key: cord-0876437-kxnrf5g5 authors: Riggioni, Carmen; Comberiati, Pasquale; Giovannini, Mattia; Agache, Ioana; Akdis, Mübeccel; Alves‐Correia, Magna; Antó, Josep M.; Arcolaci, Alessandra; Kursat Azkur, Ahmet; Azkur, Dilek; Beken, Burcin; Boccabella, Cristina; Bousquet, Jean; Breiteneder, Heimo; Carvalho, Daniela; De las Vecillas, Leticia; Diamant, Zuzana; Eguiluz‐Gracia, Ibon; Eiwegger, Thomas; Eyerich, Stefanie; Fokkens, Wytske; Gao, Ya‐dong; Hannachi, Farah; Johnston, Sebastian L.; Jutel, Marek; Karavelia, Aspasia; Klimek, Ludger; Moya, Beatriz; Nadeau, Kari; O'Hehir, Robyn; O'Mahony, Liam; Pfaar, Oliver; Sanak, Marek; Schwarze, Jürgen; Sokolowska, Milena; Torres, María J.; van de Veen, Willem; van Zelm, Menno C.; Wang, De Yun; Zhang, Luo; Jiménez‐Saiz, Rodrigo; Akdis, Cezmi A. title: A compendium answering 150 questions on COVID‐19 and SARS‐CoV‐2 date: 2020-06-14 journal: Allergy DOI: 10.1111/all.14449 sha: bc012dd14427e5edbe1feea770002da392742375 doc_id: 876437 cord_uid: kxnrf5g5 In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID‐19). This disease, caused by the severe acute respiratory syndrome‐related coronavirus 2 (SARS‐CoV‐2), has developed into a pandemic. To date it has resulted in ~6.5 million confirmed cases and caused almost 400,000 related deaths worldwide. Unequivocally, the COVID‐19 pandemic is the gravest health and socio‐economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence‐based medical advice on SARS‐CoV‐2 and COVID‐19. Although the majority of the patients show a very mild, self‐limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID‐19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thrombo‐embolic complications and multiorgan failure. The epidemiologic features of COVID‐19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID‐19‐related topics should be based on more coordinated high‐quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS‐CoV‐2, COVID‐19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID‐19 and allergic disease. The first cases of the coronavirus disease 2019 (COVID- 19) , caused by the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), were reported in China in December 2019 1 and rapidly led to pandemic. Currently, ~6.8 million confirmed cases of COVID-19 and near 400,00 COVID-19-related deaths have been reported globally. 2 These numbers, which are still rising, likely underestimate the cumulative incidence of COVID-19 due to several factors; these include limitations of current diagnostic tests, the extent of population testing and reporting, and the type and timing of community mitigation strategies adopted by each country, among others. 3 COVID-19 shows a complex clinical profile with many different presentations. Like in many other viral infections, subclinical, mild, moderate, or severe cases (10-20% of patients require hospitalization and 2-4% intensive care unit, ICU) presenting with or without pneumonia are observed. Asymptomatic cases are common but, to date, there is a lack of epidemiological surveys that provide a clear percentage of asymptomatic cases. 4, 5 The COVID-19 pandemic is the world's gravest public health crisis of the 21st century, and there is an urgent need for reliable and updated scientific and clinical information. COVID-19 is a zoonosis to CD147 (known as basigin or extracellular matrix metalloproteinase inducer), which is expressed in human airway and kidney epithelium, as well as in innate cells and lymphocytes, 14 and to TMPRSS4, which is highly expressed in intestinal epithelial cells. 15 In addition, antibody-dependent enhancement of SARS-CoV-2 cell entry may also contribute to infection as reported for SARS-CoV. 16 SARS-CoV-2 may use receptors that have been reported for other coronaviruses, such as CD26, aminopeptidase N and glutamyl aminopeptidase for cell invasion. 13, 17, 18 Among these, CD26 (encoded by DPP4) has emerged as a putative receptor for SARS-CoV-2 because structural analyses predict that the spike protein of SARS-CoV-2 binds to CD26. 19 This receptor has been shown to be expressed in the human epithelium and immune cells. 14 There is limited evidence about COVID-19-associated polymorphisms. ACE might be one of the candidate genes that influences pneumonia progression in SARS. It is conceivable that the D allele influences the renin-angiotensin system via elevation of serum or local ACE levels, which may damage the endothelium or epithelium of the lungs. 20 The variance in COVID-19 prevalence and mortality cannot be explained by an ACE insertion or deletion polymorphism alone, or one polymorphism of any single gene. However, polymorphisms in genes of toll-like receptors, inflammasome, intracellular molecular sensors, interferons (IFNs) 21 and interleukins (ILs) may contribute. Structural proteins of SARS-CoV-2 virions, such as the spike glycoprotein, envelope, membrane and nucleocapsid, are the main immunogenic molecules (Figure 1) . 22 ,23 SARS-CoV-2 adaptive responses develop mainly to the spike protein, and immunodominant T and B cell epitopes have been reported. 24 Intracellularly, the viral RNA replicase complex, and non-structural and translated proteins, activate innate immune pathways. This leads to an IFN type I response, NF-kB activation in epithelial cells, as well as activation of NLRP3 and other inflammasomes, in macrophages and dendritic cells. 23 This article is protected by copyright. All rights reserved The spike protein of SARS-CoV-2 has a receptor-binding domain that binds ACE2 with higher affinity than SARS-CoV. 8 In addition, the SARS-CoV-2 spike protein harbors a polybasic furin cleavage site (PRRAR) with an insertion of 4 amino acid residues, which is distinct from that found in SARS-CoV and other SARS-like viruses. This allows effective cleavage by furin and other proteases and determines viral infectivity and host range. 6 The severe lymphopenia observed in COVID-19 25 is similar to that reported in HIV infection and acquired immune deficiency syndrome. The latter is characterized by CD4+ T cell lymphopenia, whereas COVID-19 causes general lymphopenia. However, severe lymphopenia development in COVID-19 happens in weeks, whereas HIV-induced lymphopenia takes years. 26 HIV and SARS-CoV-2 are both RNA viruses and share some similarities in their replication pathways; hence certain RNA replication drugs may work in both diseases (Figure 1) . 27 There are 2 strains of SARS-CoV-2 that are clinically relevant. Genome analysis of SARS-CoV-2 from human samples shows high rates of mutation and deletion in several viral genes, including the spike-glycoprotein gene. 28 COVID-19 treatments, including future vaccination against SARS-CoV-2, may drive the genetic evolution of the virus affecting virulence and pathogenicity. For example, a report on a 382-nt deletion in ORF8 (Figure 1 ) of SARS-CoV2 isolated from patients in Singapore implied that mutations may arise as a result of human adaptation and could be associated with attenuation. 29 Nevertheless, the emergence of a SARS-CoV-3 is possible as long as there is close contact between humans and living animals that harbor coronaviruses. Data from 96 COVID-19 patients in China show SARS-CoV-2 detection in respiratory samples for a median of 18 days (13-29 days) . In this study, sputum and saliva were not analyzed separately. Viral shedding was significantly longer in patients with severe disease, with a median of 21 days (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) days), compared to mild disease, 14 days (10-21 days). Furthermore, glucocorticoids treatment This article is protected by copyright. All rights reserved longer than 10 days significantly extended the duration of SARS-CoV-2 shedding. 30 Viral load differed significantly by sample type, with respiratory samples showing the highest, followed by stool samples, and serum samples showing the lowest (Figure 2) . 30 Another study of 78 patients with COVID-19 (33 asymptomatic vs 42 symptomatic) has estimated that the duration of viral shedding from nasopharynx swabs was 8 days (3-12 days) for asymptomatic vs 19 days (16-24 days) for symptomatic patients. 31 The viral load range from 1.34 × 10 11 copies per mL to 7.52 × 10 5 in sputum of patients who died or survived, respectively. 32 TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of ACE-expressing human enterocytes 15 causing diarrhea in adults and children. 33,34 SARS-CoV-2 has been detected in stool samples by reverse transcription polymerase chain reaction (RT-PCR) (Figure 2) . The median duration of the virus in stool samples (22 days, interquartile range 17-31 days) was significantly longer than in respiratory samples (18 days, 13-29 days) . 30 However, SARS-CoV-2 released into the intestinal lumen was inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of patients with COVID-19. Therefore, the intestine is a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression but unlikely to contribute to the spreading of COVID- 19. 15 Section 2: Immunology of COVID-19 From previous SARS studies, it is known that the median seroconversion time for detectable IgG was 17 days after infection. 35 Detectable levels of SARS-specific IgG and neutralizing antibodies persisted for up to 720 days. This suggests that there is antibody-mediated protection from SARS-CoV recurrent infection for up to 2 years. 36 There are inconsistent reports on the humoral response to SARS-CoV-2. One study with 285 COVID-19 patients reported that SARS-CoV-2 virus-specific IgG and IgM peaked 17-19 days and 20-22 days after symptom onset, respectively. 37 On the other hand, another study of 26 hospitalized COVID-19 patients showed that seroconversion could take up Accepted Article to 50 days. 38 These discrepancies may be related to the time of SARS-CoV-2 diagnosis or the clinical characteristics of each cohort and warrant additional studies. Systemic IgA responses may play a relevant role in the pathogenesis of COVID-19. 39 Mucosal IgA likely exerts a protective role by preventing SARS-CoV-2 adherence to epithelial cells. Circulatory IgA may also contribute to SARS-CoV-2 neutralization. In addition, IgA has the ability to either promote inflammation, through the formation of immune complexes, or to dampen it via Fc-mediated inhibitory ITAM-signaling. 40, 41 A seroconversion study in COVID-19 patients has found and association between disease severity and SARS-CoV-2-specific IgA levels. These were significantly higher than SARS-CoV-2-specific-IgM and -IgG levels in critically ill COVID-19 patients. 39 Whether this association, previously unseen in SARS-CoV infection, 42 is due to a protective or detrimental role of IgA in COVID-19 remains to be elucidated. Preliminary findings indicate that asymptomatic and mild cases of COVID-19 can generate detectable levels of SARS-CoV-2-specific antibodies in serum. However, seroconversion is observed less frequently in asymptomatic compared to mild or severe cases, and many asymptomatic cases yield undetectable SARS-CoV-2-specific antibody responses. 37, [43] [44] [45] So far, no robust data are available on the qualitative differences in humoral responses between asymptomatic and symptomatic COVID-19 patients. It is not clear which molecular mechanisms underlie the milder symptoms of COVID-19 in children as compared to adults. Children may mount a SARS-CoV-2 antibody response characterized by more efficient production of the so-called natural antibodies, which arise from activated IgM+ memory B cells. 46 These cells, which are more prevalent in children than in adults, presumably produce broadly neutralizing antibodies early during the infection. This article is protected by copyright. All rights reserved B cell receptor-sequencing has been conducted in the blood of COVID-19 patients. Naive B cells exhibited little clonal expansion, whereas CD27+CD38+ memory B cells showed the highest expansion levels among diverse B cell subsets. COVID-19 patients significantly expanded specific Bcell receptor clones compared to those in the healthy controls. These findings suggest that B cells experience unique clonal variable, diversity, and joining gene segment rearrangements upon SARS-CoV-2 infection. 47 The lifespan and functionality of these B cells remain to be elucidated. The term "herd immunity" refers to the generation of population immunity that protects a region, or country, from infection. 48 The number of confirmed COVID-19 cases has reached approximately 6.5 million. 2 The world population is estimated to be 7.8 billion. To ascertain the extent of herd immunity, it is pivotal to define the prevalence of SARS-CoV-2-exposed humans. It is thought that 67% is the minimum percentage of symptomatic or asymptomatic COVID-19 population required for herd immunity. 48 That is to say that worldwide herd immunity may occur when ⁓5 billion humans have a protective immune response against SARS-CoV-2. To date, there are no reliable data, particularly on the number of asymptomatic individuals that show seroconversion, to determine the degree of herd immunity. 49 IL-4 is pleiotropic and could theoretically cause negative effects on immune responses. However, based on phase II and III studies with dupilumab (an IL-4Rα-specific monoclonal antibody that blocks IL-4 and IL-13 signaling) in the context of atopic dermatitis, chronic rhinosinusitis with nasal polyps and asthma, no increased risk of infections to viral or bacterial pathogens have been documented. 50 Furthermore, dupilumab had no impact on responses to non-live vaccines. 51 This article is protected by copyright. All rights reserved Allergic airway disease patients appear to be underrepresented among COVID-19 patients. 52-54 This could be partly attributed to the low ACE2 expression detected in allergic patients, with or without concomitant asthma. 55 Furthermore, allergen challenge, which induces T helper (Th)-2 inflammation, 56 has been shown to reduce ACE2 expression in a murine model of asthma, and ACE2 expression was inversely associated with type 2 biomarkers (IL-13, IgE, exhaled nitric oxide fraction). 57 These results are in line with previous work showing that decreased ACE expression in the airway epithelium of asthmatic subjects was associated with eosinophilic inflammation. 58 On the other hand, the analysis of nasal airway transcriptome data from 695 children identified that TMPRSS2 is highly upregulated by type 2 inflammation through the action of IL-13. Therefore, the reduced ACE2 expression seen in asthmatic patients may be compensated by an increase in TMPRSS2 production. 59 Eosinopenia has been reported in ⁓50-70% of severe COVID-19 patients. A minority of COVID-19 patients present with eosinophilic inflammation. 25,60 The Th1/Th2 cytokine balance may play a role, particularly as it pertains to IL-5, which promotes eosinophilopoiesis and eosinophil survival and activation. Eosinophilic inflammation suggests the dominance of type 2 inflammation, which may play a protective role against SARS-CoV-2. On the other hand, it may be the result of a hypersensitivity reaction to drugs used to treat COVID-19. 61-63 Anti-IL-5 treatment, which induces eosinophil deficiency, results in a higher viral load in influenza and rhinovirus infection. This might be due to the ability of eosinophils to bind and inactivate the influenza A virus and respiratory syncytial virus (RSV). 64 A similar role seems possible in SARS-CoV-2 infection, where type-2 asthma patients potentially benefit from antiviral eosinophil responses. On the other hand, COVID-19 post-mortems did not show lung eosinophilia 62 , which argues against its local protective role in SARS-CoV-2 infection, although it is important to control for glucocorticoid-driven eosinophil reduction in these studies. 61 This article is protected by copyright. All rights reserved Eosinopenia is commonly reported in severe COVID-19. 65, 66 The underlying mechanisms are largely unknown and most likely multifactorial. A number of possible explanations have been proposed: decreased eosinophilopoiesis; defective eosinophil egression from the bone marrow; and eosinophil apoptosis induced by type 1 IFN released during the acute infection. 61 Also, increased eosinophil migration and retention within inflamed tissues has been described, 67 but disputed for the aforementioned reasons. 62 There is no evidence for an enhanced susceptibility of patients on anti-IL-5/IL-5R treatment to develop viral infections. Observational studies in COVID-19 patients reported elevated eosinophil counts with a favorable outcome, whereas eosinopenia was observed in more severe cases. 25, 68 Neither was there proof of causation nor evidence for enhanced tissue presence in lungs of COVID-19 patients. 69 There is neither evidence for a protective effect of these biologicals nor a negative effect regarding SARS-CoV-2 infection. Importantly, maintaining proper asthma control is imperative and so is to follow up on severe asthmatics during the COVID-19 pandemic, for example via telemedicine. 50 More than 1 billion people worldwide are infected with helminths, with those living in resource-poor tropical areas being disproportionately affected. Helminth co-infection has been shown to influence the severity of viral infection in mice. For example, murid herpesvirus 4 respiratory infection, prior infection with Schistosoma mansoni, reduced disease severity. 70 However, immune responses to pulmonary coronaviruses and murid herpesvirus 4 are different and therefore the impact of helminth co-infection is yet to be determined. This is particularly important as the pandemic is now spreading through the helminth-endemic regions of the word. 71 This article is protected by copyright. All rights reserved SARS-CoV-2 infects human T cells via CD147-binding. 72 T cells are severely affected by SARS-CoV-2, which reduces T cell counts nearly 2 times below the reference limit. This effect is more pronounced in critically ill COVID-19 patients. 60, 73, 74 In addition to the reduction in T cell numbers, a recent study found that CD4+ and CD8+ T cells as well as natural killer cells displayed reduced antiviral cytokine production in COVID-19 patients. A reduced cytotoxic potential was identified in COVID-19 patients, particularly in those that required ICU, and was associated with high IL-6 serum levels. 75 Circulating SARS-CoV-2−specific CD8+ and CD4+ T cells have been reported in ∼70% and 100% of COVID-19 convalescent patients, respectively. 76 CD4+ T cell responses to the spike protein were robust and correlated with SARS-CoV-2-specific-IgG and -IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M proteins were recognized, with at least 8 SARS-CoV-2 ORFs targeted. Interestingly, SARS-CoV-2−reactive CD4+ T cells were detected in ∼40-60% of unexposed individuals, which indicate cross-reactive T cell recognition between circulating 'common cold' coronaviruses and SARS-CoV-2. 76 Three SARS-recovered individuals, 9-and 11-years post-infection, were analyzed for T-cell responses against 550 SARS-CoV peptides that may share homology with MERS-CoV. SARSspecific memory T cells persisted at 9 and 11 years post-SARS infection in the absence of antigen exposure. 77 Based on these data, it is likely that specific SARS-CoV-2 epitopes elicit a persistent T cell response, which may also confer protection against other 'common cold' coronaviruses. 76 However, long-term studies on the natural history of SARS-CoV-2 infection are pending. Different mechanisms have been proposed for lymphopenia: 1) T cell exhaustion. The expression of programmed cell death-1 marker (also known as PD-1), which is associated with T-cell exhaustion, was higher in T cells from COVID-19 patients than in healthy controls; the expression of PD-1 and Tim-3 (another exhaustion marker) increased as COVID-19 progressed. 78 2) Activation of P53 signaling in lymphocytes, which suggests a role for apoptosis for in lymphopenia. 3 This article is protected by copyright. All rights reserved pyroptosis, which induces lymphopenia and may be proinflammatory. 79 CoV-2, which may also cause a cytopathic effect on infected T cells. 5) Other mechanisms of lymphopenia that remain to be studied are bone marrow suppression during cytokine storm syndrome (CSS; see below) and sequestration in the lungs during extensive bilateral pneumonia. 60 Lymphopenia can be used as an early predictor of severity and clinical outcome. A significant reduction in lymphocyte counts was common in severe and critically ill COVID-19 patients. A continuing or gradual decrease of lymphocyte counts was indicative of poor prognosis and usually required ICU admission ( Table 1) 60 . In agreement with this, a number of studies have identified lymphopenia as an independent risk factor for mortality in COVID-19. 25,80 In COVID-19 patients, decreases were observed in total lymphocytes, CD4+ and CD8+ T cells, B cells and natural killer cells. T cell and natural killer cell counts were below normal levels, while B cell counts were at the low end of the normal range. A reduction in specific subsets of lymphocytes, such as CD16+CD56+ natural killer cells and regulatory T cells, was reported in severe COVID-19 patients. 60 CSS is associated with a wide variety of diseases, both infectious and noninfectious. It is a complex cascade of multicellular activation events that leads to an excessive or uncontrolled release of proinflammatory cytokines. CSS-associated inflammation begins at a local site and spreads throughout the body via the systemic circulation and can cause multi-organ failure and hyperferritinemia. 60,81 CSS encompasses the activation of large numbers of blood cells, including B cells, natural killer cells, macrophages, dendritic cells, neutrophils, monocytes, resident tissue cells and epithelial and endothelial cells. Their activation cause a massive release of pro-inflammatory cytokines, which This article is protected by copyright. All rights reserved drives pathology. 82 The cells involved in CSS during COVID-19 have not been fully determined yet. were the most important cell types releasing a large amount of proinflammatory cytokines. 60, 83 Which cytokines are most elevated during CSS? Multiple proinflammatory cytokines and inflammasome activation may contribute to CSS pathogenesis. 60 Elevated serum ferritin, IL-6, IL-1β, IFN-γ , CXCL10 (known as IP-10) and CCL2 Immunosuppression is a double-edged sword in viral infections. 86 This article is protected by copyright. All rights reserved Primary immunodeficient patients are a high-risk group in the current pandemic, but to date it is unknown if a particular immunodeficiency poses a higher risk of severe disease. International primary immunodeficiency monitoring is being carried out and few cases have been documented. Patients at higher risk are those with complications resulting from their primary immunodeficiency and strict follow-up must be done in those cases. A consensus has been established that baseline chronic treatment should be continued in those patients if they are asymptomatic or mildly symptomatic. Furthermore, recommendations regarding primary immunodeficient patients adhere to individual national guidelines emphasizing social distancing and strict hygiene measures. Systematic testing of primary immunodeficient patients is not advised, however recommendations may change as the pandemic evolves. 89 There are no longitudinal studies analyzing T regulatory cells in COVID- 19 Systemic dysregulation of metabolism, such as that seen in obesity and diabetes is a risk factor of SARS-CoV-1 and SARS-CoV-2 infection and of COVID-19 severity 69 . These diseases lead to chronic systemic inflammation, upregulation of SARS-CoV-2 receptors in the lungs and the periphery, and they disturb the glucose and lipid metabolism of tissues and immune cells. 14, 91, 92 ARDS is an acute life-threatening inflammation of the lung due to infection, trauma, or inflammatory conditions. Excessive inflammation leads to alveolar damage and increased permeability of endothelial and epithelial cells. This results in protein-rich fluid accumulation in the interstitium and the air space, which causes impaired gas exchange and hypoxemia. Reactive oxygen species, leukocyte proteases, chemokines, and cytokines also contribute to lung injury. The barrier impairment of the lung microvascular barrier is central to the pathogenesis of ARDS. 93 In COVID-19 patients, ARDS is more common in the elderly, those with multiple comorbidities, and those with continuing or gradually progressing neutrophilia and lymphopenia, and a higher level of Creactive protein, lactate dehydrogenase, D-dimer and procalcitonin. 60, 88 There are at least 2 clinical phenotypes of ARDS: 1) near normal pulmonary compliance with isolated viral pneumonia; 2) decreased pulmonary compliance. 95, 96 What specific therapies can be suggested for ARDS? Different treatments were suggested for ARDS. Corticosteroid treatment is generally not recommended, although widely used in critically ill patients. Convalescent plasma (CP) was administered to a small number of patients and was associated with virus clearance and clinical improvement ( Table 2) . Low tidal mechanical ventilation, positive end-expiratory pressure, prone positioning ventilation, and fluid management guidelines were associated with improved outcomes. Extracorporeal membrane oxygenation could be used according to the inclusion and exclusion criteria of the EOLIA trial. Other potential therapies such as mesenchymal stem cell therapy and cytokine inhibitors are still in trials and without definite results. 60,97 BCG is a live attenuated vaccine that was developed against tuberculosis at the beginning of the 20th century. BCG vaccination induces metabolic and epigenetic modifications by enhancing trained immunity (innate immunity to subsequent infections). 98 It was hypothesized that general BCG vaccination policies adopted by different countries might have impacted the transmission patterns and/or COVID-19-associated morbidity and mortality. 99 The mechanisms underlying Kawasaki disease -a generalized vasculitis, in young children, of unknown, potentially post-viral etiology-are poorly understood. The rare COVID-19-associated inflammatory syndrome also features vasculitic changes, affects older children too and is often only associated with positive SARS-CoV-2 serology, but not viral shedding. Its mechanisms need to be elucidated and may include post-infectious, antibody and immune-complex mediated pathology. In adults, there are occasional cases of COVID-19-associated cutaneous vasculitis, possibly a localized manifestation of the disease that leads to severe generalized vasculitis in some children. [104] [105] [106] Interestingly Kawasaki-like disease was not reported in Chinese cases and the first months of European cases. The season of the disease and environmental factors should be considered. The Chinese epidemic was mainly from January to March whereas the USA epidemic started in mid-March and is still ongoing. Initial results of acute phase reactants such as C-reactive protein, alanine transaminase, lactate dehydrogenase, D-dimer, procalcitonin, serum ferritin and IL-6 on admission were used to evaluate the severity and predict the mortality. However, dynamic changes of these variables will be more precise in predicting the recovery or progression of COVID-19. Continuing or progressively increasing levels of C-reactive protein, procalcitonin, D-dimer and lactate dehydrogenase were shown to be associated with a high risk of death in severe COVID-19 patients. 25,60,107 Patients with acute respiratory illness (i.e., fever and at least one sign/symptom of respiratory disease such as cough or shortness of breath) and a history of contact with a confirmed or probable COVID-19 case during the 14 days before symptom onset. Patients with any acute respiratory illness in the context of a pandemic should have SARS-CoV-2 infection in their differential diagnosis. Special attention should be given to patients with sudden onset of anosmia, loss of taste, gastrointestinal symptoms or skin lesions without respiratory symptoms who also have epidemiological links. 5,25,108 Smell loss is now a well-established diagnostic symptom of COVID-19 and can be present in otherwise asymptomatic patients, making it a useful tool in initial diagnosis. 109 This has resulted in anosmia to be included in the list of symptoms used in early screening tools for possible COVID-19 in many international bodies. 109 Rapidly progressive respiratory failure and sepsis, elevated serum proinflammatory cytokine levels, elevated acute phase reactants (e.g. C-reactive protein), cell-free-hemoglobin-leukopenia and markers of disseminated intravascular coagulation. 110 RT-PCR to generate cDNA from SARS-CoV-2 RNA extracted from respiratory samples, followed by quantitative PCR (Figure 2 ). 111 Common gene targets for SARS-CoV-2 include the envelope, nucleocapsid, spike, RNA-dependent RNA polymerase, and ORF1 genes. It is recommended to include in the analysis, at least, 2 target genes. 112 Nasopharyngeal and oropharyngeal (throat) swabs are the primary specimens for SARS-CoV-2 RT-PCR testing. Lower respiratory tract specimens (i.e. sputum, endotracheal aspirate or bronchoalveolar lavage) may have higher viral loads and be more likely to yield positive tests ( Figure 2 ). However, these locations carry a high risk of aerosolization and therefore should be reserved for severe patients with a negative test on an upper respiratory tract specimen and high suspicion for lower respiratory tract SARS-CoV-2 infection. 113, 114 Serology is useful to determine prior exposure to SARS-CoV-2 within a given period of time (the length of time following infection that one remains positive is unknown) (Figure 2) . Detection of This article is protected by copyright. All rights reserved antibodies specific to the receptor binding domain of the spike protein indicates neutralization capacity, hence informing better about the development of protective immunity. 37, 111, 115 The antibody response occurs later than initiation of symptoms as well as of the detection of viral RNA by RT-PCR in respiratory tract specimens, which usually peaks within the first week of symptom onset (Figure 2) . Although antibodies to SARS-CoV-2 have been detected as early as the first week after symptom onset, IgM, IgA and IgG seroconversion commonly occurs between the 2 nd and 3 rd week of clinical illness onset. Thereafter, IgM starts to decline, reaching low levels by week 5 and almost disappears by week 7, while IgA and IgG persist beyond this period. 37, 39, 111, 116 The main approaches include nucleic acid amplification on respiratory samples using mobile devices (RT-PCR or isothermal nucleic acid amplification) and viral antigens or host antibodies (viral protein fragments) detection using immunoassays. 117 However, individual tests need validation in large populations before use and their sensitivity, specificity, positive and negative predictive values have to be accurately ascertained. Otherwise, they may lead to COVID-19 under or over diagnosis, thus undermining the public health efforts to control the disease. 118 A high rate of false negatives with antigen point-of-care assays may be due to the fact that the majority of patients produce antibodies against SARS-CoV-2 only after the second week after of infection ( Figure 2 ). 119 Furthermore, an effective antibody response is connected with several determinants, comprising severity of the disease, age and nutritional status of the patient, medications administered and concomitant infections. 118 Nucleic acid amplification using RT-PCR directly targeting the virus is not affected by the above-mentioned limitations. 120 This article is protected by copyright. All rights reserved positive by the fifth and final test. 121 Patients with an initial positive SARS-CoV-2 result had an increased risk of progressing to severe cases. Altogether, these findings underscore how the timing of the immune response influences RT-PCR tests for SARS-CoV-2, and the importance of combining RT-PCR and seroconversion data for COVID-19 diagnosis. The decision to discontinue home isolation/quarantine should be adapted to specific groups of patients based on factors such as symptom severity, healthcare systems´ capacity, laboratory diagnostic resources and local epidemic status. Patients with suspected or confirmed symptomatic COVID-19 can discontinue self-isolation/quarantine if all the following 4 conditions are met: a) resolution of fever (without the use of fever-reducing medications) for at least 3 days; b) clinical improvement in respiratory symptoms (e.g., cough, shortness of breath) for at least 3 days; c) at least 8 days have passed since the onset of symptoms for mild cases or at least 14 days for severe cases and immunocompromised patients; d) 2 negative RT-PCR tests from respiratory specimens taken 24 hours apart. If there is limited or no testing capacity, the combined symptom/test-based strategy should be reserved to hospitalized COVID-19 cases and healthcare workers, whereas for mild or asymptomatic COVID-19 cases (suspected or confirmed) the symptom-based strategy (condition a) AND b) AND c)) without lab testing is considered acceptable to end the self-isolation period. 122 pandemic Strategies for risk minimization should be elaborated, harmonized and followed as such in allergy clinics, centers and practices. 123 In the EAACI/ARIA Position Paper by Pfaar et al. 124 experts in the field have developed practical recommendations for optimizing allergic patients 'care whilst ensuring the safety of all health care professionals (Figure 3) . General guidance from national health authorities should be strictly followed (i.e., World Health Organization, WHO; European Centre for Disease Prevention). In-person consultations should be minimized to the lowest necessary level and triaged by telemedicine whenever possible (Figure 4 ). 125 Special attention should be paid to data- protection in adherence to national data-security and -protection laws. Non-delayable diagnostic and therapeutic measures should strictly follow reasonable preventive measures. Several specific considerations regarding diagnostic and therapeutic measures are important in different allergic diseases ( Figure 5) . Moreover, socio-psychological aspects play a fundamental role in the care of allergic patients during the current pandemic and should be especially recognized and followed. Stress caused by isolation and stigmatization due to allergic symptoms may amplify the development of allergic symptoms. 126 Virtual doctor consultations have been regarded as an alternative to on-site clinical encounters and are increasing during the COVID-19 pandemic. 124 Initially, pre-visit telephonic communication is helpful to screen for patients with potential SARS-CoV-2 infection. 127 The epidemiological history should be investigated to determine if patients have fever or respiratory symptoms. In addition, previsit specific triage improves the efficiency of the patient's visit, thus reducing the length of stay in the hospital. To reduce face-to-face meetings, physicians can train some patients to self-treat at home based on the diagnosis obtained through a telephone consultation (Figure 4) . A strict screening protocol is needed to identify SARS-CoV-2 infected patients (Figure 4) . Ideally, only SARS-CoV-2 negative patients (diagnosed via RT-PCR and/or rapid test) should come to the clinic. In places where systematic testing is unavailable, at least, normal temperature and negative epidemiological history should be mandatory to proceed to the outpatient departments. Patients with a body temperature higher than 37.3ºC should have additional screening examinations, including routine blood tests, chest computed tomography scanning and even throat swabs for SARS-CoV-2 RT-PCR testing. 128 The indication and urgency of the tests for diagnosis should be considered. Contraindications for skin, provocation and lung function tests can be explained beforehand to the patient, which helps to Accepted Article avoid unnecessary in-person consultations. 124 Any test generating aerosol particles should be avoided because it is considered high risk (Figure 4) . Personal protective equipment (PPE) must be used when collecting biological samples. Biological samples collected on-site from suspected or confirmed COVID-19 patients (e.g. antibody assays, RNA isolation, flow cytometry) should be processed following BSL-2 practices. During and after the COVID-19 pandemic, the usage of BSL-2 facilities is mandatory for all newly arriving patient samples to prevent spreading the disease. Research procedures involving SARS-CoV-2 isolation or culture should be conducted in a BSL-3 facility. 124,129 Patients with common allergic diseases do not develop distinct symptoms or severe outcomes. Allergic children show a mild course similar to non-allergic children 5 . In a recent study of 182 hospitalized children, 43 of them were reported with allergies. Allergic rhinitis was the most prevalent allergic disease (83.7%), followed by drug allergy, atopic dermatitis, food allergy and asthma. In this study, allergic children showed a reduced increase in acute phase reactants, procalcitonin, D-dimer and aspartate aminotransferase levels compared to all patients. There were no deaths in allergic children in that study. 130 Clinical history is very helpful to identify seasonality-and exposure-related symptoms driving the diagnosis of pollen-induced allergic rhinitis. An atopy test (in vivo or in vitro) reinforces the diagnosis. However, COVID-19 can be superimposed on allergic rhinitis symptoms. 124 Symptoms such as fever, fatigue and sudden loss of smell, are suggestive of COVID-19 and should be closely monitored. pandemic? This article is protected by copyright. All rights reserved N95 facial masks have been proven useful in reducing allergen exposure by blocking pollen access to nose and mouth. On the other hand, surgical masks do not protect against inhalation of small airborne contaminants and are not designed to seal tightly against the user´s face, hence the contaminated air can pass through the gaps. 131 There are no conclusive data on the impact of allergic rhinitis on COVID-19 susceptibility 132 . A recent study with 24 allergic rhinitis patients demonstrated a reduction of ACE2 expression in nasal brush samples following an allergen challenge. 55 Also, this study reported lower ACE2-expression in the epithelium of asthmatic patients. On the other hand, TMPRSS2 is highly upregulated by type 2 inflammation through the action of IL-13. 59 Therefore, further studies are necessary to determine if allergic rhinitis patients have an altered risk of SARS-CoV-2 infection as compared to non-allergic individuals. Although limited, the available evidence suggests that, compared to non-allergic individuals, allergic There is no scientific evidence that treatments for allergic rhinitis either increase susceptibility to SARS-CoV-2 infection or the severity of COVID-19. Therefore, allergen avoidance measures, nasal saline douches, and background controller therapies recommended by current guidelines for allergic rhinitis, such as nasal corticosteroids or second-generation H1-blockers, should be continued as prescribed, both in non-infected and COVID-19 diagnosed patients. 124 The loss of smell in chronic rhinosinusitis is caused by type-2 inflammation of the olfactory epithelium. 135 In COVID-19, the exact mechanism of potential olfactory neuropathy is still unclear. 136 However, a study found that sustentacular cells of the olfactory epithelium express ACE2 and TMPRSS2, which enable SARS-CoV-2 entry and may subsequently impair the sense of smell. 137 A considerable percentage of COVID-19 patients experience loss of smell as an early sign of the disease. 109 In many patients smell recovers in 1-2 weeks and there is no indication that intranasal corticosteroid treatment has a positive impact on the recovery. 138 On the other hand, there is no evidence suggesting that this treatment has a negative impact on symptomatology and/or Accepted Article development of COVID-19. Consequently, it is recommended to continue regular intranasal corticosteroid treatment for chronic rhinosinusitis (Figure 5) . 124 An asthma exacerbation is difficult to differentiate from COVID-19 ARDS or pneumonia by the patient, especially if it is triggered by rhinovirus, or other common respiratory viruses, because both conditions have dry cough and dyspnea. The British Thoracic Society advises patients with asthma experiencing fever, fatigue and loss of taste or smell to alert their physician as these are indicative of COVID-19. 144 The distinction can be made by the physician based on the presence of wheeze, which is generally (but not always) absent in COVID-19 pneumonia, as well as high-resolution chest tomography and viral diagnostic tests. 124 Patients with controlled asthma are not at higher risk of severe infection than the general population. 53,54 ACE2 expression was shown to be decreased in patients with allergic asthma 55 and in those receiving inhaled corticosteroids. 145 On the other hand, ACE2 expression in asthmatic patients was increased in African-Americans, in males and associated with diabetes, 55 and type 2 inflammation in children is associated with increased expression of TMPRSS2. 59 It is clear though that uncontrolled asthma is a risk factor of severe COVID-19, thus all efforts should be focused on treating asthma by regular use of controller medication, including inhaled corticosteroids and biologicals. 53,146,147 There is no evidence available that patients on inhaled corticosteroids are at higher risk of COVID-19 infection or of more severe symptoms than the general population. It is strongly advised by international scientific societies that patients continue with their routine control medication including inhaled corticosteroids during the pandemic (Figure 5) . 132,148 This article is protected by copyright. All rights reserved Recent evidence indicates that inhaled corticosteroid treatment reduces the expression of viral membrane receptors used to infect the human airways in a dose-dependent manner. 145 On the other hand, the immune suppression exerted by corticosteroids may impair anti-viral responses. 141 However, there are no clinical studies investigating the effect of inhaled corticosteroid on SARS-CoV-2 infection rates. Spirometry is essential for the diagnosis of new asthma cases as stated by the Global Initiative for Asthma guidelines. Therefore, it should be conducted, but under special conditions (negative pressure chamber, etc.) and only in areas with low SARS-CoV-2 infection incidence. Healthcare providers performing lung function testing need to wear maximum PPE (filtering face-piece particles 2 or 3 face mask, goggles, or disposable face shield covering the front and sides of the face, clean gloves, and clean isolation gowns), and the spirometer devices should be properly disinfected between patients (Figure 3) . 149 An alternative, less precise, is monitoring morning and evening peak expiratory flow variability over a week. 150, 151 The Global Initiative for Asthma guidelines state that routine spirometry should be avoided, especially in high-risk areas of COVID-19 transmission. If spirometry needs to be performed, maximum PPE should be used (Figures 3 and 4) . 148 The treatment of asthmatic patients can be monitored using personal devices measuring forced expiratory volume and peak expiratory flow. Many of these devices are equipped with remote transmission functions and thus are amenable for the telemedicine management of patients. 152 pandemic? This article is protected by copyright. All rights reserved There is no evidence suggesting that the current approach to treat asthmatic patients during an exacerbation should change during the COVID-19 pandemic. Moreover, there is no proof that a short course of systemic corticosteroids impacts the evolution of COVID-19. Thus, oral corticosteroids should be given as usual for the treatment of an asthma exacerbation ( Figure 5) . 144, 148 In the few cases in which patients are treated with long-term oral corticosteroids in addition to their high dose inhaled corticosteroids this should be continued in the lowest dose possible to prevent exacerbations. 148 The cause of the asthma exacerbation should be studied thoroughly to rule out potential exacerbations due to viral infections. 89 The preferred treatment is a pressurized metered-dose inhaler with a spacer. Each patient should have an individual spacer, and this should not be shared at home. The use of nebulizers should be avoided when possible because they increase the risk of disseminating viral particles, which could affect other patients and healthcare personnel. 148 Anti-IgE treatment with omalizumab (or other biologics indicated for asthma) should be continued in non-infected patients. Self-administration devices at home, whenever this option is available, are preferred, to minimize face-to-face contact in the clinic. In infected patients, omalizumab administration should be delayed until complete clinical recovery and viral clearance is achieved ( Figure 5) . 50,153 endotype is associated with severe asthma in obese patients, are obese asthmatic patients more likely to develop severe COVID-19? Obesity, as part of the metabolic syndrome, increases the risk of severe COVID-19. This is due to the pre-existent systemic low-grade inflammation and increased expression of SARS-CoV-2 entry receptors (ACE2, TMPRSS2 and CD147). 154, 155 Obese patients tend to have worse asthma control, increased hospitalizations and suboptimal response to standard controller therapy. Thus, both difficult-to-control asthma and underlying metabolic syndrome are risk factors for severe COVID-19. This article is protected by copyright. All rights reserved The IL-6/TH17 endotype encountered in late-onset obese asthma might be an additional risk factor. 156,157 The dermatological manifestations of COVID-19 range from an un-specific macular erythematous rash, urticarial lesions, chickenpox-like vesicles and acro-ischemic lesions. 158, 159 They can result from local inflammation due to circulating immune complexes or from systemic manifestations leading to vasculitis and thrombosis. 160 These patients are also at increased risk of drug hypersensitivity lesions ( Figure 6 ). 161 There is no evidence that patients with barrier defects such as atopic eczema have a higher risk for SARS-CoV-2 infection or skin complications during COVID-19. However, patients with atopic dermatitis are often on systemic immunosuppressants and should be monitored closely. Optimal topical treatment regime should also be encouraged in all patients. 162 Hand hygiene procedures are pivotal to prevent self-infection and virus spreading. However, extensive water contact enhances dry skin, disturbs the commensal microbiota and leads to barrier disruption in healthy individuals. Moreover, it exacerbates diseases with an intrinsic barrier defect such as atopic dermatitis. 163, 164 Effective skin-care after hand hygiene is therefore essential to prevent barrier disruption and sensitization events. Here, emollients containing hyaluronic acid, Vitamin E, ceramide or urea are recommended. 165 Dupilumab is approved for the treatment of moderate-to-severe atopic dermatitis. First data from Italy on dupilumab-treated non-infected in high epidemic areas, and current evidence from dupilumab trials, suggest no negative effect of dupilumab regarding viral infections 166 with reports on a reduced number of herpes simplex superinfections and less bacterial superinfections. [167] [168] [169] Accepted Article This article is protected by copyright. All rights reserved The current EAACI statement on the usage of biologicals in the context of COVID-19 advices no change of therapy in non-infected individuals and to withhold/delay the application of biologicals for a minimum of two weeks or the resolution of the disease in case of SARS-CoV-2 infection (Figure 5) . 50 This is based on expert opinion in the light of missing data and may be adapted if more information becomes available. Acro-ischemic lesions on toes and fingers have been identified in a subgroup of COVID-19 patients. 25, 170 The data available are scarce and it is unclear if preventive or active anticoagulation should be initiated. However, acro-ischemic lesions could predate other SARS-CoV-2 symptoms in children and young adults. COVID-19-induced skin lesions can be related to thrombovascular events (i.e. petechiae, acroischemia, dry gangrene) or to typical viral infections (i.e. erythematous rash, urticaria, maculopapular exanthema). 161 Drug hypersensitivity has to be considered as a differential diagnosis, mainly in the second group, being a distinction difficult during the acute phase. Diagnosis relies mostly on clinical observations. In that regard, an accurate chronology of the reaction and the drug exposure timeline is very informative 63 . Laboratory and histopathological findings may also help. Immunomodulatory drugs (including azithromycin), hydroxychloroquine/chloroquine and IFNs, are the ones most frequently involved in hypersensitivity reactions. Most reactions are non-immediate and further studies are required to clarify whether this increased frequency is caused by the drug immunogenicity or simply derives from a greater consumption as compared to other treatments. 161 This article is protected by copyright. All rights reserved Drug provocation tests are not recommended because reactions can occur during the tests, including the generation and spreading of virus-containing aerosols. However, they may be considered after careful risk-benefit assessment in cases of urgent need, such as chemotherapy in cancer patients, perioperative drugs and radiocontrast media in subjects needing urgent procedures, and antibiotics if no effective alternative drug is available. 124 Most AIT products authorized for use in Europe indicate that AIT should be discontinued in case of infection; the same principle will apply to the COVID-19 pandemic. Patients on subcutaneous or sublingual AIT, who are diagnosed with COVID-19, those suspected of SARS-CoV-2 infection or symptomatic patients with a positive contact to SARS-CoV-2 individuals, AIT should be interrupted until the patient has recovered. In patients not infected or who have recovered from the infection, AIT could be continued ( Table 3) . These recommendations are conditional and could change as clinical data evolve. 124 ,134 AIT should continue in non-infected patients or those recovered from COVID-19 ( Figure 5 ). This is especially important in patients with life-threatening conditions such as venom allergy. It is possible to extend the intervals between vaccines during subcutaneous AIT, as done for inhalant allergens, to minimize visits to the allergy clinic. If venom AIT was stopped due to SARS-CoV-2 infection, it is unclear when it should be re-initiated because data from convalescent patients is scarce. 134 In patients diagnosed with COVID-19 or cases with suspected SARS-CoV-2 infection, oral immunotherapy dosing should continue as indicated in the dosing plan and in coordination with the treating physician. Oral immunotherapy can be continued in non-infected patients and those who have recovered from COVID-19 ( Figure 5 ). In areas with high level of SARS-CoV-2 community transmission, visits to the allergy clinic for oral immunotherapy up-dosing should be postponed. 124, 134 Accepted Article This article is protected by copyright. All rights reserved These patients are generally on symptomatic treatment. They need to look out for symptoms suggesting hypoxia or pneumonia, such as shortness of breath, deep shallow breathing, chest pains or persistent tachycardia. Special attention needs to be given to those with risk factors for disease progression, such as patients older than 65 years, cardiac or pulmonary comorbidities and immunosuppression. 171, 172 Prophylactic low molecular weight heparin, or heparin, has been recommended by the WHO in severe to critically ill COVID-19 patients. 141 However, the International Society on Thrombosis and Haemostasis recommended that all hospitalized COVID-19 patients, not just those in ICU, should receive prophylactic low molecular weight heparin in the absence of contraindications. 173 During the SARS outbreak in 2003, corticosteroids did not change the course of the viral infection and delayed viral clearance. 174 On the other hand, a retrospective study on SARS patients in Hong Kong suggested a better survival rate in patients treated with prednisolone for milder pneumonia or methylprednisolone in more severe cases. 175 Recently, Chinese experts stated that, in COVID-19 patients, systemic corticosteroids should be considered on individual indications in a low-to-moderate dose and for no longer than a week. 176 The National Institutes of Health in their COVID-19 Treatment Guidelines advises against the use of systemic corticosteroids in non-critically ill patients. 177 There are over 170 clinical trials on COVID-19 treatment registered now in the international databases and very few have been completed. Currently promoted pharmacological treatments are, at the most, based on anecdotic data collected in small numbers of COVID-19 patients. These studies did not satisfy evidence-based medicine criteria, but caught general attention through news media, for example hydroxychloroquine (see below). Tocilizumab is a humanized monoclonal antibody specific for IL-6R, and it is approved for the treatment of rheumatoid arthritis. A positive response to tocilizumab points towards an imbalanced innate immune response in severe COVID-19. Luo et al. 178 reported that of the 15 patients treated with tocilizumab, 7 of them critically ill, 11 of the patients recovered within a week. Prompt resolution of symptoms and encouraging results have also been reported in uncontrolled or retrospective trials. [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] These zoonotic beta-coronaviruses share structural and genomic similarities that are useful to patients? This article is protected by copyright. All rights reserved Fang et al. 192 suggested that there is ACE2 overexpression upon treatment with ACE inhibitors, thiazolidinediones and ibuprofen. There were concerns pertaining to the use of nonsteroidal antiinflammatory drugs in COVID-19 patients. The European Medicines Agency clarified that no scientific evidence established a link between ibuprofen, or other nonsteroidal anti-inflammatory drugs, and a risk to worsen COVID- 19. 193 Section 7: Clinical trials and drug discovery in COVID-19 Adaptations for clinical trials during the pandemic must include all concerned parties such as There are drugs that interfere with ACE2 and TMPRSS2, which are molecules used by the virus to enter the cell. 9, 195 For example, camostat mesylate is a clinically proven serine protease inhibitor with affinity for TMPRSS2. It has shown activity against SARS-CoV-2 in human lung Calu-3 cells. 9 Several drugs that target virus internalization are being investigated, including chloroquine phosphate and hydroxychloroquine, which have shown limited efficacy in humans and raised concerns due to side effects (see below). 196 Drugs designed to inhibit the viral replication machinery may be effective against SARS-CoV-2. For example, remdesivir inhibits viral RNA polymerases, which prevents SARS-CoV-2 replication (see below). It is uncertain whether lopinavir-boosted ritonavir and other antiretrovirals improve clinical outcomes or prophylaxis among patients at high risk of SARS-CoV-2 infection. 200 Additional potential candidates include other broad-spectrum antiviral drugs such as arbidol and favipiravir and phytochemicals with anti-viral activity such as resveratrol ( Figure. 1) . 197 In a cohort of severe COVID-19 patients, compassionate-use of remdesivir showed clinical improvement in 68% of patients (36 out of 53). 201 Of note, a double-blind, randomized, placebocontrolled trial of intravenous remdesivir was conducted in 1,063 adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement; remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection. 202 Furthermore, in a study of 5 HIV-positive hospitalized patients with severe COVID-19, three of them were given lopinavir-boosted ritonavir and 2 darunavir-boosted cobicistat for 14 days. Four patients recovered and 1 remained hospitalized. 203 Meplazumab is a CD147-specific humanized monoclonal antibody that has been shown to prevent SARS-CoV-2 infection of fibroblasts (VeroE6 cells). 72 Currently, there is insufficient evidence to draw any conclusions on the benefits of meplazumab for the therapy of COVID-19 patients. In an observational Chinese study, adults hospitalized with COVID-19 pneumonia (n=17) who were treated with an intravenous infusion of meplazumab as an add-on therapy showed a higher recovery rate compared to controls (n=11). 198 However, these results should be interpreted with caution because they were generated in a non-randomized, non-stratified study, with a small sample size. Large-scale studies are needed to assess the effectiveness and safety profile of meplazumab as a potential therapy for COVID-19. CP therapy for COVID-19 treatment has yielded promising results. For example, in a trial of 10 severe COVID-19 patients, 205 CP therapy was well tolerated and improved the clinical outcomes. The viral load was undetectable after CP transfusion in 7 patients who had viremia. No severe adverse effects were observed. Other clinical trials have shown the beneficial effect of CP therapy in COVID-19 patients and ongoing clinical trials will provide additional data on its efficacy, safety and optimal timing for treatment ( Table 2) . In this regard, it is unclear whether in patients with a high viral load, such as severely ill patients, CP therapy may drive tissue pathology through immune complexes or complement activation. Baricitinib, fedratinib, and ruxolitinib are potent and selective JAK-STAT signaling inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis. These drugs are powerful antiinflammatory medications that may reduce the systemic levels of cytokines associated with COVID-19. 206 Indeed, in a pilot study of 12 COVID-19 patients, baricitinib limited the CSS and was beneficial for the patients. 207 The use of JAK inhibitors has been associated with a higher risk of opportunistic viral infections, such as herpes zoster, which suggests that the reduced inflammation caused by JAK inhibitors may limit, to some extent, anti-viral responses. 208 This article is protected by copyright. All rights reserved Ivermectin (avermectin B1a and avermectin B1b) is an anti-parasitic drug that has shown broadspectrum anti-viral activity in vitro. In SARS-CoV-2-infected fibroblasts (Vero-hSLAM cells), a single addition of Ivermectin at 2 h post-infection reduced viral RNA ~5000-fold at 48 hours. 209 However, plasma concentrations of total and unbound ivermectin did not reach the IC50 determined in vitro, even at a 10-times higher dose than approved by the Food and Drug Administration (USA). 210 Consequently, the likelihood of a successful clinical trial using ivermectin is low. In an observational study of 1,446 COVID-19 patients, 811 received hydroxychloroquine treatment, which did not change the risk of intubation or death. 211 Furthermore, in a Brazilian randomized control study evaluating 2 different doses of chloroquine in COVID-19 patients with severe respiratory symptoms, mortality was 2.5 times higher in the high-dose chloroquine arm. 212 Moreover, pre-published results from US Veterans Health Administration Hospitals did not support any advantages of hydroxychloroquine administered alone or with azithromycin. 213 In addition, the results of a clinical study conducted in 821 individuals showed that hydroxychloroquine did not prevent illness compatible with COVID-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. 214 However, because of the retraction of two main papers on hydroxychloroquine treatment for COVID-19 patients, this area requires further attention by the European Medicines Agency and the Food and Drug Administration. Mesenchymal stem cells may exert antiviral mechanisms in the context of SARS-CoV-2 infection. The basal IFN-stimulated gene expression of mesenchymal stem cells is high, which enhances their responsiveness to IFN signaling, potentially inducing broad viral resistance. Mesenchymal stem cell therapy may potentiate the low IFN-I and -III levels and moderate IFN-stimulated gene response reported in SARS-CoV-2-infected ferrets and COVID-19 patients. 215 It is is being used in some centers but its efficacy in COVID-19 has not been proven. Data available are mainly experimental with few records in humans and no reports on its efficacy in randomized clinical trials. 216 Common anti-hypertensive drugs inhibit ACE, but not ACE2. Importantly, ACE2 opposes ACE actions and lowers blood pressure by converting angiotensin-II (a vasoconstrictor peptide) into its metabolites-angiotensin (1-7) (vasodilators). 217 Other common related antihypertensive drugs are angiotensin-2 receptors blockers, which block AT-1, a receptor for angiotensin-II, through which it exerts its vasoconstrictor effect. However, AT-1 is not known to be used by SARS-CoV-2 to infect cells. It was shown in animal models that ACE inhibitors might increase ACE2 expression, thus increasing susceptibility to infection. It has not been proven in humans but it raised the concerns during the COVID-19 pandemic. 217 Based on the data available to date, antihypertensive treatment with these medications should be continued. 218 At the moment, the animal model that resembles more closely human COVID-19 is the Rhesus macaque, whose ACE2 receptor is identical to that in humans. This model recently showed that SARS-CoV-2 reinfection was hampered due to infection-acquired immunity and demonstrated the therapeutic effect of remdesivir in COVID-19 prior use in human clinical trials. 219, 220 The murine ACE2 receptor is different from humans, hence humanized murine models with recombinant human ACE2 are necessary. 221 Previous vaccine research for SARS/MERS facilitates rapid translation. 222 In the WHO vaccine Single-domain antibodies have been investigated as potential therapeutics for influenza, RSV and HIV in addition to coronaviruses. SARS-CoV-2 mainly targets the respiratory tract, hence the development of vaccines directed to the respiratory epithelia and lung parenchyma using a nebulizer has been considered to maximize bioavailability and function. 229 Although active research against respiratory viruses has focused on aerosolized plasmid DNA vaccines, other forms of vaccine administration are currently further advanced in clinical trials. 222 Veterinary medicine commonly uses aerosolized coronavirus vaccines for chicken farms. 230 A novel vaccine platform requires careful evaluation and should ideally include toxicological studies in valid animal models. Early progress towards SARS vaccines has facilitated a "running start" but standards of care and safety must be maintained. Acceleration rather than omission of clinical trials is key. Preliminary data from Oxford University is anticipated by mid-2020. 222 Of note, a doseescalation, single-center, open-label, non-randomized, phase 1 was conducted in 108 healthy individuals that received an Ad5 vectored COVID-19 vaccine. The vaccine was tolerable and This article is protected by copyright. All rights reserved immunogenic at 28 days post-vaccination. SARS-CoV-2-specific antibodies peaked at day 28 postvaccination and specific T-cell responses were detected from day 14 post-vaccination. 231 An important aspect is that COVID-19-associated mortality is very high, almost unavoidable when the pandemic control fails. This is due to rapid community spread, high community virus, especially in the elderly and co-morbid, but also in younger non-comorbid persons, including healthcare workers, young adults and children. The COVID-19 pandemic also seems to be characterized by a significant level of asymptomatic spread. [232] [233] [234] The iceberg of COVID-19: are there asymptomatic cases below the surface? The The differences are almost entirely due to the timing and effectiveness of public health interventions. Countries that failed to control did too little, too late, and allowed SARS-CoV-2 to rip through their population, with catastrophic outcomes. Those that intervened early effectively stopped the disease transmission. 235 This article is protected by copyright. All rights reserved It is difficult to determine as it varies greatly from country to country, depending on how well countries control their epidemics with widespread testing, case isolation and vigorous contact tracing, testing and isolation if positive. In countries that do this well, the R0 can be very low indeed. In countries that fail to control the spread of the virus, the R0 is high but unknown as SARS-CoV-2 spreads untested and therefore undetected. It has been estimated to be ~2.2. 236 SARS-CoV-2 transmits more readily than either SARS-CoV or MERS-CoV. The R0 of SARS-CoV-2 is controversial but if left unchecked it is likely to be greater than 3-4. However, the R0 number cannot be precisely defined as no country has left it to spread completely unchecked. In any case, even when preventative measures are taken, the R0 of SARS-CoV-2 is higher than that of SARS-CoV (1.7-1.9) and MERS-CoV (<1). 237 There is a considerable frequency of very mild COVID-19 patients as well as asymptomatic SARS-CoV-2-infected people. This makes transmission control more challenging than either SARS-CoV or MERS-CoV, where illness is frequently more severe. Children are at low risk of severe COVID-19 outcomes. 238, 239 Most patients in pediatric age with SARS-CoV2 infection presented with no or mild clinical manifestations, including fever, fatigue and dry cough. They were typically managed with supportive treatments only and they had generally a favorable prognosis with a recovery within 2 weeks. [240] [241] [242] Young children also frequently carry other respiratory viruses, which potentially limit SARS-CoV-2 infection, as reported for other viral infections. 243 Differences between children and adults in the regulation of ACE2 expression may also play a role. 46 ACE2 mRNA expression was high in type I and II alveolar epithelial cells, in nasal and oral mucosa and nasopharynx, in smooth muscle cells and endothelium of vessels from the stomach, small intestine, colon, and in the kidney of human adults (mean age 52±22). 244 Interestingly, a recent study demonstrated age-dependent ACE2 gene expression in the nasal epithelium, which was lowest in younger children and increased with age. 245 In addition, CD147, CD26 and their molecular interaction proteins seem to be differently expressed in peripheral blood mononuclear cells and T cells in children in comparison with adults. 14 Many children remain asymptomatic, even when they have radiologic pneumonia detected on screening. 238 Given that children are effective transmitters of other respiratory viruses, 246 it is expected that they will be just as good at transmitting SARS-CoV-2. Bats are likely the natural reservoir of SARS- severity (see questions below). Data on ethnicity and COVID-19 are scarce and further research on ethnicity and COVID-19 outcomes is needed. 250 However, the data available show a disproportionate number of COVID-19 deaths in Black, Asian and minority ethnic backgrounds. In fact, one third of UK ICU admissions are reportedly from them. 251 In the USA, African Americans had more COVID-19 diagnoses and deaths, after adjusting for age, poverty, comorbidities, and epidemic duration. These disparities are also seen in the Hispanic and Asian communities. 252 Pregnant women may be at a higher risk of poorer COVID-19 outcomes because they have deficient IFN-α and IFN-λ responses to viral infections. 253 However, reported pregnancy outcomes in COVID-19 are reassuring as they appear similar to non-pregnant adult females. 254 This article is protected by copyright. All rights reserved Testing treatments is problematic because pregnant women are excluded from most trials. 255 It is known that azithromycin doubles innate IFN production from virus-infected lung cells. 256 It is safe for all trimesters of pregnancy 257 and has been shown effective in high-quality clinical trials of virusinduced lung disease. 258, 259 Given that the human ACE2 protein is encoded on the X chromosome, this may be relevant for malefemale differences in outcomes. Particularly in males with rare ACE2 coding variants as they will express those variants in all ACE2-expressing cells compared to a mosaic pattern of expression in females. 260 Males may also have differences in certain innate antiviral responses compared to female counterparts. 261 There is reasonably robust data of COVID-19 deaths in hospitals because most people who die in hospital are tested. Deaths outside hospitals are likely underestimated as people are dying in care homes where mortality approaches ~40%, 267 and may die without being tested and diagnosed. It is difficult to determine prevalence as testing practices vary so much from country to country. Seroprevalence studies will help to collect these data. COVID-19 was introduced rapidly to many industrialized countries as a result of air travel. 268 Most of Europe and the USA probably did not react in a timely and efficient manner, resulting in the rapid spread and subsequent high mortality rates. In light of the devastating situation in many European countries and the USA, less industrialized countries had a little more time to better prepare to control the pandemic. 269 An important factor for prevalence studies is the percentage of the population that has undergone a diagnostic test, which seems to be at lower levels in developing countries. This article is protected by copyright. All rights reserved Respiratory viruses spread less readily in summer than in winter for reasons that are not well understood. Dry air and higher temperatures are slowing down the spread of respiratory viruses. Absence of school attendance, more time outdoors, greater household ventilation, warmer temperatures facilitating virus inactivation and higher vitamin D levels are all likely to play a part. Although social distancing measures are implemented, the summer weather should play a role in hampering the spread of COVID-19. However, based on the analogy of previous influenza pandemic, it is unlikely that summer, on its own, could stop transmission of SARS-CoV-2. [270] [271] [272] It largely depends on the SARS-CoV-2 seroprevalence developed in each country, which is still unknown. Countries that have had widespread transmission may be hit by a second wave, but presumably with less severe consequences. Countries that effectively controlled the pandemic are at a higher risk of second wave of COVID-19 if those effective controls are relaxed due to the limited viral transmission and lack of active immunization. SARS-CoV-2 has spread worldwide in humans, causing mild or no disease in many cases. It will continue circulating similar to other human coronaviruses (229E, HKU1, NL63, OC43), and it may well become an endemic, seasonal virus. 273 The main route of SARS-CoV-2 transmission is via respiratory droplets and aerosols. [274] [275] [276] Avoidance of high virus loads, acquired through aerosol and droplet transmission, is paramount to prevent severe outcomes. Consequently, social distancing, masks and hand sanitation are undoubtedly effective because they prevent the droplet and surface contact-associated initial high virus load and the increased risk of severe disease. [277] [278] [279] What is the evidence supporting social distancing and face mask to prevent SARS-CoV-2 infection? This article is protected by copyright. All rights reserved A systematic review and meta-analysis has found that transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 (OR 0.18) and protection was increased as distance was lengthened. In addition, face mask use could result in a large reduction in risk of infection (OR 0.15), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar. Eye protection also was associated with less infection (OR 0.22). 280 Therefore, the COVID-19 pandemic can be controlled if social distancing is combined with widespread testing, case isolation, vigorous contact tracing and personal protection. Indeed, severe and critical illness among Chinese healthcare workers before January 10 th was 45%, a time when personal protection equipment and infectious control measures were likely not implemented. After February 1 st , when personal protection measures were in place, the percentage of severe and critically ill Chinese healthcare workers dropped to 8.7%. 281 SARS-CoV-2 remained viable in aerosols for 3 h with a ~10-fold reduction in infectious titre. 282 SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard; viable virus was detected up to 3 days after application to plastic and 2 days to stainless steel, on each surface the virus titer was reduced nearly ~100-fold. 282 Importantly, sunlight exposure inactivated 98% of infectious SARS-CoV-2 every 6.8 minutes in simulated saliva and every 14.3 minutes in culture media. This study suggests that persistence, and subsequently exposure risk, may vary significantly between indoor and outdoor environments. 272 Therefore, it is convenient to minimize contact with surfaces touched by others (even before SARS-CoV-2 existed), particularly at indoor environments, for example when using public transportation. In 248 COVİD-19 patients, the estimated median time from symptom onset to viral clearance in the nasal swabs was 11 days, while in asymptomatic cases it was 2 days. 283 In patients that recovered, the median duration of viral shedding was ⁓20 days, while in non-survivors it was detected until death. The longest duration of viral shedding in survivors was 37 days. 110 Accepted Article and found that a slow viral clearance is associated with an increased risk of high disease severity with a 1% mortality rate. 285 The individual variation in the transmission of an infection is described by a factor called "dispersion factor or k". The lower "k" value, the more transmission comes from a small proportion of individuals acting like superspreaders. Superspreading clusters have been observed in past coronavirus outbreaks (SARS/MERS), where a small number of infected individuals was responsible for a large proportion of secondary transmissions, with an estimated "k" of about 0.16 for SARS and 0.25 for MERS. 286 It is unclear whether superspreading clusters have contributed to the COVID-19 outbreak. A simulation of early outbreak trajectories estimated that "k" for COVID-19 is higher than for SARS and MERS. 286 However, in a recent preprint study, the estimate of "k" for SARS-CoV-2 was around 0.1, suggesting that around 10% of infected patients may have been responsible for 80% of secondary transmissions. 287 Individual variation in infectiousness is difficult to measure, as it is mostly empirical, but the identification of any SARS-CoV-2 superspreading will be of primary importance for pandemic control. The designation of COVID-19-dedicated wards and personnel within hospitals is useful to limit nosocomial SARS-CoV-2 infections. 124 It also allows other non-COVID-19 conditions to be treated using routine healthcare resources more safely and effectively. Maintaining such separation requires intensive SARS-CoV-2 testing in view of the high asymptomatic infection rate. 288 Community-based strategies are effective at controlling the transmission of SARS-CoV-2. Australia, Hong Kong, Japan, Singapore, South Korea, and New Zealand have all controlled effectively. Their cumulative COVID-19 mortality is >100-fold less than that in Belgium, France, Italy, Spain and the UK, countries which have had difficulties to adequately control the pandemic. 147, 289, 290 It is important to implement measures to contain the spread of the virus, such as developing models to predict SARS-CoV-2-related mortality. 291 Closing live animal markets is likely to reduce the risk of future viral outbreaks although this is not a practical way to prevent viral outbreaks for multiple reasons including social and economic. Lifestyle factors that may influence SARS-CoV-2 infection susceptibility and COVID-19 severity include smoking, stress, diet and alcohol intake, among others. For example, smoking has been shown to increase the susceptibility to respiratory tract infections and its severity, 294 and it is a risk factor for severe COVID-19. 295 Moreover, alcohol consumption may impair anti-viral immunity; 296 in vitro studies with human monocytes have shown that both acute and prolonged alcohol exposures inhibit type I IFN induction upon Toll-like receptor-8 and -4 stimulation 297 . Dietary habits may also play a role as obese patients have been shown to have a higher risk of developing severe COVID-19. 298 Furthermore, there are bioactive food compounds with antiviral activity, such as resveratrol, 299 although the amount of them obtained through the diet is unlikely to play a relevant role in COVID- It is known that respiratory virus infection causes perturbations in the gut microbiota and that germfree mice are more susceptible to viral infections, which intimates a role for the microbiota in COVID- 19 . 300 However, the impact of the commensal microbiota on SARS-CoV-2 infection susceptibility and COVID-19 severity is unknown. 301 An essential step is identifying the bacterial species interacting with SARS-CoV-2. This is rather challenging given the large number of bacterial species in the lung and respiratory tract, 302 and especially in the gut. However, a number of lung metagenomic studies have reported an abundance of Prevotella in the lung of SARS-CoV-2 infected patients 303 . While in Accepted Article silico analysis have revealed that Prevotella proteins may promote viral infection 304 , prospective studies are necessary to ascertain if this is a consequence of the infection or a risk factor for it. It is well-established that epithelial barrier defects and/or damage favor the development of Th2 immunity. 305, 306 Increased hygiene, in general, as well as overexposure to epithelial barrier opening molecules, such as detergents, can promote the onset of allergic disease. 307 To date, there is no evidence linking the COVID-19 protective measures (gloves, hand-sanitizers, etc.) with increased allergy prevalence. In this regard, multifactorial epidemiological studies are needed. These studies should consider the impact on allergic diseases of virus-specific type 1 responses and psychosocial and environmental changes caused by the pandemic and efforts to contain it. Although there has been a significant change in pollution parameters, unfortunately this reduction in pollution is transient and consequently unlikely to be significant. The exposome-related allergy and asthma risk is multifactorial. It includes climate change, biodiversity, the microbiome and nutrition among others, which have not changed during the pandemic. 308 In addition, although pollution levels have dropped, climate change still occurs at an accelerated pace. Lifestyle changes during the lockdown 309 , weight gain and increased exposure to indoor allergens and pollutants may even increase the incidence of allergic diseases in the long-run. With the rapid spread of COVID-19 at a pandemic scale, we are overwhelmed and drowned with a wealth of information. A global fight to contain the pandemic has started in which we need international solidarity and prompt sharing of accurate scientific information. We strongly support the This article is protected by copyright. All rights reserved Continue SCIT or SLIT: Non-infected individuals This article is protected by copyright. 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