Brown, JS

Chambers, RC

Lipman, M

Singer, M

English

UCL Discovery

 1 SARS-CoV2 pandemic: the clinical picture of COVID-19 and implications for 1 research  2  3 Marc Lipman1, Rachel Chambers1, Mervyn Singer2, Jeremy S Brown1 4 1UCL Respiratory, Division of Medicine, University College London, Rayne 5 Institute, 5 University Street, London WC1E 6JF, United Kingdom.  6  7 2Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University 8 College London, Cruciform Building, Gower St, London WC1E 6BT, United 9 Kingdom.  10  11 Corresponding author: 12 UCL Respiratory,  13 Division of Medicine,  14 University College London,  15 Rayne Institute,  16 5 University Street,  17 London WC1E 6JF,  18 United Kingdom.  19 Phone: +44 20 3108 7728 20 E-mail: jeremy.brown@ucl.ac.uk. 21  22 Word count: 1241 words 23   24  2 The SARS-CoV2 pandemic represents an extraordinary medical challenge that has 25 already had massive economic and societal impacts.  In contrast to the SARS and 26 MERS coronavirus outbreaks, every respiratory physician and intensivist is likely to 27 encounter patients infected with SARS-CoV2 and need a good understanding of the 28 management of the associated disease COVID-19.  We are facing the first wave of 29 the SARS-CoV2 pandemic, but the infectivity of the virus and lack of population 30 immunity suggest future waves are possible.  For this article (summarised in Table 1) 31 we have used our recent clinical experience of COVID-19 combined with the limited 32 published data to discuss how the clinical presentation relates to pathogenesis, key 33 research questions, and particular issues relevant for respiratory medicine.  34  35 Most infections with SARS-CoV2 are mild, but a minority of patients develop COVID-36 19 pneumonia. The main differential diagnosis for COVID-19 is community acquired 37 pneumonia (CAP), which is also commonly caused by infection with respiratory 38 viruses. However, COVID-19 has several clinical features distinct to CAP which both 39 indicate the diagnosis and suggest it has distinct mechanisms of pathogenesis.  With 40 CAP, symptoms, signs and alveolar consolidation usually develop rapidly after 41 infection, whereas for COVID-19 patients a 6+ day lag between the start of infective 42 symptoms and admission with pneumonia is usual1,2. COVID-19 also often causes 43 marked malaise and extrapulmonary symptoms such as anosmia, headache, myalgia, 44 and myocarditis3,4. The leading cause of death in COVID-19 is respiratory failure from 45 extensive lung injury. This usually presents with severe hypoxaemia yet highly 46 compliant lungs, and only later develops physiological features usually found in acute 47 respiratory distress syndrome (ARDS) such as high airway pressures and 48 hypercapnia. COVID-19 pneumonia is strikingly slow to improve, and patients require 49 oxygen support for days with a mean duration of hospital admission of 16 days1. The 50 radiology of COVID-19 pneumonia is also distinct from CAP, causing basal atelectasis 51 and bilateral poorly defined infiltrates on chest radiographs rather than lobar 52 consolidation3. The CT scan abnormalities in COVID-19 are uncommon in other 53 causes of pneumonia, with focal areas of ground glass infiltrates, peripheral patchy 54 consolidation similar to an organising pneumonia (OP), or ARDS-like widespread 55 extensive bilateral infiltrates5,6.  56  57  3 In keeping with the clinical picture SARS-CoV2 viral RNA is detected in sputum later 58 than in nasal samples7, but the mechanisms driving COVID-19 pneumonia and how it 59 is sustained over days are uncertain. Without a better understanding of the 60 pathogenesis, why COVID-19 pneumonia only affects a minority of SARS-CoV2 61 infected subjects, and what constitutes optimum management will remain speculative.  62 An unanswered question is whether severity is proportional to viral load. Severe 63 COVID-19 cases routinely present with lymphopenia and (in contrast to other viral 64 pneumonias) biochemical evidence of severe systemic inflammation, including raised 65 C-reactive protein, fibrinogen, D-dimers, lactate dehydrogenase, troponin and ferritin 66 levels1,2,3. These features (partly shared with haemophagocytic lymphohistiocytosis), 67 the delay in development of severe disease, and the radiology suggest that the lung 68 infiltrates may be caused by an excessive inflammatory response to SARS-CoV2. 69 Abnormalities consistent with thrombotic microangiopathy are also common in severe 70 disease, suggesting some of the pathology is driven by endothelial activation and 71 thrombosis. Two potential overlapping stages of COVID-19 are plausible: an initial 72 ‘standard’ viral infection followed by a hyperinflammatory response in the subset of 73 severely affected patients.  Clinical trials have started assessing the efficacy of the 74 early use of antivirals, and many immunomodulatory approaches including, but not 75 restricted to corticosteroids, macrolides, hydroxychloroquine, blockade of interleukin 76 (IL)-6 (e.g. tocilizumab, sarilumab), IL-1 (e.g. anakinra) or GM-CSF, plasma exchange, 77 and hyperimmune serum. The risk / benefit of these agents requires careful 78 consideration, and the rapid identification of COVID-19 endotypes that benefit from 79 specific treatment modalities is challenging.  Defining clinically relevant and treatment-80 responsive patient subpopulations will be critical for effective management, and will 81 require integration of clinical, imaging, virology, immunological, and inflammatory 82 biomarker data at key timepoints during disease development and in response to 83 different therapies. 84  85 The mortality of COVID-19 increases in patients with hypertension, diabetes or 86 obesity, and markedly so with age8. Important questions are whether this is causal or 87 an epiphenomenon, and why these subgroups are targeted? Could this be a 88 manifestation of pre-existing microvascular disease, ‘inflammaging’ (chronic low-89 grade inflammation in the elderly) or immunosenescence, (age-related impairment of 90 innate and adaptive immunity)?  The pathogenetic mechanisms underlying severe 91  4 COVID-19 may vary between the elderly and younger adults, potentially requiring a 92 different management strategy. Other unexplained features of severe COVID-19 is the 93 male preponderance, with 65-70% of deaths occurring in men1,3, and the higher 94 incidence in black, Asian and minority ethnic background (BAME) subjects. The male 95 preponderance may relate in part to the effects of sex on disease pathogenesis, 96 whereas the high incidence of disease in BAME subjects could reflect potentially 97 higher expression of ACE2 (the SARS-CoV-2 receptor), the incidence of comorbidities 98 and / or socioeconomic factors. 99  100 The most important clinical manifestation of COVID-19 is hypoxaemia, successful 101 management of which is essential for a good outcome. The severity of hypoxaemia 102 can be out of proportion to a patient’s apparent dyspnoea, so accurate and continuous 103 monitoring of oxygenation is essential.  A high proportion of COVID-19 pneumonia 104 patients need prolonged ventilatory support (>10-14 days).  CPAP could be a practical 105 option as an alternative to mechanical ventilation in a subset of patients given that 106 high patient load can overwhelm ventilator provision. 107  108 The SARS-CoV2 pandemic has major implications for patients with chronic respiratory 109 disease.  COVID-19 infection in patients with COPD is 2.7 times more likely to have 110 an adverse outcome4, though it is not clear whether this relates to poor lung reserve 111 or if COPD impairs viral clearance and/or negatively impacts the inflammatory 112 response to SARS-CoV2.  In addition, whether other chronic lung diseases, their 113 treatment, or smoking history alone increase the risk of severe COVID-19 is uncertain.  114 The prevalence and efficacy of post-infective immunity to SARS-CoV2 needs to be 115 determined in chronic lung disease patients to help target future vaccination 116 programmes.  Data are needed on the long-term effects of severe COVID-19; the high 117 prevalence of extensive lung injury suggest there could be permanent loss of lung 118 function as well as other physical, cognitive and behavioural issues. 119  120 The challenge of COVID-19 is requiring a massive clinical effort, and there is a parallel 121 concerted academic approach to address key research priorities.  The efficacy of 122 lopinavir-ritonavir (antivirals used to treat HIV), low-dose dexamethasone, 123 hydroxychloroquine and inhaled interferon are being evaluated in the world’s largest 124 COVID-19 clinical trial, RECOVERY (Randomised Evaluation of COVID-19 Therapy 125  5 trial, endorsed by the UK Chief Medical Officer).  COVID19 has been integrated into 126 the global REMAP-CAP platform (Randomised, Embedded, Multi-factorial, Adaptive 127 Platform Trial for Community-Acquired Pneumonia) with treatment arms including 128 lopinavir/ritonavir, hydroxychloroquine, macrolides, corticosteroids, interferon beta-1a, 129 and the IL-1 receptor antagonist anakinra. Other immunomodulatory therapies being 130 investigated include monoclonal antibodies targeting the interleukin-6 (IL-6) receptor 131 antibodies e.g. tocilizumab (NCT04320615) and sarilumab (NCT04327388), IL-6 e.g. 132 siltuximab (NCT04329650), or the GM-CSF receptor e.g. lenzilumab (NCT04351152). 133 Trials of the experimental anti-viral remdesivir or of convalescent serum therapy (e.g. 134 NCT04345523) are either ongoing or about to start recruiting. Despite the warnings 135 provided by SARS and MERS, our understanding of the pathogenesis of coronavirus 136 pneumonia remains poor. Hence, alongside multi-centre clinical trials there is a need 137 for translational and basic science research which will require expansion of category 138 3 laboratory facilities capable of handling SARS-CoV2 infected samples. These 139 academic efforts will be essential to improve our understanding of both the pathogen 140 and the host response so we can reduce the future morbidity and mortality caused by 141 COVID-19 or other potential novel viral pneumonias. 142   143  6 References: 144 1. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 145 coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091 doi: 146 10.1136/bmj.m1091. 147 2. Zhou F, Ting Y, Ronghui D, et al. Clinical course and risk factors for mortality of 148 adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 149 Lancet 2020; 395: 1054–62 150 3. Mo P, Xing Y, Xiao Yu, et al.  Clinical characteristics of refractory COVID-19 151 pneumonia in Wuhan, China. Clin Infect Dis 2020: pii: ciaa270. doi: 152 10.1093/cid/ciaa270. 153 4. Guan W-j, Wen-hua L, Zhao Y, et al. Comorbidity and its impact on 1,590 patients 154 with Covid-19 in China: A Nationwide Analysis. Europ Resp J 2020: Mar 26. pii: 155 2000547. doi: 10.1183/13993003.00547-2020. 156 5. Chen Z, Fan H, Cai J, et al. High-resolution computed tomography manifestations 157 of COVID-19 infections in patients of different ages. European Journal of Radiology 158 2020; 126.     doi: https://doi.org/10.1016/j.ejrad.2020.108972 159 6. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 160 coronavirus in Wuhan, China. Lancet 2020 ;395(10223):497-506.   doi: 161 10.1016/S0140-6736(20)30183-5 162 7. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized 163 patients with COVID-2019. Nature 2020 doi: 10.1038/s41586-020-2196-x.  164 PMID:32235945  165 8. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with 166 SARS-CoV2 pneumonia in Wuhan, China: a single-centered, retrospective, 167 observational study. Lancet Respir Med 2020: S2213-2600(20)30079-5. doi: 168 10.1016/S2213-2600(20)30079-5.  169  7 Table 1: Summary of COVID-19 disease features, the research questions these raise, and potential therapeutic relevance Disease features Research question Potential therapeutic consequences Clinical / demographic   Delay between infection and pneumonia Related to later viral replication in the lung? Abnormal inflammation in a subset of infected subjects? Related to development of adaptive immunity? Antiviral treatment to prevent severe disease Immunomodulation to prevent severe disease Variable severity within an age group Driven by viral load? Driven by genetics / epigenetics? Driven by environmental factors? Improved identification of at risk subjects Targeted antiviral / immunodulation treatments to prevent severe disease in at risk subjects Increased severity with age / male sex / comorbidities Related to comorbidities alone? Direct effects on the inflammatory response?  Related to ‘inflammaging’ / immunosenescence? Improved identification of at risk subjects Targeted antiviral / immunodulation treatments to prevent severe disease in at risk subjects High burden of disease in BAME background Related to ACE2 expression, comorbidities and/or socioeconomic factors? Improved identification of at risk subjects Prolonged disease course What mechanisms maintain the lung infiltrations? Therapies to help clear pneumonic infiltrates High Mortality Detailed post-mortem studies to identify cause(s) Improved management of severe cases    Investigations / radiology / physiology   Marked increase in inflammatory markers What are the mechanisms driving inflammation? What cells are the source of inflammatory responses? Does inflammation cause poor outcomes? Clinical risk scoring  Improved anti-inflammatory treatment  Variations between patients in inflammatory markers Relationship to diseases subtypes and outcome? Endotyping for targeted treatments Evidence for cardiac / other extra-pulmonary disease Role for poor outcomes? Specific targeted therapies Evidence for micro- and macroangiopathic thrombosis Role for disease pathogenesis / poor outcomes? Potential role for anticoagulation Radiological patterns Relationship to clinical severity? Relationship between the CT patterns over time? Relationship between CT patterns and pathogenesis? Clinical risk scoring Endotyping for targeted treatments Severe hypoxia with low compliance ventilation What are the pathophysiological mechanisms? What is the role of CPAP? What is the best ventilation strategy? Improved ventilatory support strategies Pharmacological enhancement of oxygenation    Specific issues for respiratory physicians   Severe COVID-19 pneumonia survivors Is there a long term reduction in lung function, if so who is at risk and is this related to management? Are there other physical / psychological consequences  Screening for impaired lung function Acute management to reduce lung function loss Appropriate post-discharge support Chronic lung disease patients   Which chronic lung disease patients are susceptible? What mechanisms cause the increased susceptibility? Can antivirals prevent severe COVID-19? What proportion of patients are immune? Improved identification of at risk subjects  Early use of preventative therapies Early use of antivirals  Targeted vaccination in high risk subjects  8  

SARS-CoV-2 pandemic: clinical picture of COVID-19 and implications for research

https://discovery.ucl.ac.uk/id/eprint/10103297/1/Covid%2019%20editorial%20April%202020%20resubmission%20text%20unmarked.pdf

SARS-CoV-2 pandemic: clinical picture of COVID-19 and implications for research

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