key: cord-304418-k9owyolj
authors: Le Maréchal, M.; Morand, P.; Epaulard, O.; Némoz, B.
title: COVID-19 in clinical practice: a narrative synthesis
date: 2020-09-29
journal: Med Mal Infect
DOI: 10.1016/j.medmal.2020.09.012
sha: 
doc_id: 304418
cord_uid: k9owyolj

The coronavirus disease 2019 (COVID-19) was first reported in the city of Wuhan, China. The disease rapidly spread to the rest of China, to Southern-East Asia, then to Europe, America, and on to the rest of the world. COVID-19 is associated with a betacoronavirus named SARS-CoV-2. The virus penetrates the organism through the respiratory tract, conveyed by contaminated droplets. The main cell receptor targeted is the surface-bound ACE-2. As of the 26th July 2020, 15,200,000 COVID-19 cases and 650,000 deaths were reported worldwide. The mortality rate is estimated between 1.3 and 18.3%. The reproductive rate without any public health intervention is estimated around 4-5.1 in France. Most hospitalized patients for COVID-19 present respiratory symptoms, which in some cases is associated with fever. Up to 86% of admissions to ICU are related to acute respiratory failure. To date, no anti-viral therapy has proven its efficacy considering randomized trials. Only immunomodulatory treatments such as corticosteroids have shown to cause significant improvement in patient outcome.

A study estimated the Rt in the city of Wuhan, China, between the 1 st January 2020 and the 8 t March 2020 [22] , during five successive time periods (corresponding to different public health interventions).

Rt peaked at 3.82 on the 24 th January 2020 (with no major public health intervention), and subsequently declined, to below 1.0 on the 6 th February 2020 (after one week of city lockdown, traffic suspension, and home quarantine) and was below 0.3 on the 1 st March 2020 (after 15 days of quarantine) [22] . In South Korea, reproduction number Rt was estimated at 1.5 (95% confidence interval (CI) 1.4-1.6) [18] . In France, Flaxman et al. estimated Rt before lockdown between 4-5.1 (95%CI), and around 0.5 during lockdown [23] .

The virus penetrates the organism through the respiratory tract, conveyed by contaminated droplets.

While the exact viral progression remains elusive, the virus seems to have a favorable tropism for epithelial cells within the airways, leading to viral replication both in the nasal cavities and in distal bronchioles [24] . The main cell receptor targeted by the viral surface glycoprotein (S) is the surfacebound angiotensin-converter enzyme 2 (ACE2) [8] , yet it is still unclear if the virus can benefit from a second receptor to achieve gain cell entry. TMPRSS2 is a cellular serine proteinase whose role has been pointed out to prime SARS-CoV-2 cellular entry [25] .

The viral S protein, also known as spike, is responsible for both cell attachment and membrane fusion.

It is formed by three dimers of two non-covalently bound domains S1 and S2. Both subunits are synthetized as a protomer resulting from the expression of the S gene. S1 and S2 are efficiently cleaved by a cellular furin [26] thanks to a polybasic motif (PRRA) specific of SARS-CoV-2 [27] . Because of its specificity and key role in viral cycle, the S protein constitutes the main target for vaccine candidates [28] .

Diagnosis of COVID-19 requires laboratory confirmation, usually performed by detection of viral RNA by a reverse-transcription polymerase chain reaction (RT-PCR). While the first laboratory confirmed cases in Wuhan early in January 2020 relied on deep sequencing techniques [29] , highly scalable assays have since been developed after the viral sequence was published. The first RT-PCR protocol was published by Drosten and colleagues [30] from Charité University in Berlin, and since then adopted by the WHO. This approach relies on the amplification and detection of the following sequences among the SARS-CoV-2 genetic sequence: the E gene encoding the envelope protein is used as a screening assay targeting all members of the betacoronavirus genera, and both the RdRp gene or the N gene are used as confirmatory assays due to their specific sequence in the SARS-CoV-2 species. This protocol has been widely adopted in commercially available test kits and is now used in most facilities. The Paris Institut Pasteur has developed its own assay [31] , based on the detection of two sequences in the RdRp gene spanning nucleotides 12621-12727 and 14010-14116. This protocol has been widely used in French laboratories to manage early COVID-19 suspicions and cases [32] .

Such assays can be performed on several samples, and the choice of sampling site has been a debated issue considering the consequences of false negative results. Nasal swabs, oropharyngeal swabs, saliva, sputum and bronchoalveolar lavage fluid (BAL) were mostly reported. Nasal swabs have proven to be effective and provided adequate sensitivity (80%) [33, 34] , if performed properly. Oropharyngeal swabs tend to be less sensitive (32%) [35] . Saliva collection has been proposed as a viable alternative yielding higher sensitivity (91.7%) [36] , also addressing the availability of swabs issue as worldwide demand surge and laboratories face shortages in stocks. Sputum samples, while being more sensitive than upper respiratory tract samples (95.7%) [37, 38] , raise security concerns for the safety of healthcare workers regarding the droplet dissemination nature of the COVID-19. BAL and other lower respiratory tract samples are widely used in intensive care units and yield very good results (93% sensitivity) [35] . The viral load seemed higher in early stages of the disease [39] , with symptomatic patients exhibiting higher viral titers as assessed by the lower Ct numbers [40] .

When analyzed by RT-PCR, stools are frequently positive (41%), and high viral loads have been pointed out in such samples in both asymptomatic and symptomatic patients [41] . No relation has been established as of today between enteric viral excretion and clinical outcome and disease severity. In children, the average duration of viral RNA shedding in stools are 29 days (+/-12 days). The duration of viral shredding seemed to decrease with age [42] and infectivity of stools is low to non-existent. Due to feces positivity, the sampling of wastewater has been proposed to assess viral circulation [43] .

Plasmatic detection of SARS-CoV-2 has been reported but only with low viral titers, and mainly in clinically severe cases [44] ; bloodstream infectivity has yet to be demonstrated. Urine has remained virus-free except in one study [45] .

Most genomic testing in asymptomatic patients [46] returned negative after 2-3 weeks, with exceptional long shedding up to 45 days after symptom onset [47, 48] , raising the question of the infectivity of such viral shedding. Excretion of infectious virions is thought to span two days before onset of symptoms up to 8 days after onset [49] , viral excretion peaking at day 4 post-infection [50] , supporting the effectiveness of a 14-day quarantine period for case isolation. However, results do not fully correlate with infectivity: viral culture from clinical samples is usually infeasible after 8 days after onset of symptoms [51] . Nucleic acid testing (NAT) is key to patient management and surveillance of disease propagation.

According to several works, incubation period has been estimated between a mean of 4.8 and 6.4 days [52] [53] [54] [55] . Lauer et al. estimated that symptom onset will occur within 11.5 days for 97.5% of patients, and that a 14 days quarantine would be sufficient [53] . A large work from Zhou et al. described clinical timeline for an 813 patient cohort [56] . The mean time from illness onset to intensive care unit (ICU) admission was 9-12 days [21, 56] ; it was 7 days (4-9) to dyspnea [56] , 11-12.5 days to hospital admission [56, 57] , 9 days (7-13) to sepsis, 12 days (8-15) to respiratory failure, and 21-44 days to death, depending on studies [56, 58] . Time between onset of symptoms and dyspnea is 5-7 days, to ARDS 8-12 days [56, 59] .

One initially described symptom was fever; however, up to 60% of patients were described as nonfebrile, and up to 52% of patients admitted in ICU were non-febrile [52] . Coughing was reported in 60-82% of cases, asthenia in 38-70% of cases, myalgia in 11-44% of cases, dyspnea/shortness of breath in 19-55% of cases, and diarrhea in 2-10% of cases [55, [59] [60] [61] . No symptoms are specific of COVID-19, but surprisingly, anosmia and ageusia appeared to be strongly linked with COVID-19 infection.

Mechanism for these symptoms is still to be unveiled, as well as for digestive forms in elderly patients presenting with only diarrhea.

A study described imaging data among 37 asymptomatic patients [48] . Chest CT evidenced in 11 of them (30%) focal ground glass opacities, and in 10/37 (27%) stripe shadows and/or diffuse consolidation; 16/37 (43%) had a normal CT scan. In a 63 asymptomatic Chinese cohort, 29/63 patients had abnormal CT scans; few patients (13%) had comorbidities [62] .

The most frequent presentation of hospitalized COVID-19 is pneumonia (91-100%) with dyspnea and a rarely productive cough [52, 55, 56, 59, 61] . In case of patients diagnosed with clinical pneumonia, chest X-ray and CT-scanner found bilateral ground-glass opacity in 25-100% of cases [56, 59] . When considering all hospitalized COVID-19 patients, CT scans evidenced ground-glass opacities in 56-71% of patients and consolidation in 59% of patients [52, 56] . Pulmonary injury was bilateral in 52-75% of patients [52, 56] .

Thromboembolic complications Several works have described the high incidence in COVID-19 patients of both venous and arterial thromboembolic diseases. In Klok's study of 184 patients with proven COVID-19 pneumonia admitted to the ICU in the Netherlands, and who all received at least standard dose thromboprophylaxis, the incidence of thrombotic complication was 31% (95%CI 20-41%) [63] . In an Italian study of 362 cases (in ICU and on general wards), 28 presented a thromboembolic event (7.7%). The authors estimated that those events were highly underestimated due to the low number of specific imaging tests performed [64] . Known risk factors for thromboembolic events that are reported in COVID-19 are excessive inflammation and immobilization [65] . However, in a large multicenter international work published by Freund et al among 3,253 patients who underwent a computed tomography pulmonary angiogram for a suspected pulmonary embolism, a positive COVID-19 status was not associated with pulmonary embolism in multivariate analysis (p=0.40) [66] .

Cardiac injuries have been described in COVID-19 patients. Viruses are a common cause of myocarditis [67] ; myocardial injury can be related to direct cell injury caused by the virus, to T lymphocyte mediated cytotoxicity, to hemodynamic damage induced by hypoxia or shock, or related to cytokine storm [67] . Arrhythmia has been described as a cause of transfer in ICU in 44% of COVID-19 patients [59] ; in an COVID-19 acute setting, it can result from direct cardiomyocyte injury, to an infection of the pericardium causing massive edema, or to an ischemia due to microcirculation lesions [68] . In a 416 cohort of patients in Wuhan, China, 82 patients with elevated levels of cardiac troponin had a higher risk of hospital death [69] .

Several neurological manifestations of COVID-19 have been reported. Manifestations are very diverse: -Olfactory dysfunction: Generally, post-viral olfactory loss account for 11% of acute olfactory dysfunction [70, 71] . Several studies reported olfactory dysfunction among COVID-19 patients (5-86%) [72] [73] [74] . This may be related to a localized olfactory cleft edema (local inflammation), or a direct neuroinvasion of the olfactory nerve [70, 73] . The loss of flavor perception is also frequently reported; it is considered to be mainly due to a loss of retronasal olfaction rather than a loss of sense of taste itself [70] , -Central nervous system manifestations: confusion [72, 75, 76] , acute cognitive disorder, acute myelitis, encephalopathy, encephalitis [77] , intracranial hemorrhage, strokes [72, 75, 76] , seizures, -Peripheral nervous system manifestations: Guillain-Barré syndrome [78] [79] [80] [81] , skeletal muscle damage (hyperCKemia, rhabdomyolysis, myopathy [72, 76] ), dysautonomia), -Neuropsychiatric symptoms [82] : anxiety, depression, insomnia, and psychosis Suggested mechanisms are the hypoxic brain injury on severe pneumonia with peripheral vasodilatation, hypoxia, hypercapnia, and anaerobic metabolism, immune mediated injury related to the cytokine storm, and SARS-CoV-2 direct neurovirulence, since it has already been described for other coronaviruses [76, 83] .

Prevalence of reported comorbidities among patients with COVID-19 has largely varied according to countries. The largest published cohorts are among Chinese and American patients, and main comorbidities are hypertension (17-57%) [19, 84, 85] , obesity (42%) [84] , diabetes (8-34%) [84] , and cardiovascular disease (4%) [19, 85] . Being a man was described as the main risk factor for COVID-19 [61, 85] .

Most ICU admissions were related with a respiratory failure (54-86%) [56, 86, 87] , that is also the leading cause of mortality (93-100%) [56, 87] . Patients with respiratory failure are described to present an acute respiratory distress syndrome (ARDS), defined as a respiratory failure not fully explained by cardiac failure or fluid overload, bilateral opacities in chest imaging, and oxygenation PaO2/FiO2 < 300 mmHg [88] .

Report from critically-ill-patients series suggested that those patients presented a "cytokine storm". Biological data showed a higher level of IL-6 in critically-ill and non-surviving patients, a higher level of CRP and a higher level of ferritin [56, 59, 86, 89] . Among severe patients, the lymphocytes count was lower than mid patients or healthy controls (respectively 1,132mol/L, 1,256mol/L, and 2,215mol/L). CD4+ and CD8+ lymphocytes were also lower in the severe-patients group [89] .

Necropsy of patients who died from COVID-19 allowed histological analysis of lung tissue samples.

Reported patients spent between 1 and 23 days in ICU before death. Macroscopic examination found lungs which were heavy, congested and edematous with patchy involvement. Histological examination found features corresponding to the exudative and early or intermediate proliferative phases of diffuse alveolar damage (capillary congestion, interstitial and intra-alveolar edema, dilated alveolar ducts, collapsed alveoli and loss of pneumocytes). Authors also reported interstitial pneumonia (inflammatory lymphomonocytic infiltrate along the slightly thickened interalveolar septa), organizing pneumonia, and acute fibrinous organizing pneumonia [90] .

A review article on children presenting COVID-19 was published by Cui et al. reporting clinical, biological and imaging features on 2.597 children [91] . Among all cases 7.6% were asymptomatic, 45 .5% were mild, 41.5% were moderate, 4.4% were severe, 0.9% were critical, and 0.1% (3) led to death. Regarding clinical characteristics, authors collected data from 23 articles (452 children): 43% presented with fever, 43% with cough, 20% with sore throat, 17% with tachycardia, 16% with rhinorrhea, 15% with nasal congestion, and 13% with shortness of breath. Among 23 critical cases, six had an underlying disease. Pulmonary imaging in 294 cases reported 30% of ground glass opacities, 20% of local patchy shadow, 15% of bilateral patchy shadow, and 1% of interstitial lesions. In an international study among 582 children presenting COVID-19 infection, reported risk factors for admission to ICU or requiring mechanical ventilation were being less than 1-month-old (p<0.001) and

having an underlying disease (p<0.001) [92] .

Observations described a higher risk of Kawasaki-like inflammatory syndrome in children infected by SARS-CoV-2, also called by WHO the COVID-19 associated pediatric multisystem inflammatory syndrome [93] ; e.g., a 497% increase of children admitted for a Kawasaki-like syndrome during COVID-19 epidemic was described in a small French cohort [94] ; IgG antibodies against SARS-CoV-2 infection were detected among 19/21 of children presenting with a Kawasaki-like syndrome during the epidemic in another French cohort [95] . Kawasaki disease is described as an acute febrile systemic vasculitis that affects medium and small-sized blood vessels. One suspected mechanism is a post-viral immunological reaction to several viruses (influenza [96] , enterovirus [97] , adenovirus [98] , parvovirus [99] , VZV [100] , EBV [100] , measles [101] , or Dengue [102] ).

Upon infection, humoral antiviral immunity is triggered, owing to the development of specific antibodies. A vast majority of infected patients will generate anti-SARS-CoV-2 antibodies [103] .

Antibody titers peak around day 30 post-infection [104] , but from this point forward only decrease.. IgM and IgG kinetics do not differ significantly [105] , thus making differential isolation of these markers void. Seroconversion is witnessed at a median of 14 days after symptom onset [106] . High antibody titers are associated with severe respiratory symptoms, asymptomatic patients having lower titers [105] . This raises the so far unresolved question of COVID-19 immune mechanisms and protection. It is not clear whether high antibody titers could promote severe clinical presentations by a mechanism similar to antibody dependent enhancement [107, 108] . On the other hand, pauci-symptomatic forms of COVID-19 could trigger a reduced humoral response only that could correlate with a shortened duration of protection [109] .

Anti-SARS-CoV-2 antibodies are directed towards both the spike (S) protein and the nucleocapsid (NP) [110] . Neutralising antibodies are observed in most patients and recognise specifically the spike (S) protein [111] . Neutralising activity appears to be correlated with the presence of antibodies binding the receptor-binding domain (RBD) in its closed conformation within the spike protein [112] , and the detection of such antibodies could be a surrogate marker of protection. No cross-reactivity with other human coronavirus (HCoV-OC43, HCoV-NL63, HCoV-229E and HCoV-HKU1) has been evidenced to date (ref). However, cross-reactivity with SARS-CoV-1 has been shown at least in vitro [26] .

While serological assays allow large epidemiological studies and enable better evaluations of epidemic parameters (Rt, for instance), individual benefit is scarce, if existent. Accordingly, we believe patient management should focus on molecular based assays.

To date, no anti-viral therapy has proven its efficacy and the current management of COVID-19 remains supportive care and ventilatory support when needed.

Remdesivir Remdesivir (GS-5734) is a nucleotide analog that targets viral RNA polymerases. It has an established in vitro (culture cells) and in vivo (mouse and primate models) efficiency on multiple genetically distinct coronaviruses, and on Ebola virus [113, 114] . Its in vitro effect on SARS-CoV-2 has been reported in Wang et al.'s work, with a high 90% effective concentration value against infection of Vero E6 cells [115] . Williamson explored remdesivir's efficiency in 12 rhesus macaques infected with SARS-CoV-2 infection [116] . One over six macaques in the remdesivir group developed a respiratory disease vs 6/6 in the control group. After euthanasia and lung analysis, no virus was detected in lung tissue samples in the remdesivir group; remdesivir was detected in all six lungs of the treated animals. Only 3/36 lobe lungs in the control group were virus-free. There was no difference in viral load in BAL between both groups.

Gilead restricted access to remdesivir since the beginning of COVID-19 pandemic to compassionate use and to clinical trials [117] . The first clinical study on remdesivir was published by Grein et al. on 53 patients, without any control group. Treatment was started 12 days after symptom onset; 68% of treated patients showed an improvement regarding oxygen support, and 13% of patients who completed treatment died [118] . A large international clinical trial compared 541 patients receiving remdesivir with 522 patients treated with placebo. A shorter time to recovery (11 days vs 15 days) was reported in the remdesivir group (p<0.001). Adverse events were reported (21% in the remdesivir group and 27% in the placebo group [119] ). Goldman et al. compared 5 vs 10 days of remdesivir treatment in a multicentric, international clinical trial among 397 patients and did not observe any difference between the 2 groups at 14 days after treatment onset on primary outcome (clinical efficacy on a 7-points scale) [120] .

Lopinavir is an antiviral agent developed to target HIV protease; it is generally used in association with ritonavir, a pharmacokinetic "booster" increasing lopinavir plasma concentration. It is widely used in adults living with HIV/AIDS [121] . LPV/RTV is regarded as a potential anti-SARS-Cov-2 agent since several trials on SARS-CoV-1 showed a favorable effect. Indeed, in a 2003 study of 1,521 patients with SARS, Chan et al. reported a 2% death rate in the LPV/RTV group vs 16% in the SoC group (p<0.05) if LPV/RTV was used as initial treatment, but with no difference as a rescue treatment [122] . In a 2004 study exploring the efficacy of LPV/RTV in patients with SARS regarding a composite primary outcome (severe hypoxemia or death at day 21), Chu et al observed that 2% in the LPV/RTV group met the primary outcome, vs 29% in a historic control group (p<0.001) [123] . The first large clinical trial published on LPV/RTV on SARS-CoV-2 compared 99 patients receiving the antiviral vs 100 receiving SoC alone [124] ; there was no difference between the 2 groups regarding the primary end point (time to improvement) (15 vs 16 days, p=0.09). Noteworthily, the median time between symptom onset and treatment was 13 days. 48% of patients in the LPV/RTV group vs 50% in the SoC group who underwent an adverse event.

Hydroxychloroquine (HCQ) is a widely used molecule in limited forms of lupus, with a low price, and it has an established clinical safety profile [125] In vitro studies showed the effect of chloroquine [115] and HCQ in inhibiting SARS-CoV2 infection [126] . In vitro activity of HCQ and chloroquine against SARS-Cov-2 were not different in Liu et. al's work [126] , and HCQ was found, in vitro, to reach three times the potent antiviral activity of chloroquine in Yao et. al's work [127] . Noteworthily, HCQ was four times less toxic than chloroquine in animal study [128] . However, a recent in vitro study showed that chloroquine did not block SARS-CoV-2 infection of the TMPRSS2-positive lung cell [129] . Another in vitro study also found that HCQ did not show any antiviral activity in a model of reconstituted human airway epithelium [130] . Due to such in vitro results, several trials assessed the efficiency of HCQ on viral load in respiratory samples (without clinical considerations [131] [132] [133] [135] . Association of HCQ and azithromycin was associated with a higher risk of ventricular tachycardia and prolonged QT.

HCQ alone was responsible for more conduction disorder. However, in patients receiving azithromycin alone compared with HCQ alone, there was more prolonged QT and ventricular tachycardia. unchanged before and after hemodialysis [137] .

Moreover, several observations reported the onset of severe COVID-19 in patients who were already receiving HCQ as a long-term treatment for an inflammatory disease [138] .

One randomized trial evaluated the outcome of HCQ whether or not in association with azithromycine on mild to moderate COVID-19 [139] . primary endpoint (escalation in ICU, mechanical ventilation or death) was reached by 35% of patients in the early corticosteroid group vs 54% in the control group (p=0.005) [141] . RECOVERY was a randomized, controlled trial of the use of 6 mg of dexamethasone vs SoC in hospitalized patients with COVID-19. At 28 days, 454/2,104 (21.6%) patients had died in the dexamethasone group vs 1,065/4,321 (24.6%) in the SoC group (p<0.001) [142] .

Tocilizumab is a monoclonal antibody against IL-6 receptor. It is mainly prescribed in rheumatoid

arthritis. An Italian team reported the use of tocilizumab to the first 100 patients presenting to the Brescia University hospital with a COVID-19 ARDS requiring ventilatory support. At 72h, 58% of patients showed an improvement, and at 10 days after treatment inset, 77% of patients had improved and/or stabilized [143] .

Anakinra is an antagonist of IL-1 receptor. An Italian team reported the use of anakinra in 29 patients with moderate to severe COVID-19 ARDS before mechanical ventilation, compared with 16 patients not receiving anakinra. Survival rate at 21 days was 90% in the anakinra group vs 56% in the control group (p =0.009). However, there was no difference regarding the mechanical ventilation-free survival (72% in the anakinra group vs 50% in the control group, p=0.150) [144] .

A Chinese team reported the use in 51 COVID-19 patients of convalescent plasma compared with a control group of 50 patients. Their primary endpoint was clinical improvement within a 28 day-period (reduction of 2 points on a 6-points disease severity scale). There was no difference between both groups (p = 0.260). In sub-group analysis among patients presenting a severe disease, 91% of patients met the primary endpoint in the plasma therapy group vs 68% in the control group (p = 0.003) [145] .

In another study, the outcomes of 1,430 severe or critical patients treated with SoC and 138 patients treated with convalescent plasma therapy were compared; 2.2% of patients died in the plasma group vs 4.1% in the SoC group (no comparison). 2.4% of patients were admitted to ICU in the plasma group vs 5.1% in the SoC group (p=0.2) [146] .

The effect of ACE inhibitor and ARB treatment on COVID-19 severity and/or mortality has been reported in several studies but seems variable. In Zhang et al's work, on 1,128 patients with hypertension and COVID-19, multivariate analysis found a lower all-cause mortality in the ACE inhibitor/ARB group, than in the other group (p = 0.03) [147] . However, Li et al did not found any difference in COVID-19 severity (p=0.645) or mortality (p=0.340) among 362 patients admitted for hypertension and COVID-19 [148] .

In Chu et al.'s meta-analysis, social distancing was considered as efficient with a -10.2% risk difference (95%CI [-11.5 to -7.5%] of infection in short distance vs further distance [149] . Wearing respirators or face masks was associated with a large reduction in risk of infection (risk difference -14.3%, 95%CI [-15.9 to -10.7%]) [149] . Eye protection also seemed efficient in infection reduction with a risk difference of -10.6% 95%CI [-12.5 to 7.7%] [149] . However, lockdown had the larger impact on transmission with an 81% [75%-87%] reduction [23] .

In France, the number of daily cases of COVID-19 was growing by the end of summer 2020, suggesting the debut of a second epidemic wave, as many other countries are facing. The first wave allowed us to develop and strengthen our laboratory tests. Since then, French health authorities have implemented a systematic contact tracing (CONTACT-COVID) around each patient presenting a positive SARS-CoV-2 RT-PCR. This highlighted the high number of asymptomatic and mild cases, and made French people massively adapt their daily habits with a systematic face mask protection in all public areas, and restrictions in social events. However, none of the evaluated pharmacological treatments have showna clear efficacy on SARS-CoV-2. One of the main limitations seem to be the long period between symptom onset and initiation of treatment. An effective vaccine against SARS-CoV-2 appears to be the only way to end this pandemic. At the end of August 2020, 203 trials were registered on Clinicaltrial for a vaccine against COVID-19, thus raising hope to end this pandemic in a reasonable amount of time.

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Guillain Barre syndrome associated with COVID-19 infection: A case report

Guillain-Barré Syndrome associated with SARS-CoV-2 infection

Guillain-Barré syndrome associated with SARS-CoV-2

Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry

Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)

Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area

Comorbidity and its impact on 1,590 patients with Covid-19 in China: A nationwide analysis

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Acute respiratory distress syndrome: The Berlin definition

Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

Multisystem inflammatory syndrome in children and adolescents with COVID-19 n

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic

Influenza A (H1N1) pdm09 virus infection in a patient with incomplete Kawasaki disease: A case report

Enterovirus Infection and Subsequent Risk of Kawasaki Disease: A Population-based Cohort Study

Adenovirus, adenoassociated virus and Kawasaki disease

Acute respiratory distress syndrome in a child with human parvovirus B19 infection

Kawasaki disease onset during concomitant infections with varicella zoster and Epstein-Barr virus

Incomplete Kawasaki disease induced by measles in a 6-month-old male infant

Dengue-triggered kawasaki disease: A report of 2 cases

A Peptide-Based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Coronavirus Disease

Neutralizing Antibodies Responses to SARS-CoV-2 in COVID-19 Inpatients and Convalescent Patients

Antibody responses to SARS-CoV-2 in patients with COVID-19

Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19)

The potential danger of suboptimal antibody responses in COVID-19

Dissecting antibody-mediated protection against SARS-CoV-2

The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection

Comparison of the diagnostic sensitivity of SARS-CoV-2 nucleoprotein and glycoprotein-based antibody tests

Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike

Potent Neutralizing Monoclonal Antibodies Directed to Multiple Epitopes on the SARS-CoV-2 Spike

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Emergency Access to Remdesivir Outside of Clinical Trials

Compassionate Use of Remdesivir for Patients with Severe Covid-19

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

LopinavirRitonavir: A review of its use in the management of HIV-1 infection

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: A multicentre retrospective matched cohort study

Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Main point : Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vit

Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2

Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

Observational study of hydroxychloroquine in hospitalized patients with COVID-19

Cardiovascular Toxicities Associated with Hydroxychloroquine and Azithromycin: An Analysis of the World Health Organization Pharmacovigilance Database

Hydroxychloroquine pharmacokinetic in COVID-19 critically ill patients: an observational cohort study

COVID-19 infection also Page 28 of 29 patients taking hydroxychloroquine

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Successful use of methylprednisolone for treating severe COVID-19

Early Short Course Corticosteroids in Hospitalized Patients with COVID-19

Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Improved Clinical Symptoms and Mortality on Severe/Critical COVID-19 Patients Utilizing Convalescent Plasma Transfusion

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality among Patients with Hypertension Hospitalized with COVID-19

Association of Renin-Angiotensin System Inhibitors with

Severity or Risk of Death in Patients with Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis