Editorial: Coronavirus disease 2019 (COVID-19) - advances in epidemiology, diagnostics, treatments, host-directed therapies, pathogenesis, vaccines, and ongoing challenges.

Abstract

Over the past year, the world has witnessed an unprecedented nightmare scenario of an explosive pandemic outbreak of novel Coronavirus disease 2019 (COVID-19) [1,2]. The number of COVID-19 related deaths is a key indicator for assessing the human toll of the ongoing pandemic. COVID-19 is now the top cause of death from a single infectious disease globally, dislodging Tuberculosis (TB) to second place [1,3]. COVID-19 was the long-anticipated disease ‘X’ [4] that the global public health community had dreaded but had not adequately prepared for. Since the end of December, 2019, when the World Health Organization (WHO) was made aware of several cases of atypical pneumonia in Wuhan, China caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 cases have been reported from every corner of the globe. As of February 10, 2021, there have been 108,484,800 confirmed COVID-19 cases, with 2,394,323 deaths, reported to WHO [1]. COVID-19 also continues to have, a major negative impact on the mental health of billions of people throughout the world [5,6]. The public health, political, scientific, and public–private sector response to the COVID-19 outbreak, although initially slow, has progressed at an unprecedented scale [4]. The intense search for new diagnostics, treatments, and vaccines has been relentless. Over 2,000 COVID-19 related clinical trials are registered on the clinical trials.gov website and over 90,000 COVID-19 articles have been published [7]. A plethora of information and updates on real-time COVID-19 data dashboards, clinical management, travel advice, ongoing research on vaccines and newer treatments, is available on the WHO [8–13] , CDC [14,15] and ECDC [16] websites. The review articles in this issue of COPM focus mainly on COVID-19 and highlight current opinions, developments and advances in epidemiology, diagnostics, treatments, pathogenesis, and host-directed therapies (HDTs). Recent developments in COVID-19 vaccines, new SARS-CoV-2 variants, ongoing challenges due to the additional burden of COVID-19 to the existing huge load of Respiratory tract infections, including Tuberculosis, community acquired pneumonia, and atypical mycobacterial infections, are highlighted. COMPARATIVE EPIDEMIOLOGY OF COVID-19, MIDDLE EAST RESPIRATORY SYNDROME (MERS) AND SEVERE ACUTE RESPIRATORY SYNDROME (SARS) Hiu et al.[17] give a comparative analysis of the phylogenetics, epidemiology, transmission, and salient clinical features of COVID-19, Middle East Respiratory Syndrome (MERS), and SARS. Bats appear to be the common ancestral natural reservoirs and sources. Whilst civet cats are the intermediary animal source for SARS-CoV-1, and dromedary camels for MERS-CoV, the intermediary source of SARS-CoV-2 remains evasive. Nosocomial outbreaks are hallmarks of SARS and MERS, but these have been infrequently reported for COVID-19. SARS-CoV-2 viral load in clinical specimens peak early on days 2–4 of symptom onset, with resultant high community transmission from both. symptomatic and presymptomatic individuals. New genetic variants of SARS-CoV-2 such as D614G, N501Y have increased transmission potential, and concerns are being raised regarding effect of mutations on the efficacy of COVID-19 vaccines. Proactive surveillance for SARS-CoV-2 mutations is essential to monitor the changing epidemiology of COVID-19. This also applies to the continuing circulation of MERS-CoV in the Middle East 8 years after first discovery [18]. Of concern is the first report of MERS-CoV infection from West Africa [19,20]. DIAGNOSTICS Soon after first detection of SARS-CoV-2 as a human pathogen, an immediate public health and clinical priority was the development of rapid diagnostic tests and platforms to detect SARS-CoV-2 infection, tools that are essential for clinical management, surveillance, and infection control. A wide variety of analytical diagnostic tools that directly detect SARS-CoV-2 RNA, antigen or antibodies, were developed [15]. A specific reverse transcription Polymerase Chain Reaction SARS-CoV-2 test was rapidly developed and adopted by the WHO as a gold standard method for confirming SARS-CoV-2 infection. Other novel, easy to use, practical, affordable point of care tests utilizing noninvasive clinical samples have spanned the technological space including genomics, proteomics, organic chemistry, and advanced microscopy. Huggett et al.[21], provide an overview and focus on development of in vitro diagnostics and their performance. They highlight that current authorised nucleic acid and antigen detection tests are not optimal, and measurement science, analytical considerations and standardization are important for their translation to routine. Internationally agreed standards and metrics are needed to ensure comparability of clinical, epidemiological, and research data. IMAGING MODALITIES IN CORONAVIRUS DISEASE 2019 The WHO guidance on the use of chest imaging in COVID-19 examines the evidence and makes recommendations for chest imaging in acute care of adult patients with suspected, probable, or confirmed COVID-19 [11]. Imaging modalities considered are radiography, computed tomography (CT), and ultrasound. This guide addresses the care pathway from presentation of the patient to a health facility to patient discharge. It considers different levels of disease severity, from asymptomatic individuals to critically ill patients. The guide also includes implementation considerations for different settings. Several other imaging modalities such as ultrasound scans, and CT scans have been described for COVID-19 management and these are reviewed by Ariana Axiaq et al. [22]. CT scanning may also have utility in following patients with post-COVID respiratory symptoms MANAGEMENT OF CORONAVIRUS DISEASE 2019 A study of 44,000 COVID-19 cases from China defined COVID-19 clinical presentations that range from mild, moderate to severe and fulminant disease [23]. Studies from across all continents have confirmed this consistent pattern. The WHO and CDC provide guidance on COVID-19 management and these are updated regularly as evidence accumulates and interventions are approved by regulatory authorities [10]. These meet the needs of front-line clinicians, promoting a multidisciplinary approach to care for patients with COVID-19, including those with mild, moderate, severe, and critical disease. The documents include COVID-19 care pathways, treatment of acute and chronic infections, management of neurological, psychological and mental manifestations, co-morbidity with noncommunicable diseases, rehabilitation, palliative care, ethical principles. A range of therapeutics interventions for COVID-19 have been developed and evaluated. Kevin Wilson [24] summarizes the current body of evidence on therapeutics and provides a pragmatic approach to applying the evidence at the bedside. The antiviral agent, remdemsivir, and the immunomodulator, dexamethasone, are the first therapeutics for which there is evidence of efficacy from randomized trials. The body of evidence related to COVID-19 therapeutics continues to evolve and, as a result, management guidelines are constantly updated and are likely to change over time. CORONAVIRUS DISEASE 2019 RISK IN PEOPLE ON IMMUNOSUPPRESSIVE THERAPIES Patients receiving immunosuppressive therapies for a range of clinical indications who acquire SARS-CoV-2 infections may be at increased risk of severe disease. Manansala and colleagues [25] review the risks of acquiring SARS-CoV-2 infection and progressing to developing severe COVID-19 in those receiving chronic immunosuppressive therapy. Currently, there is no conclusive evidence to suggest that solid organ transplant recipients on chronic immunosuppression are at increased risk of contracting COVID-19. More data are required to confirm or refute this. Patients with rheumatologic disorders or inflammatory bowel diseases appear not at increased risk of contracting SARS-CoV-2 and do not experience worse clinical outcomes. Patients with sarcoidosis also appear not to be at increased risk of COVID-19, although more data are required to determine effect on management outcomes. PATHOGENESIS OF CORONAVIRUS DISEASE 2019 – AUTOPSY AND IMMUNOLOGICAL STUDIES Full-body autopsy studies of COVID-19 patients have been few due to several issues of infection control, and logistical and operational reasons. Whole-body autopsy studies have defined the extent of COVID-19 pathology, and they also allow adequate tissue to be obtained for further pathological and molecular evaluation and for research purposes. Alain C Borczuk [26] reviews the pathology case reports and autopsy series and concludes that COVID-19 predominantly causes acute lung injury and diffuse alveolar damage, which is associated with multisystem involvement and significant pathology across most body organs in patients with and without comorbid disease. Diffuse alveolar damage seen on histology is part of acute respiratory distress syndrome and lung injury can be temporally heterogeneous, with patterns of healing alongside new injury. Thrombosis is also an important feature. Rita Carsetti and colleagues [27] review the innate and diverse adaptive immune responses to SARS-CoV-2 seen across the clinical spectrum of patients infected with SARS-CoV-2. T cells specific for SARS-CoV-2 have been demonstrated both in patients and unexposed individuals indicating that preexisting memory T cells, natural IgM and IgA isotypes and interferons may be protective in early phase of infection. Whether the immune responses persist postrecovery from SARS-CoV-2 infection and for how long the protective effects last, remains to be defined, since they may guide targeted therapy and vaccination. CARE OF PATIENTS POST-CORONAVIRUS DISEASE 2019 ILLNESS As with all other severe respiratory tract viral illnesses, people who have survived COVID-19 can continue to be ill for many months after recovery. The long-term disabilities arise from pulmonary and nonpulmonary complications of COVID-19. Pulmonary complications seen in COVID-19 survivors include dyspnea without hypoxemia, organizing pneumonia, and pulmonary fibrosis. Nonpulmonary complications of COVID-19 infection include exhaustion, breathlessness, headache, stroke, anosmia, ageusia, chest pain, thrombosis, palpitations, weakness, nerve injury, vocal cord injury, dysphagia, and mental health disorders. Lafond et al.[28] highlight the need for standardized evaluation of the post-COVID-19 patient. They review the current literature on the major clinical findings in post-COVID-19 patients and provide guidelines for the evaluation and management of prolonged symptoms. As time progresses more information will become available about the long-term physical, social and mental effects in COVID-19 survivors. COVID-19 survivors who required ICU level of care, are at high risk for developing post-ICU syndrome, characterized by new and marked physical, mental, and cognitive deficits, and require special care. HOST-DIRECTED THERAPIES TO IMPROVE MANAGEMENT OUTCOMES Management outcomes are determined by a range of pathogen (SARS-CoV-2) and host factors including comorbidities, innate and adaptive cellular immune responses. Clinical studies have indicated that acute respiratory distress syndrome and multiple organ failure may be underpinned by an excessive immune response. Many patients who survive severe COVID-19 develop end organ tissue damage due to excessive inflammation, including deleterious cytokine responses with consequential fibrosis leading to long term functional disability. Apart from reducing death rates, an important clinical management need today is to prevent long term functional disability [29]. Host Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses is an area of growing interest for more holistic treatment of patients with severe COVID-19 disease. Maeurer et al. [30] highlight a range of HDTs with different mechanisms of action which are being considered as adjunct treatment for COVID-19. They discuss data from recent trials of the use of adjunct Mesenchymal Stem Cells and monoclonal antibody/anti-IL-6 trials emphasize the importance of advancing HDTs for improving long term management outcomes. CORONAVIRUS DISEASE 2019 VACCINES COVID-19 vaccine development for the prevention of SARS-CoV-2 infection or protection against severe disease and mortality has advanced with unprecedented speed. With a collaborative global effort over 214 candidate vaccines are in the pipeline and up to 50 COVID-19 vaccine candidates in clinical trials [12,13]. The use of novel and different approaches and technologies has facilitated vaccine development, and fastrack evaluation in phase 1, 2 and 3 trials. The COVAX initiative, was facilitated by the Coalition for Epidemic Preparedness Innovations (CEPI); GAVI Vaccine Alliance and WHO. They are working with vaccine manufacturers to offer low-cost COVID-19 vaccines to developing countries. CEPI's candidate vaccines will come from companies Inovio, Moderna, CureVac, Institut Pasteur/Merck/Themis, AstraZeneca/University of Oxford, Novavax, University of Hong Kong, Clover Biopharmaceuticals, and University of Queensland/CSL who are part of the COVAX initiative [12,13]. The USA joined COVAX on January 21, 2020. Real-time data on rollout of vaccines are given on the WHO website [13]. CORONAVIRUS DISEASE 2019 CHALLENGES AHEAD Multiple variants of SARS-CoV-2 are now circulating globally [16,17]. The UK identified a variant called B.1.1.7 with a large number of mutations in the fall of 2020. This variant spreads more easily and quickly than other variants, and it has been detected in many countries. In the USA it was first detected end of December 2020. In South Africa, is another variant called B.1.351. Cases caused by this variant have been reported in the US at the end of January 2021. In Brazil, a variant called P.1 emerged that was first identified in travelers from Brazil, tested during routine screening at an airport in early January. This and other variants may have additional mutations that could evade recognition by antibodies. This variant was first detected in the USA at the end of January 2021. Variants seem to spread more easily and quickly than the initial SARS-CoV-2 strain and thus COVID-19 continues to impose a huge strain on healthcare resources. COMMUNITY ACQUIRED PNEUMONIA COVID-19 adds a huge burden to the existing load of lower respiratory tract infections (RTIs). Community-acquired pneumonia (sCAP) is one of the most common cause of sepsis in patients admitted to hospitals worldwide. Torres and Martin-Loeches [31] highlight the recent advances in the guidelines for treating patients with sCAP that is a significant cause of hospital admissions. The mortality rate remains unacceptably high. the choice of empirical antibiotic therapy for sCAP depends on multiple factors, such as national and local antimicrobial susceptibility data and the characteristics of the patients, including their risk factors for acquiring infections caused by multidrug resistant pathogens. ATYPICAL MYCOBACTERIA Human infections with atypical Mycobacterial Infections caused by nontuberculous mycobacteria (NTM) are increasing. Gill Li, and colleagues [32] review treatment and management of NTM lung infections, including diagnostic advances and emphasize the need for increased awareness of an ever-larger at-risk population. Recent additions to NTM treatment are inhaled liposomal amikacin and the anti-TB drug bedaquiline. Several other new or repurposed treatments are being explored in vitro, in animal models and in clinical trials, including novel beta-lactamase inhibitor/lactam combinations, dual-lactam combinations, efflux pump inhibitors, novel antimicrobials, inhaled clofazimine suspension and bacteriophages. COPING WITH CORONAVIRUS DISEASE 2019 DISRUPTION OF HEALTH SERVICES The widespread disruption caused to global health services by COVID-19 is reversing gains made in global TB, HIV and malaria control efforts [33,34]. Although urgent measures are required to slow the spread of COVID-19, every effort must be made by to ensure that health services and prevention programs for other infectious diseases such as TB, HIV, malaria, and RTI's are not compromised. Integration of COVID-19 services and aligning them to routine health services [35] will be essential to preventing a reversal of gains being made. CONCLUSION Control of the global COVID-19 pandemic will require sustained efficient community screening, testing, and contact tracing; behavioral change interventions; adequate resources; and well supported, community-based teams of trained, protected personnel [34]. The long-term physical, mental and socio-economic consequences of COVID-19 remain to be defined. The rapid development and rollout of COVID-19 vaccines and ongoing routine public health measures bring some hope of bringing the pandemic under control. Generation of some degree of vaccine-induced and postinfection herd immunity, SARS-CoV-2 may pan out to be like seasonal influenza manifesting as self-limiting disease and severe disease among older people or those with comorbidities. However, the rapid adaptation of SARS-CoV-2 to human beings as a new zoonotic pathogen, generation of immune responses that facilitate mutations into more transmissible new variant strains that then become dominant, beckons caution. In addition to rollout of COVID-19 vaccines, and constant development of new vaccines to SARS-CoV-2 variant strains, rigorous and increased compliance with public health mitigation strategies, physical distancing, use of masks, hand hygiene, isolation and quarantine measures, are required to curtail the continuing spread of SARS-CoV-2. The ongoing COVID-19 pandemic is one of the most challenging health crisis the world has faced. The pandemic has progressed rapidly despite the best pandemic preparedness plans. Preventing future pandemics will be dependent on more effective cross-continental ONE-HUMAN-ANIMAL-HEALTH networks based an equitable partnerships model, and empowerment the younger generation to take leadership of the epidemic agenda. Acknowledgements Sir Prof Alimuddin Zumla is a co-PI of the Pan-African-European Network for Pandemic Preparedness, Research and capacity development for Emerging and Re-Emerging Infections (PANDORA-ID-NET; https://www.pandora-id.net/) and Member of the CANTAM and EACCR networks of excellence, funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) the EU Horizon 2020 Framework Programme for Research and Innovation. Sir Zumla is also in receipt of an United Kingdom National Institutes of Health Research senior investigator award and he is a Mahathir Science Award Laureate Financial support and sponsorship None. Conflicts of interest MSD and AZ both have a specialist interest in respiratory tract infections and are editors of this volume of COPM. Sir Zumla is founder member of the Global Cancer and Infectious Diseases consortium for Host-directed therapies: Weblink: https://www.fchampalimaud.org/covid19/aci/.