key: cord-0734577-prpooezh authors: Berhe, Brhane; Legese, Haftom; Degefa, Hagos; Adhanom, Gebre; Gebrewahd, Aderajew; Mardu, Fitsum; Tesfay, Kebede; Welay, Miglas; Negash, Hadush title: Global epidemiology, pathogenesis, immune response, diagnosis, treatment, economic and psychological impact, challenges, and future prevention of COVID-19: A scoping review date: 2020-04-06 journal: nan DOI: 10.1101/2020.04.02.20051052 sha: 53726a84035f04167440dde803026c996d8794c0 doc_id: 734577 cord_uid: prpooezh Background: Globally, the novel coronavirus, is a public health problem causing respiratory infections. Since the outbreak of severe acute and Middle East respiratory syndromes coronavirus was not reported to cause human infections. Now, it become an epidemic proportion with growing number of cases and deaths. Methods: A scoping review was conducted following the methodological framework. In this scoping review, 50 records published before 28 March, 2020 were included and discussed to better understand the current epidemiology, pathogenesis, immunological response, diagnosis, evasion mechanisms and suggested strategies to boost the immune system, challenges, treatment, and future preventions of the virus. PubMed, BioRxiv, MedRxiv, Global Health and google scholars were searched comprehensively for articles, preprints, grey literatures, reports, websites, conference proceedings and expert information. Studies conducted in human and published in the English language were included in the analysis. All the findings and statements of the review regarding the outbreak are based on published information as listed in citations. Results: We identified 360 records, of which 50 studies met the inclusion criteria. We synthesized the data from the included records and dig out the deep insights of them and pooled into this review. The burden of the outbreak is worsening due to overcrowding, presence of asymptomatic carriers, scarcity of test kits, the immune escaping ability of the virus and lack of awareness. Conclusions and recommendations: Due to the fast-spreading nature of COVID-19 the prevention and control strategies become challenging. It is imposing social, psychological, and socio-economic impacts. We recommended that following social distancing, isolation suspects, using personal protective equipment, health education and introducing handwashing practices, avoiding contact with animals, vaccine development and treatment for controlling and prevention. Globally, the novel coronavirus is , is an emerging pandemic disease causing respiratory syndrome that needs urgent attention 1 After the declaration of COVID-19 as global public health emergency 6 , about 118 598 confirmed cases were reported from more than 100 countries 6, 7 . Currently, COVID-19 is affecting 199 countries and 2 territories named the Diamond Princess in Yokohama, Japan, and the Holland America's MS Zaandam) with a total of 571,678 confirmed cases, 26,494 deaths and 142,474 recovered cases was reported as of 28 March 2020 2020 8 . As per the previous studies reports median age of COVID-19 cases was 59 years (15 to 89 years) with the majority being male 7 . The average incubation period of COVID-19 was estimated to be 4.8±2.6, ranging from 2 to 11 days 9, 10 . The outbreak has distributed throughout the globe. WHO and national guidelines have endorsed preventive strategies to the current outbreak. However, the current prevention and control All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint strategies of COVID-19 is facing challenges. Hence, we conducted this scoping review to assess the current epidemiology, pathogenesis, immunological response, diagnosis, evasion mechanisms and suggested strategies to boost immune system, challenges, and future preventions. We used the following methodological framework to conduct this scoping review. (1) Identification review question (2), Developing review objectives, (3) Developing search strategy and identification of search sources, (4) Screening records and data extraction and (5) Setting eligibility criteria. A search strategy was developed using specific key concepts in our research question: "epidemiology of COVID-19", "burden of COVID-19", "pathogenesis of COVID-19", "COVID and immune system", "diagnosis of COVID-19", "immune invading and evasion mechanisms", "current preventions and treatment strategies of COVID-19" and "challenges to the current strategies and future preventions". We comprehensively searched PubMed, Cochrane, Global Health and google scholars. To avoid missing relevant studies we included preprints and grey literatures using BioRxiv, MedRxiv, World Health Organization and Centers for Disease Control and Prevention websites, conference proceedings and expert information. After the literature search, all the references were imported to Zotero. Four researchers (BB, HD, HL and HN) independently screened studies for eligibility and relevance. A fifth researcher (GA) was consulted for discrepancies. We resolved differences in opinion through discussion. Articles, reports, preprints, expert opinions, and information from websites conducted among human participants, published in English language, and briefly showing the data regarding the current outbreak COVID-19 were included. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint Most of the records were retrieved from WHO, CDC reports, Global health, and websites. Out of the 50 included articles (Figure 1 ) more than half were reports and expert opinions. The confirmed cases of COVID-19 are increasing from time to time. In the first two months the number of cases were higher among countries in the West pacific Asian region than other regions where the lowest cases were reported in Africa. And later as of March 2020 the number of cases was observed to be exponentially increased among countries in the European, American, and Eastern Mediterranean regions (Figure 2) . Furthermore, the reports of death were predominant in the Western Pacific Asian region in January and February 2020. However, the reported deaths outnumbered among countries in European region by March 2020 (Figure 3 ). Individuals infected with COVID-19 presented with early symptom of high fever (39 0 c), headache and abnormal respiratory findings such as cough, and difficult breathing. The virus might pass through the mucous membranes, especially nasal and larynx mucosa then enters the lungs through the respiratory tract 11 . After the virus reach in the lung it spreads to peripheral blood, causing viremia. Then the virus would adhere and express to the angiotensin converting enzyme 2 (ACE2), of the organs like lungs, heart, renal, gastrointestinal tract. Patients infected with the virus have higher number of leukocytes, increased plasma pro-inflammatory cytokines [12] [13] [14] . The main pathogenesis of COVID-19 infection as a respiratory system targeting virus was severe pneumonia, viremia, combined with the incidence of ground-glass opacities, and acute cardiac injury 15 . The immune system is responsible for the controlling, resolution and immunopathogenesis of CoV infections. The immune response is due to receptor recognition between the pathogenassociated molecular patterns (PAMPs) and the pattern recognition receptors (PRRs). Usually, Toll-like receptor (TLR) 3, TLR7, TLR8, and TLR9 sense viral RNA and DNA in the endosome 16, 17 . The most important recognition mechanisms of viral RNA are viral RNA All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint receptor (retinoic-acid inducible gene I), cytosolic receptor (melanoma differentiation-associated gene 5) and nucleotide transferase cyclic GMP-AMP synthase 18, 19 . This complex signaling recruit adaptors, including TLR-domain-containing adaptor protein, mitochondrial antiviralsignaling protein 20 and stimulator of interferon genes protein 21 to trigger downstream cascade molecules. This will also be involved in adaptor molecule MyD88 and lead to the activation of the transcription factor nuclear factor-κB and interferon regulatory factor 3 and the production of type I Interferons and a series of pro-inflammatory cytokines 22 . Hence, virus-cell interactions produce a diverse set of immune mediators against the invading virus 23 . To mount an antiviral response, innate immune cells need to recognize the invasion of the Unlike the other corona viruses, a limited serology details of COVID-19 were reported. In a previous study, peak IgM antibodies were observed after day 9 of disease onset. additionally, sera from 5 patients of confirmed COVID-19 showed some cross-reactivity with SARS-CoV. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint Furthermore, antibodies were observed to be neutralized by COVID-19 in an in vitro plaque assay, suggesting a possible successful mounting of the humoral responses 14 . Another study reported that CD8+ T cell responses were frequently observed than CD4+ T cell response. Generally, the virus specific T cells were the central memory phenotypes with a significantly higher frequency of polyfunctional CD4+ T cells (IFNγ, TNFα, and IL-2) and CD8+ T cells (IFNγ and TNFα). Having considered few controversial issues, strong T cell response was correlated significantly with higher neutralizing antibody while more serum TH2 cytokines (IL-4, IL-5, IL-10) 32 . Current observations indicate that coronaviruses are particularly adapted to evade immune detection and dampen human immune responses. This partly explains why they tend to have a longer incubation period, 2-11 days than other viral infections 33 . The longer incubation period is probably due to their immune evasion properties. Hence the viral antigen can escape host immune detection at the early stage. The immune evasion mechanism is potentially like SARS-CoV and MERS-CoV. The other immune escaping mechanism is inhibition of innate immune responses, inhibition of interferon recognition and signaling, immune modulation including membrane or nonstructural proteins (NS4a, NS4b, NS15), Viral mutations, Immune exhaustion, Immune deviation: TH2 bias [34] [35] [36] . Furthermore, in the adaptive immune response the evasion mechanism is due to down regulation of antigen presentation via MHC class I and MHC class II. Whenever, macrophages or dendritic cells get infected with MERS-CoV, T cells activation will be markedly diminished 37 . In the presence of controversial ideas between immune system and COVID-19, some scientist and reports suggested that taking items listed below are some supplements to trigger the immune system 38, 39 . • Reducing stress: Stress have negative impact the production of lymphocytes. As stress increase the risk of viral disease increases. • Exercise: Regular exercise promotes cardiovascular health, lowers blood pressure, helps control body weight, and offers protection against diseases. Exercise also improves blood All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint circulation, allowing immune system cells to move through the body more freely and do their job more effectively. However, intensive exercise can cause inflammation in the body that boosts undesired immune response. • Eat a balanced diet with fruits and vegetables: Previous evidence suggested that lack of these nutrients can alter the immune response. The following laboratory diagnostic techniques are used to detect COVID-19 [41] [42] [43] . • Viral nucleic acid test: Is the routine confirmation test for COVID-19 based on detecting a unique sequence that shows presence or absence of the virus. • Serological testing: Used for outbreak investigation. • Viral sequencing: After the virus is detected by nucleic acid test viral sequencing is important for monitoring genome mutation. • Viral culture: It is not routine test but used for further investigation. • Hematological test: Is supportive test to the routine tests for screening the distribution of cells. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. • Blood oxygen saturation test: This test also uncommon and not routinely applied as confirmatory test rather used as further investigation of the virus 42 . Neither an effective vaccines nor anti-viral therapeutic agents is approved to treat COVID-19. Hence, we mostly focus on supportive care. Rapid public health interventions with antibodies, anti-viral or novel vaccine strategies are highly essential. Passive antibody therapy is considered to limit COVID-19 epidemics which can recognize epitope regions in the foreign virus particle and reduce the virus replication and disease severity 44, 45 . Although there is no specific treatment, some reports recommended that using some anti-bacterial or anti-malaria and antiviral drugs are important as pre or shortly after the onset of the virus as prophylaxis to reduce infectiousness to others by reducing viral shedding in the respiratory secretions 44 . Some of the prophylactic drugs are listed below. Azithromycin: This antibacterial drug is acts by down regulate inflammatory responses and reduce the excessive cytokine production associated with respiratory viral infections 45 . Chloroquine: this anti malaria drug also acts by inhibition of viral enzymes or processes such as viral DNA and RNA polymerase, viral protein glycosylation, virus assembly, new virus particle transport, and virus release. It also involves ACE2 cellular receptor inhibition, acidification at the surface of the cell membrane inhibiting fusion of the virus, and immunomodulation of cytokine release. Lopinavir and Ritonavir: these ant viral drugs are acts by bind to Mpro, a key enzyme for coronavirus replication 46 . Alpha interferon: as immunomodulation as adjuvant treatment 47 . Acetaminophen: it considered as temperature control 48 . The use of monoclonal antibodies with serum therapy and intravenous immunoglobulins preparations as passive immunization 46, 49 . This can be achieved by using peptide fusion inhibitors, anti SARS-CoV-2 neutralizing antibodies, anti-angiotensin converting enzyme 2 (ACE-2) and protease inhibitors. The spike protein present on the viral membrane All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint plays a vital role in virus entry and is the principal antigenic component responsible for inducing host immune response [47] [48] [49] [50] . Following To minimize the risk factors reports suggested that cleaning and disinfecting surfaces in home and in areas that people touch the most is effective. Following the same preventive measures as people went out. Contact healthcare providers whenever developed signs and symptoms of COVID-19. Furthermore, individuals are requested to limit shared spaces, when having guests and keeping recommended social distancing 55 . Challenges: The challenges for the effective controlling of COVID-19 outbreak include absence validated vaccine and treatment 56,57 , ability of the viral antigen to stay longer in the air, sociocultural behaviour of people, lack of awareness, viral capacity of staying in animate objective for weeks 58 , overcrowding environment, having asymptomatic carriers, unavailability of test kits 61 , having wide host range 57 , lack of readiness to follow the recommended social distancing, difficulty of interpreting social distancing, unknown infective dose, unknown degree of infectivity prior the onset of clinical manifestation and after recovery. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint At government level: International, National, regional governments should participate by allocating budget for training, isolation of suspects, testing and supportive cares and awareness creation. Health institutions should also screen and early detection, giving supportive care and treatment, distributing medical protective equipment, give health education and introducing hand washing practices to customers and preparing isolation rooms 60 . author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.02.20051052 doi: medRxiv preprint Not applicable All data are incorporated in the manuscript. Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts Three Emerging Coronaviruses in Two Decades Genetic Recombination, and Pathogenesis of Coronaviruses Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review World Health Organization. Coronavirus disease 2019 (COVID-19) situation report-11. All rights reserved. No reuse allowed without permission author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the World Health Organization COVID-19) pandemic: increased transmission in the EU/EEA and the UK -sixth update -12 MEuropean Centre for Disease Prevention and Control. Novel coronavirus disease, Stockholm. Novel coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK -sixth update COVID-19) situation report-68 Report of the WHO-China Joint Mission on Coronavirus Disease Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia Clinical characteristics of 2019 novel coronavirus infection in China CT imaging of the 2019 novel coronavirus (2019-nCoV) pneumonia A Novel Coronavirus from Patients with Pneumonia in China A Novel Coronavirus Emerging in China -Key Questions for Impact Assessment Recognition of doublestranded RNA and activation of NF-kappaB by toll-like receptor 3 All rights reserved. No reuse allowed without permission author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the Innate immune sensing and signaling of cytosolic nucleic acids Sensing viral invasion by RIG-I like receptors Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3 STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling The role of pattern-recognition receptors in innate immunity: update on toll-like receptors Innate immunity to virus infection Clinical features of patients infected with 2019 novel coronavirus in Wuhan Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies 2019-novel coronavirus (2019-nCoV) infections trigger an exaggerated cytokine response aggravating lung injury General anatomy report of novel coronavirus pneumonia death corpse A new coronavirus associated with human respiratory disease in China All rights reserved. No reuse allowed without permission MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome A pneumonia outbreak associated with a new coronavirus of probable bat origin T cell responses to whole SARS coronavirus in humans Incubation periods of acute respiratory viral infections: a systematic review Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? COVID-19: what has been learned and to be learned about the novel coronavirus disease Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic Modulation of the immune response by Middle East respiratory syndrome coronavirus Boosting your immune system to fight the coronavirus: what you need to know How to boost the immune system against coronavirus All rights reserved. No reuse allowed without permission author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) -China COVID-19) in suspected human cases. Interim guidance 2 COVID-19 Drug Therapy-Potential Options. Clinical Drug Information / Clinical Solutions Potential inhibitors for 2019-nCoV coronavirus M protease from clinically proven medicines A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Use of antiviral drugs to reduce COVID-19 transmission Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS All rights reserved. No reuse allowed without permission author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the WHO. Mental health and psychosocial considerations during the COVID-19 outbreak CORONAVIRUS SURVIVAL STRATEGY: Keep Calm and Boost Your Immune System! Carpathia Collaborative Coronavirus infections and immune responses New Study Indicates How Long Coronaviruses Can Survive on a Surface COVID-19: epidemiology, virology, and clinical features -GOV.UK n COVID-19) -Prevention & Treatment COVID-19) -Preventing COVID-19 Spread in Co All rights reserved. No reuse allowed without permission author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the Not applicable The authors declare that they have no competing interests. All authors contributed equally to conduct this review, read, and approved the final manuscript.