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Consulter Le Manuscrit Expert Review of Clinical Immunology For Peer Review Only Natural history and therapeutic options for COVID-19 Journal: Expert Review of Clinical Immunology Manuscript ID ERM-2020--0073.R1 Manuscript Type: Review (Invited) SARS-CoV-2, COVID-19, Physiopathology, Treatment, Chloroquine, Keywords: Azithromycin URL: https://mc.manuscriptcentral.com/erm Email: [email protected] Page 1 of 77 Expert Review of Clinical Immunology 1 2 3 1 Natural history of COVID-19 and therapeutic options 4 5 6 2 7 8 3 9 10 4 11 12 5 13 14 15 6 16 17 7 18 For Peer Review Only 19 8 20 21 22 9 23 24 10 25 26 11 27 28 29 12 30 31 13 32 33 14 34 35 15 36 37 38 16 39 40 17 41 42 18 43 44 45 19 46 47 20 48 49 21 50 51 52 22 53 54 23 55 56 24 57 58 25 59 60 1 URL: https://mc.manuscriptcentral.com/erm Email: [email protected] Expert Review of Clinical Immunology Page 2 of 77 1 2 3 26 Abstract 4 5 6 27 Introduction 7 8 9 28 COVID-19 presents benign forms in young patients who frequently present with anosmia. 10 11 29 Infants are rarely infected, while severe forms occur in patients over 65 years of age with 12 13 30 comorbidities, including hypertension and diabetes. Lymphopenia, eosinopenia, 14 15 16 31 thrombopenia, increased lactate dehydrogenase, troponin, C-reactive protein, D-dimers, and 17 18 32 low zinc levels areFor associated Peer with severity. Review Only 19 20 33 Areas covered 21 22 34 The authors review the literature and provide an overview of the current state of knowledge 23 24 25 35 regarding the natural history of and therapeutic options for COVID-19. 26 27 36 Expert opinion 28 29 37 Diagnosis should rely on PCR and not on clinical presumption. Because of discrepancies 30 31 32 38 between clinical symptoms, oxygen saturation or radiological signs on CT scans, pulse 33 34 39 oximetry and radiological investigation should be systematic. The disease evolves in 35 36 40 successive phases: an acute virological phase, and, in some patients, a cytokine storm phase; 37 38 39 41 an uncontrolled coagulopathy; and an acute respiratory distress syndrome. Therapeutic 40 41 42 options include antivirals, oxygen therapy, immunomodulators, anticoagulants and prolonged 42 43 43 mechanical treatment. Early diagnosis, care, and implementation of an antiviral treatment; the 44 45 44 use of immunomodulators at a later stage; and the quality of intensive care are critical 46 47 48 45 regarding mortality rates. The higher mortality observed in Western countries remains 49 50 46 unexplained. Pulmonary fibrosis may occur in some patients. Its future is unpredictable. 51 52 47 53 54 55 48 Keywords: SARS-CoV-2, COVID, Humans, Pathophysiology, Treatment, 56 57 49 Hydroxychloroquine, Azithromycin, Tocilizumab, Remdesivir, Care 58 59 60 2 URL: https://mc.manuscriptcentral.com/erm Email: [email protected] Page 3 of 77 Expert Review of Clinical Immunology 1 2 3 50 Highlights 4 5 6 51 Diagnosis of COVID-19 should rely on PCR and not on clinical presumption. 7 8 52 Because of “happy hypoxia”, pulse oximetry and radiological investigation should be 9 10 53 systematic. 11 12 13 54 The disease evolves in successive phases: an acute virological phase, and, in some 14 15 55 patients, a cytokine storm phase; an uncontrolled coagulopathy; and an acute 16 17 56 respiratory distress syndrome. 18 For Peer Review Only 19 20 57 Massive screening allowing early diagnosis, care (oxygen, anticoagulants), and 21 22 58 implementation of an antiviral treatment; the use of immunomodulators at a later 23 24 59 stage; and the quality of intensive care are critical regarding mortality rates. 25 26 27 60 Intravenous catheterization should be avoided, and early oral treatment in an 28 29 61 outpatient basis should be preferred. 30 31 62 Treatment with an oral combination of hydroxychloroquine, azithromycin and zinc 32 33 34 63 may represent the best current therapeutic option in relation to its antiviral and 35 36 64 immunomodulatory effects. 37 38 65 Preventive anticoagulants should be prescribed in patients with coagulopathy (positive 39 40 D-dimers). 41 66 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 URL: https://mc.manuscriptcentral.com/erm Email: [email protected] Expert Review of Clinical Immunology Page 4 of 77 1 2 3 67 1. Introduction 4 5 6 68 COVID-19 has a pleomorphic clinical presentation including asymptomatic individuals and 7 8 69 patients with mild to severe involvement with several evolutionary stages [1-3]. Age and 9 10 70 comorbidities including, notably, hypertension, diabetes and coronary heart disease are the 11 12 71 main risk factors for evolving toward severe infections [1-3]. Schematically, after the 13 14 15 72 incubation period, two main clinical presentations can occur: upper respiratory tract infections 16 17 73 (URTIs) with severe headaches, anosmia, ageusia (or dysgeusia) and rhinitis, which are 18 For Peer Review Only 19 74 mainly observed in young patients who then have a good clinical outcome; and lower 20 21 22 75 respiratory tract infections (LRTIs) with pneumonia symptoms that are observed more 23 24 76 frequently in patients with comorbidities and can be severe to fatal in older patients [1-3]. At 25 26 77 admission, prognosis can be assessed through the National Early Warning Score (NEWS-2), a 27 28 simple aggregate scoring system including respiration rate, oxygen saturation, systolic blood 29 78 30 31 79 pressure, pulse rate, level of consciousness or new confusion, and temperature. Age has been 32 33 80 added in a modified version of this score [4]. 34 35 81 During the onset of the COVID-19 outbreak, olfactory and gustative disorders, 36 37 38 82 including anosmia and ageusia were described in infected patients [5]. In Marseille, 3,497 39 40 83 adults who underwent PCR between 24 March and 25 April 2020 were asked the following 41 42 84 question prior to being tested for SARS-CoV-2: “Have you lost your sense of smell or taste in 43 44 45 85 the past two months?” The prevalence of the loss of smell and/or taste in COVID-19 patients 46 47 86 was 356/673 (53%), and the positive predictive value (PPV) for the diagnosis of COVID-19 48 49 87 by PCR was 67% when smell and taste disorders were reported (submitted). Asking patients 50 51 and healthcare workers (HCWs) about loss of smell and taste could be useful in areas where 52 88 53 54 89 testing for SARS-CoV-2 is politically or technically limited or impossible. Interestingly, 55 56 90 “happy hypoxemia”, a hypoxia observed in patients who are SARS-CoV-2 positive yet 57 58 91 comfortable and without dyspnea emphasizes the need to perform a low-dose CT-scan on 59 60 4 URL: https://mc.manuscriptcentral.com/erm Email: [email protected] Page 5 of 77 Expert Review of Clinical Immunology 1 2 3 92 most patients to detect pneumonia at an early stage [6]. Most COVID patients are definitively 4 5 6 93 cured, but extreme caution is needed in patients with comorbidities and/or biological 7 8 94 parameter abnormalities such as lymphopenia, eosinopenia, increased D-dimers, troponin, 9 10 95 lactate dehydrogenase (LDH) or C-reactive protein (CRP) [1, 3]. Venous thromboembolism is 11 12 96 relatively common [7], is mainly characterized by pulmonary embolism, and is found in up to 13 14 15 97 one-third of critical cases [8]. Acute respiratory distress syndrome (ARDS), pulmonary 16 17 98 embolism and bacterial superinfection may result in a fatal evolution [9, 10]. Finally, delayed 18 For Peer Review Only 19 99 pulmonary fibrosis may occur in an as yet unknown proportion of patients [11]. 20 21 22 100 At the beginning of the health crisis, the use of chest X-rays was restricted to patients in 23 24 101 intensive care units due to its low value in detecting ground-glass opacities. However, low- 25 26 102 dose chest computed tomography (LDCT) appears to be a useful tool in the management of 27 28 patients with regards to diagnosing, assessing and quantifying disease severity and for 29 103 30 31 104 differential diagnosis. LDCT might be of interest in predicting lung fibrosis during healing 32 33 105 [12-15]. The main findings of COVID-19 pneumonia on chest CT include ground-glass 34 35 106 opacities, consolidation, and a crazy-paving pattern. These features are not specific, but the 36 37 38 107 distribution of lesions during COVID-19 pneumonia is more likely to be peripheral, 39 40 108 asymmetric and located in the lower lobes [16]. CT features revealed a good sensitivity and 41 42 109 specificity for COVID-19 diseases in centers where CT was used as a diagnostic tool [17]. 43 44 45 110 Furthermore, Li et al. developed a deep learning algorithm able to discriminate COVID-19 46 47 111 pneumonia from community-acquired pneumonia, with good results (Figure 1) [18]. COVID- 48 49 112 19 pneumonia is also characterized by the high prevalence of lung involvement in 50 51 paucisymptomatic patients. In our center, we decided to perform LDCT on all patients with a 52 113 53 54 114 positive PCR for COVID-19. Of the 2,065 LDCTs that were performed on COVID-19 55 56 115 patients, more than 70% revealed pneumonia.
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