches can be very difficult in large and bureaucratic organizations. In fact, many of us have heard from programs that would prefer to stick with older paradigms even when new interventions are demonstrably superior.

Because there are so many new aspects of diagnosis and treatment, it is now time to embrace change and make it an integral part of TB control. Measures that might help include:

- Algorithms that account for the varying speed and sensitivity of newer diagnostics. It would be simpler if any given country adopted a new diagnostic modality at all nationwide sites simultaneously. This will not happen. Instead, TB controllers are going to be faced with different types of information on each patient at each site. They will need help in understanding how to interpret these tests and what each finding should trigger for treatment and contact tracing.

- Rapid recognition of drug resistance. Earlier appropriate treatment is associated with decreased transmission but, in many programs, resistance isn’t recognized until clinical failure occurs. Finding patients with drug resistance not only benefits them but has important consequences for public health.

- An ability to rapidly incorporate advances in therapeutics. WHO guidelines are changing rapidly and the pace of change is likely to accelerate. Not all drugs are equally accessible in all parts of the world. But some of these hold the promise of having a significant impact on individuals and populations. TB control programs should be planning for how they will change rather than simply responding to new guidelines when they arise.

- Creating structures for individualized therapy. Identifying and optimally treating drug resistant TB requires a separate pathway within control programs. The best programs not only diagnose drug resistance early but also create individualized treatment regimens based on the specific resistance profiles of isolates. This can be accomplished either through expert guidance for each individual or, perhaps more practically, through predefined algorithms that change as new information becomes available. In fact, most clinical trials have been performed with patients with varying degrees of drug resistance, enabling the creation of appropriate algorithms.

- Integration or, at least, coordination with HIV treatment programs. Patients, particularly those with low CD4 counts, benefit from starting HIV treatment early when TB is diagnosed. And a single program is best suited to monitor drug-drug interactions between antiretrovirals and TB antibiotics.

We live in an exciting time for TB control. After decades of incremental changes we are on the edge of substantive advancements in how we approach the identification, treatment and prevention of TB. But they will only make a difference if we can apply them across the spectrum of translation, all the way from the lab to the public health program.

作者介绍

Kristine M. Guinn

Project Manager, Harvard T.H. Chan School of Public Health

Eric J. Rubin

Professor, Harvard T.H. Chan School of Public Health；Editor-in-Chief, New England Journal of Medicine

作者单位：Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA

通讯作者：Eric J. Rubin, erubin@hsph.harvard.edu

参考文献 

[1]  World Health Organization. Global tuberculosis report. 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf. [2021-2-7].https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf  

[2]  Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363(11):1005 − 15.  

[3]  Nikam C, Jagannath M, Narayanan MM, Ramanabhiraman V, Kazi M, Shetty A, et al. Rapid diagnosis of Mycobacterium tuberculosis with truenat MTB: a near-care approach. PLoS One 2013;8(1):e51121.

[4]  Naidoo P, Theron G, Rangaka MX, Chihota VN, Vaughan L, Brey ZO, et al. The South African tuberculosis care cascade: estimated losses and methodological challenges. J Infect Dis 2017;216(S7):S702 − 13.   

[5]  Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 2014;371(8):723 − 32.

[6]  Nimmo C, Millard J, van Dorp L, Brien K, Moodley S, Wolf A, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe 2020;1(4):e165 − 74. 

[7]  Gupta R, Gao MQ, Cirule A, Xiao HP, Geiter LJ, Wells CD. Delamanid for extensively drug-resistant tuberculosis. N Engl J Med 2015;373(3):291 − 2.  

[8]  Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet 2015;385(9979):1738 − 47.  

[9]  Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012;367(16):1508 − 18. 

[10]  Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med 2020;382(10):893 − 902.  

[11]  Xu J, Li SY, Almeida DV, Tasneen R, Barnes-Boyle K, Converse PJ, et al. Contribution of pretomanid to novel regimens containing bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis. Antimicrob Agents Chemother 2019;63(5):e00021 − 19.  

[12]  Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med 2018;379(2):138 − 49. 

[13]  Tait DR, Hatherill M, van der Meeren O, Ginsberg AM, van Brakel E, Salaun B, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med 2019;381(25):2429 − 39. 

* 本篇中英文版权为China CDC Weekly 所有。如需转载，请注明出处；如需引用，建议引用格式为：Kristine M. Guinn, Eric J. Rubin. Implementing New Approaches to Tuberculosis Control 2021[J]. China CDC Weekly, 2021. doi: 10.46234/ccdcw2021.053.

本文完

排版：Jerry