RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1626 (Published 28 April 2020) Cite this as: BMJ 2020;369:m1626Read our latest coverage of the coronavirus pandemic
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Dear Editor
I read this article with interest. It appears that for a large problem we need a large solution. So the RECOVERY trial is the largest of its kind, i.e. cost and patients numbers. It also appears that large problems can only be solved by large institutions or large companies. However, the fact is that these projects are developed by individuals who happened to be in large settings. This leaves individuals in small companies that have been working on respiratory RNA virus, including Coronavirus, out on their own.
It was reported by one of these small companies that they produced a new drug made of combination of Trimethoprim and zinc (Tri-Z). The mechanism of action was diverse acting on the host, thus overcoming the potential mutations of these RNA viruses. Although trimethoprim and zinc are well known and the combination showed good response for influenza, rhinovirus and respiratory Syncytial virus, that simple solution is not acceptable for large problems like a pandemic. We experienced good response with Tri-Z against COVID-19 and none of the patients needed hospital admission. Setting up a trial is more than just challenging.. Perhaps, policy makers need to facilitate for such small organisations to receive funding to develop and sort out large problems like the COVID-19 pandemic.
Elhabbal M. Zn/Trimethoprim combination therapy. International publication number: WO 2009/109531 (11.09.2009 Gazette 2009/37) therapy. https://patentimages.storage.googleapis.com/6f/ee/f3/555aad40853f57/EP22...
Competing interests: No competing interests
Dear Editor
Rapid and effective large scale recruitment into the NIHR RECOVERY trial is something we can be proud of as a nation. However the design of RECOVERY requires closer scrutiny bearing in mind that these were sick hospitalised patients with severe COVID-19 infection. In broad terms treatments may be divided into those which address the upstream disease pathway with antivirals or drugs which block viral host cell entry such as hydroxychloroquine; or the downstream pathway by modifying the adaptive cytokine cascade and associated hyper-inflammatory response [1]. In many respects COVID-19 presents in its later phase as a viral induced multi-organ autoimmune disease and hence strategies are required to selectively block the cytokine cascade. It is therefore somewhat naïve to believe that using monotherapy in the first randomised treatment arm of RECOVERY would be a successful strategy.
Somewhat late in the day a second randomisation arm has now been added to RECOVERY where the anti-IL 6 agent tocilizumab [2] or no additional treatment may be given concurrently within hours of the first arm in patients with evidence of hypoxia (SaO2<92%) and hyperiflammation (CRP >65mg/l), if and when their condition deteriorates. Unfortunately this will mean that it is not possible to assess the potential for any facilitation of response between the first and second randomisation arms due to simultaneous dosing regimens, for example, between hydroxychloroquine and tocilizumab, considering the former also inhibits IL6 production [3].
One also perhaps has to question the ethical aspects of a patient with severe deteriorating COVID-19 having a 10% overall chance of being randomised to standard of care in both the first and second arms. We believe a more cogent strategy would have been to add in a first randomisation arm comprising the combination of upstream and downstream treatments with hydroxychloroquine plus tocilizumab so that this could be compared head to head versus hydroxychloroquine alone to evaluate putative synergy [4]. As such we have reservations about the inherent design flaws in RECOVERY due to confounding carryover effects between the first and second randomisation arms, which in turn will obviate a proper evaluation of combination therapy for severe COVID-19.
1. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033-34. doi: 10.1016/S0140-6736(20)30628-0 [published Online First: 2020/03/21]
2. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences 2020:202005615. doi: 10.1073/pnas.2005615117
3. Sperber K, Quraishi H, Kalb TH, et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993;20(5):803-8. [published Online First: 1993/05/01]
4. Lipworth B, Chan R, Lipworth S, et al. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020 doi: 10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21]
Competing interests: No competing interests
Dear Editor
A short while ago, I listened to a voiced-over doctor on the BBC. She said that some senior doctors had written to the UK’s Chief Medical Officer complaining about restrictions on their ability to prescribe for Covid-19. Apparently, they were being asked not to use hydroxychloroquine (HCQ) outside the relevant experimental arm of the Government RECOVERY project. There was, in their view, little chance that the other two experimental arms would work. They were therefore being asked to randomise some patients to what might well be a preventable death, while withholding a potentially useful treatment from others. As an 82-year-old man, vulnerable to Covid-19 and with experience of non-medical research, I was concerned by this news. This reply reflects my continuing need for reassurance.
The RECOVERY Trial proved to be an impressively large and rapidly commissioned study with an ‘off-the-shelf’ design (one arm per drug tested), in danger of being overtaken by events. One drug tested (Lopinavir-Ritonavir) has now failed in two trials (1, 2). Another (Dexamethasone) is (according to WHO (3)) an ‘adjunctive treatment’ not to be used for Covid-19 outside trials. Dexamethasone reduces inflammation but may embolden viruses, was not shown to work for SARS (4), and used with influenza may kill (5). Azithromycin, also tested, is an antibiotic with anti-inflammatory properties, a logical response to possible cytokine storms and secondary infections, but not to the virus itself. The conflicting and inconclusive evidence on Corticosteroids (6) and Azithromycin (7) relates to their use in combination with other drugs. Why use them on their own rather than in a cross-cutting design (8) where antivirals (relevant to all) are randomly matched with anti-inflammatories (used with discretion) and placebos?
There was better news on HCQ. A small Chinese trial (9) (unfairly dismissed IMHO in a BMJ editorial) suggests that taken at the right time (10) it can stop the disease in its tracks. HCQ provides an arm of the RECOVERY trial for hospital patients (this may be the wrong time for them (11)) but the impressive Principle trial randomises it among selected patients in the community. Sadly, an underlying heart condition means that the recommended dose might kill me (12). It reports in March 2021, too late to influence our lockdown exit. Will this enable me to cuddle my grandchildren? I think not.
Meanwhile there is new evidence from trials of Remdesivir (13,14) and Sovodak (15). Many trials report by July (16). Clinical developments in the delivery of Oxygen (17) may anticipate the results of an 18-month trial (18). Surely, medicine does not advance by trials alone? Practice in my field, and perhaps even in this more scientific one, reflects growing experience and inconclusive but hopefully converging, research. It evolves messily. From my patient’s viewpoint our trials should not hold this back.
Fortunately, the trials are adaptive. They will change with emerging results. Nevertheless, questions remain. Are there strong formal links between these trials and similar international ones (e.g. the French-led DISCOVERY, and WHO SOLIDARITY trials) thus allowing comparable outcome criteria, meta-analyses, and – crucially – quicker recognition that some arms should be stopped? Is there capacity for real-time statistical, and scientific/medical appraisal of both the developing clinical and research evidence? Are there mechanisms for taking decisions on the trials balancing both the internal and external evidence?
In summary, we bet on two trials. Each follows traditional practice in comparing single variables. One has experimental arms unlikely to work; the other an experimental arm, not suitable for everyone and with risks likely to require close monitoring. Practice will vary between these arms because of the treatments involved. Methods for ensuring up-to-date best practice in all arms are not described. Without this, the results are scientifically dubious (if the risks of HCQ require monitoring it may be this that produces a result) and potentially out-of-date. The challenge for the trials is to adapt in such a way that, without loss of rigour, they test whatever is, at the moment, best practice against something potentially better.
1 https://www.nejm.org/doi/full/10.1056/NEJMoa2001282
2 https://www.medrxiv.org/content/10.1101/2020.03.19.20038984v2
3 https://www.who.int/publications-detail/clinical-management-of-severe-ac...(ncov)-infection-is-suspected
4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/
5 https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2395-8
6 https://www.medrxiv.org/content/10.1101/2020.03.06.20032342v1
7 https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30172-7/fulltext
8) https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30172-7/fulltext
9) https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
10) https://www.who.int/csr/resources/publications/influenza/11_29_01_A.pdf
11) https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf
12) https://www.acc.org/latest-in-cardiology/articles/2020/04/10/15/06/acc-j...
13) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
14) https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/g...
15) https://publicaddress.net/hardnews/has-iran-found-an-effective-covid-19-...
16) https://www.biocentury.com/trial-timeline
17) https://www.warringtonguardian.co.uk/news/18402785.warrington-hospital-c...
18) https://www.hra.nhs.uk/covid-19-research/approved-covid-19-research/282338/
Competing interests: No competing interests
Dear Editor
As clinical researchers in stroke we applaud the rapid mobilisation of clinical research into COVID-19 in response to this new global health threat. As deaths in UK hospitals and care homes from COVID-19 pass 30,000 (as of 6 May), nearly 100 urgent research studies in COVID-19 have been approved within just the last few weeks, many of them, like RECOVERY, complex clinical trials of drugs that would have taken months or even years to start before the pandemic. [1] This rapid progress has been achieved in part due to streamlined regulation and expedited approvals, whilst still preserving the rights of patients and the public.
However our admiration is tempered by frustration. Year after year, stroke kills around 40,000 people in the UK [2] – most of whom are older people with ‘underlying health conditions’ – and five and a half million people worldwide. [3] Globally stroke is the second leading cause of premature death, a situation expected to prevail for the next 20 years or more. [4] Worldwide, there are 80 million stroke survivors, many living with the disabling effects of stroke and it’s devastating social and economic consequences.[3] When we talk to patients with stroke and their families, they immediately grasp the urgency of stroke research, and they share our frustration when they hear of the disproportionate regulatory and bureaucratic hurdles that slow the approval, start-up and conduct of valuable research into their disease. [5]
So as clinical researchers in stroke we commend the rapid response of regulators and funders in support of our counterparts in virus and public health research in the face of this global public health emergency. Our call is to take this further, and to see the same streamlined and proportionate approach taken to research into the other major threats to worldwide health. Let one of the many lessons that nations learn from COVID-19 be a reappraisal of the regulatory burden for clinical research and audit into the leading communicable and non-communicable causes of death and disability, proportionate to the threat that these diseases represent. Let the evidence we have seen of streamlined and reduced regulation of clinical research result in the widespread adoption of new and enlightened approaches. At least some of the trauma and heartbreak of COVID-19 could be turned to good if it prompts a dramatic reduction in the burden of regulation, such that clinical research into all the big killers – communicable and non-communicable alike – is allowed to flourish unhindered.
1. https://www.hra.nhs.uk/covid-19-research/approved-covid-19-research/ (accessed 07 May 2020).
2. Office for National Statistics (2019). Deaths registered in England and Wales: 2018. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarri... (accessed 07 May 2020)
3. World Stroke Organisation Global Stroke Fact Sheet. https://www.world-stroke.org/publications-and-resources/resources/global... (accessed 07 May 2020).
4. Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease Study 2017. Seattle, WA: IHME, 2018. http://www.healthdata.org/sites/default/files/files/policy_report/2019/G... (accessed 07 May 2020).
5. Al-Shahi Salman R, Beller E, Kagan J et al. Increasing value and reducing waste in biomedical research regulation and management. Lancet 2014; 383(9912): 176‒185.
Competing interests: No competing interests
Dear Editor,
Patient response to the Recovery trial has been remarkable: it may now have surplus statistical power for the handful of agents currently being considered. Other credible pharmaceutical agents should be introduced and patients should, as part of informed consent, be permitted open access to the reasons that the chosen agents were included or excluded from this exercise.
It is important that treatments have a credible mechanism and that they are sufficiently available for scaling beyond the trial.
Low dose PDE5 inhibitors are inexpensive, available and oral. They could be included in the trial with minimal additional work for nursing staff.
We know a little of the mode of infection of SARS-CoV2-19 and its effect on the RAAS system.
Angiotensin Converting Enzyme 1 (ACE1) cells convert Angiotensin I to its active form, Angiotensin II, which causes peripheral blood vessels to contract and helps maintain systemic (body) blood pressure. ACE inhibitors block the action of ACE1 and though their effect on ACE2 is not known, the following paradigm might explain the side effect of cough in some hypertensive patients given the drugs.
Angiotensin Converting Enzyme 2 (ACE2) cells convert active Angiotensin II to an inactive form, Angiotensin 1-7 .(1) ACE inhibitors with no known activity against ACE2 may actually lead to upregulation of ACE2. (2)
Angiotensin II causes contraction of smooth muscle via the Phosphodiesterase 5 (PDE5) pathway (3).
Thus under physiological conditions ACE2 effectively protects pulmonary smooth muscle from active Angiotensin II.
The Current Virus (SARS-COV-2) is known to target ACE2 cells in the lung (4) (5)
ACE2 is in the lower respiratory tract. At present there is no evidence that SARS-COV-2 reduces expression of ACE2 but this is an assumption that is consistent with clinical observations of the disease, COVID-19, which leads to cough and reduced oxygenation. Risk factors observed for poor outcomes in COVID-19 are associated with prior upregulation of ACE2 (2): this is consistent with the assumption that SARS-COV-2 acts by reducing expression of ACE2.
Thus SARS-COV-2 reduces ACE2 expression, thereby exposing smooth muscle in small vessels in the lung to be exposed to (vasoconstricting) Angiotensin II which acts on the vessels via PDE5, leading to some of the clinical findings in COVID-19. Vasoconstriction leads to reduce flow through the (downstream) gas exchange alveoli with the consequences of
• Reduced gas exchange and therefore reduced oxygen supply to the systemic circulation
• Reduced blood-borne immune response to the viral particles
• Increased pressure in the Pulmonary artery with shunting of deoxygenated pulmonary arterial blood to the systemic circulation.
As well as small vessel smooth muscle being exposed to the PDE5 effects of Angiotensin II, this paradigm explains the persistent dry cough of COVID19 by the same PDE5 medicated action on bronchiolar smooth muscle.
Drugs to prevent Angiotensin II having these smooth muscle effects via the PDE5 receptor are already available in the form of the PDE 5 inhibitors Sildanafil (available orally and parenterally) and Tadafil (available orally) and are considered safe enough to be sold, without prescription by pharmacies in the UK. These drugs appear to have significant promise in addressing the increased exposure of pulmonary smooth muscle to Angiotensin II in COVID-19.
1. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
2. Lei Fang, George Karakiulakis, *Michael Roth Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? www.thelancet.com/respiratory 2020 https://doi.org/10.1016/S2213-2600(20)30116-8
3. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
4. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.02.052,
5. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7
Competing interests: No competing interests
Dear Editor
COVID-19 – Vitamins C & D may protect and treat patients and NHS staff
It is unfortunate that the Recovery Trial is not investigating the value of vitamin C for COVID-19. [1] This vitamin is often disregarded as an ‘alternative or complementary medicine’ treatment. Strangely, its very large basic science background may be overlooked. Even so, the WHO lists vitamin C among its research priorities for strategies for supportive care of seriously ill patients and as an adjunctive intervention with biological plausibility for COVID-19. [2]
Vitamin C is a potent antioxidant and may be useful when given in very high doses as an adjuvant therapy for COVID-19. [3] Requirements for this vitamin increase significantly in severe infections (although doctors should be aware that high doses may precipitate haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency). An anti-viral immune response has been detected for vitamin C through production of interferon in the early stages of influenza A. It also has an immunomodulatory effect on cytokine production. [3, 4] Vitamin C has been used in hospitals in China for patients with COVID-19 disease and some clinical trials are in progress. (If given with proton pump inhibitors, Vitamin C levels are lowered. [5] )
Vitamin D supplementation reduces the risk of acute respiratory infections and may be useful for COVID-19 disease. [6] Deficiency is common in countries with limited exposure to sunlight and levels may be particularly low if more melanin in the skin restricts the absorption of ultraviolet light. Possibly, this may be a contributory factor in some of the serious infections reported in certain NHS and social care workers. (Ultraviolet light is also useful in that it can inactivate the virus.)
1. Grant ECG. https://www.bmj.com/content/369/bmj.m1626/rapid-response to Wilkinson E. RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials. BMJ 2020; 369: m1626 (Published 28 Apr 2020)
2. World Health Organization (2020) A Coordinated Global Research Roadmap: 2019 Novel Coronavirus. March, 2020, p 36-37. https://www.who.int/blueprint/priority-diseases/key-action/Coronavirus_R...
3. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in Drug Discovery 2020; 5:100028 doi.org/10.1016/j.medidd.2020.100028
4. Hartel C, Puzik A, Gopel W, Temming P, Bucsky P, Schultz C. Immunomodulatory effect of vitamin C on intracytoplasmic cytokine production in neonatal cord blood cells. Neonatology. 2007;91(1):54-60.
5. Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Ther Adv Drug Saf. 2013 Jun;4(3):125-33. doi: 10.1177/2042098613482484.
6. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020 Apr 2;12(4). pii: E988. doi: 10.3390/nu12040988.
Competing interests: No competing interests
Dear Editor
Covid 19 and High-dose Vitamin C
The UK Recovery trial is reported to be the world’s biggest Covid-19 drug trial but does not seem to include use of Vitamin C. [1] In contrast, a high-dose vitamin C trial has been started in New Zealand following use in China as a safe and non-drug way to treat Covid 19 infection. [2]
Dr Richard Cheng writes that a quick, deployable and accessible, effective and safe treatment is urgently needed to save lives and curtail the spreading of Covid 19 infections. Significantly increased oxidative stress due to rapid release of free radicals and cytokines is the hallmark of acute respiratory distress syndrome (ARDS) which leads to cellular injury, organ failure and death. Early use of large dose antioxidants, such as VC can be an effective treatment for these patients. Clinical studies also show that high-dose oral VC provides certain protection against viral infections. Neither intravenous nor oral administration of high-dose VC is associated with significant side effects. [3] High-dose intravenous vitamin C (VC) was used successfully in the treatment of 50 moderate to severe COVID-19 patients. The doses used varied between 10 g and 20 g per day, given over a period of 8–10 h. Additional VC bolus can be required for patients in critical conditions. The oxygenation index improved in real time and all the patients were eventually cured and discharged. [4]
Just recently registered on clincialtrials.gov (Identifier: NCT04264533), a new clinical trial to investigate vitamin C infusion for the treatment of severe 2019-nCoV infected pneumonia has begun in Wuhan, China. This is one of the first RCTs to test the effects of IV vitamin C in patients infected with this virus. In this trial, the investigators will treat 140 patients with a placebo control or intravenous vitamin C at a dose of 24 g/day for 7 days. They will assess requirements for mechanical ventilation and vasopressor drugs, organ failure scores, ICU length of stay and 28-day mortality.
1 Wilkinson E. RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials . BMJ 2020; 369: m1626 (Published 28 Apr 2020)
2 Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Crit Care. 2020; 24: 133.Published online 2020 Apr 7. doi: 10.1186/s13054-020-02851-4
3 Cheng R Z. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in Drug Discovery, March 2020;5:100028.
4 Hernández A, Papadakos PJ, Torres A, González DA, Vives M, Ferrando C, Baeza J.Hernández A, et al.Rev Esp Anestesiol Reanim. Two known therapies could be usful as adjuvant therapy in critical patients infected by Covid-19. 2020 Apr 14:S0034-9356(20)30075-X. doi: 10.1016/j.redar.2020.03.004.
Competing interests: No competing interests
Re: RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials
Dear Editor,
As a junior doctor on a COVID-19 medical ward, it has been exciting to see the rapid progress of the RECOVERY trial, from patient recruitment to physician education and involvement. Our hospital was one of the first centres to introduce tocilizumab – an interleukin-6 (IL-6) receptor antibody – into its second randomisation arm for participants with progressive COVID-19. From my perspective as a junior doctor, the last few weeks have shown me how quick progress from bench to bedside can be made. I have experienced something like nothing before: a new condition that requires a new treatment.
Patients with COVID-19 on our ward often respond well to initial supportive therapy with oxygen, but then tend to go one of two ways: either steadily improving and recovering completely, or rapidly deteriorating (heralded by rising CRP, LDH, ferritin and D-dimer), requiring an escalation to HDU or ICU. Sadly, the outcome may be death for some.
It is evident that an uncontrollable hyper inflammatory response to the virus – a cytokine storm – is a crucial element in the pathogenesis of severe COVID-19 [1]. High numbers of pro-inflammatory cytokines recruit neutrophils and macrophages en masse into the lungs and other organs, driving tissue damage, hyper coagulation, systemic shock and multi-organ failure. This rise in inflammatory cytokines could also cause the exhaustion of T cell populations, driving the worsening lymphopenia seen in deteriorating patients [2].
It is also becoming increasingly apparent that IL-6, a multi-faceted immune messenger, is a central cytokine in this virus-induced storm. In the early days of the pandemic, researchers in Wuhan found that IL-6 serum levels significantly correlated with disease severity [3]. Now there is promising evidence that blocking the IL-6 receptor via neutralising antibodies may calm the cytokine storm and save lives. A clinical trial using tocilizumab in China found rapid improvement in fever and respiratory function in 21 patients with severe COVID-19 and all were discharged from hospital [4].
These encouraging initial results clearly need to be explored in a much larger randomised trial. This is why RECOVERY – at the time of writing the largest COVID-19 trial in the world – is so exciting. While we await its initial findings, let’s celebrate it for what it is: a scientific, medical and logistical achievement in a short period of time. From what I see in so many of our deteriorating patients, and from the emerging immunological research, drugs targeting IL-6 could well become important weapons against this global scourge. Like the name of the study, its findings will help us as we move to the recovery phase post COVID-19.
1. Chen, L., Liu, H.G., Liu, W., Liu, J., Liu, K., Shang, J., Deng, Y. and Wei, S., 2020. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Chinese journal of tuberculosis and respiratory diseases, 43, pp.E005-E005
2. Diao, B., Wang, C., Tan, Y., Chen, X., Liu, Y., Ning, L., Chen, L., Li, M., Liu, Y., Wang, G. and Yuan, Z., 2020. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Frontiers in Immunology, 11, p.827
3. Liu, F., Li, L., Xu, M., Wu, J., Luo, D., Zhu, Y., Li, B., Song, X. and Zhou, X., 2020. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. Journal of Clinical Virology, p.104370
4. Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., Li, X. and Zhang, X., 2020. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences
Competing interests: No competing interests