European Respiratory Society

The story of COVID-19 now seems so familiar: from the first reported case of a new respiratory infection in China in December 2019, to a pandemic that rapidly changed the world. Respiratory clinicians and scientists were at the forefront of delivering healthcare for people with COVID-19, leading efforts to understand this novel virus and disease, and developing and testing strategies to better prevent and treat it. These endeavours extended not only to the acute illness, but also to understanding the longer-term consequences. The pace of knowledge acquisition was rapid but is now maturing. This Monograph therefore provides a timely and valuable state-of-the-art summary for clinicians and scientists on our understanding of this virus and its consequences to date. It is essential reading for all those involved in the care of people who are or who have been affected by COVID-19.

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  4. Page 1
    Stefano Aliberti (

    The major morbidity and mortality from COVID-19 is due to acute viral pneumonitis that evolves to ARDS. Furthermore, COVID-19 patients may be affected by extrarespiratory involvement, including cardiac, renal, neurological and vascular complications. Different hospitals reorganised their logistical structures to optimise the care of COVID-19 patients and ensure infection control, and the public health scenario worldwide was characterised by the rapid spread of multidisciplinary units specifically dedicated to COVID-19 patients. This chapter describes the personal experience and clinical case of a previously healthy and active patient who suffered from severe COVID-19. Two other cases of patients hospitalised because of severe acute respiratory failure due to COVID-19 are also discussed.

    Cite as: Amati F, Vigni A, Misuraca S, et al. Respiratory failure: a patient's perspective and clinical cases. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 1–13 [].

  5. Page 14
    Joan B. Soriano (

    There are many unknowns surrounding COVID-19 and the ongoing pandemic. Standard epidemiological methods helped to determine the initial and ongoing distribution of COVID-19 in time and space, with unprecedented global coverage in almost real-time, and the forecasting methods used already had a reasonable predictive ability. Cumulative incidence and other complex epidemiological estimators have been widely disseminated via the media and are becoming lay terms thanks to persistent use, but their thresholds to determine public health interventions are yet to achieve consensus. The natural history of SARS-CoV-2, the interplay of risk factors and the effectiveness of mitigating factors in subpopulations remain unmet challenges. Establishing standard definitions of COVID-19 and its consequences is essential to the implementation of research. Pending widespread vaccine coverage, the world is experiencing unleashed community transmission in many countries, and the COVID-19 endgame is a distant goal. Several characteristics differentiate the transmissibility of SARS-CoV-2 from other viruses, making COVID-19 much more difficult to control with universal hygiene interventions. Epidemiology remains a necessary discipline to help end the COVID-19 pandemic; economic, social and health policy decision-making analysis are also needed.

    Cite as: Soriano JB, Infante A. Epidemiology: global spread, risk factors for disease incidence, severity and mortality. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 14–27 [].

  6. Page 28
    David S. Hui (

    Alphacoronaviruses (HCoV-229E and HCoV-NL63) and betacoronaviruses (HCoV-OC43 and HCoV-HKU1) are common causes of upper respiratory tract infection in humans. SARS-CoV-1 and MERS-CoV emerged in 2002 and 2012, respectively, with the potential of causing severe and lethal disease in humans, termed SARS and MERS, respectively. Bats appear to be the common natural source of SARS-like coronaviruses including SARS-CoV-1, but their role in MERS-CoV is less clear. Civet cats and dromedary camels are the intermediary animal sources for SARS-CoV-1 and MERS-CoV, respectively. Nosocomial outbreaks are hallmarks of SARS and MERS. MERS patients with comorbidities or immunosuppression tend to progress more rapidly to respiratory failure and have a higher case fatality rate than SARS patients. SARS has disappeared since 2004, while there are still sporadic cases of MERS in the Middle East. Continued global surveillance is essential for SARS-like coronaviruses and MERS-CoV to monitor changing epidemiology due to viral variants.

    Cite as: Hui DS, Zumla A. Historical perspective: other human coronavirus infectious diseases, SARS and MERS. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 28–38 [].

  7. Page 39
    Virginie Gautier (

    The recent and recurrent spillover of three highly pathogenic coronaviruses, SARS-CoV-1, MERS-CoV and SARS-CoV-2, into human populations has stressed the importance of pandemic preparedness. Here, we describe how, in the absence of antiviral therapeutic options against coronaviruses, early clinical investigations have focused on the prompt repurposing of approved antiviral therapies. We discuss how, despite international collaborative efforts, their outcomes so far have been disappointing as none of the early drugs tested demonstrated effective clinical efficacy. We also outline innovative strategies and tools developed to fast-track development of novel classes of antivirals. These capitalise on a deeper understanding of viral molecular pathogenesis and how coronaviruses hijack the host cellular machinery to maximise their replication and counteract host defences. Collectively, these approaches are crucial to identify and validate novel targets for therapeutic interventions and expand the repertoire of broad-spectrum antiviral agents, so that these can be promptly deployed for current and future pandemics.

    Cite as: O'Reilly S, Angeliadis M, Murtagh R, et al. Drug repurposing and other strategies for rapid antiviral development: lessons from the early stage of the pandemic. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 39–68 [].

  8. Page 69
    Sarah Abdelhafeez (

    In COVID-19, SARS-CoV-2 has been shown to activate both innate and adaptive immune responses. However, uncontrolled or impaired immunity can lead to the development of severe forms of the disease. Understanding the underlying immunology influencing disease expression as well as the natural history of the virus is imperative to develop preventative and therapeutic strategies to tackle the COVID-19 pandemic. This chapter aims to discuss the literature surrounding the immunology of COVID-19 in a clinical context, specifically applied to the development of therapeutics and vaccines to SARS-CoV-2.

    Cite as: Abdelhafeez S, Doherty D. Can the immune system be targeted to treat COVID-19? In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 69–85 [].

  9. Page 86
    Marie-Christine Copin (

    The series of autopsies reported since the beginning of the pandemic have highlighted several patterns of lung damage, both isolated and combined. The factors influencing the occurrence of these different tissue responses to viral aggression by SARS-CoV-2 have not yet been determined. In asymptomatic patients or patients with respiratory symptoms who were not ventilated, lymphocyte pneumonia associated with type II pneumocyte atypical hyperplasia and a few hyaline membranes or focal lesions of acute fibrinous pneumonia have been observed. In critically ill patients, the most frequent pattern is diffuse alveolar damage with interstitial lymphoid infiltration, type II pneumocyte atypia and, very often, capillary or arteriolar microthromboses and/or endothelitis. The precise description of these lesions, which is becoming more and more consensual, makes it possible to understand the favourable effects of corticosteroid therapy in seriously ill patients and the evolution under ventilation towards fibrosis.

    Cite as: Copin M-C, Gibier J-B, Hofman V, et al. Lung pathology. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 86–100 [].

  10. Page 101
    Rachel Moores (

    COVID-19 is a multisystem disease that requires holistic management. Most patients will experience mild symptoms including cough, fever and mild dyspnoea. A small proportion of patients will have severe manifestations including respiratory failure, ARDS and multiorgan failure. Extrapulmonary features are common and include gastrointestinal, thromboembolic, neurological, cardiac, renal, endocrine and dermatological manifestations. The care of COVID-19 patients requires close attention to these features. This includes respiratory support (such as supplemental oxygen, NIV and awake proning); fluid, electrolyte and nutrition management; prevention, detection and treatment of thrombotic events; management of diabetic complications; review of medications; appropriate use of antibiotics; and evidence-based use of therapeutic agents such as corticosteroids, antivirals such as remdesivir and other emerging therapies such as immunomodulating agents. Early planning for treatment escalation and decision making around the appropriateness of cardiopulmonary resuscitation are crucial as deterioration can be rapid. Prolonged symptoms occur in a minority of patients and longitudinal follow-up is required.

    Cite as: Khan N, Lamb L, Moores R. Clinical features and acute management in adults. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 101–123 [].

  11. Page 124
    Lieuwe D. Bos (

    Patients hospitalised due to infection with SARS-CoV-2 frequently require admission to the ICU for organ support. Most of these admissions are due to acute respiratory failure, often fulfilling the criteria for ARDS. This chapter will review current evidence-based management of this patient population. We discuss how oxygenation can be supported via noninvasive and invasive methods, and describe how invasive ventilation should be set to provide lung protection. We discuss how there is no place for routine antiviral, antibiotic and therapeutic anticoagulation in ICU patients with COVID-19-related ARDS, but there is a place for steroids and immunomodulation via anti-IL-6. Finally, we provide an overview of the complications and long-term consequences of critical illness caused by COVID-19.

    Cite as: Ananth S, Aujayeb A, Brosnahan SB, et al. Management in the ICU. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 124–143 [].

  12. Page 144
    Elizabeth Whittaker (

    Children account for a minority of cases of SARS-CoV-2 infection. The majority with acute infection are asymptomatic or have mild disease. Severe disease and mortality are reported in children with associated comorbidities such as complex neurodisability. Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS; also referred to as multisystem inflammatory syndrome in children (MIS-C)) is observed ∼3–6 weeks after acute infection in an estimated 0.05% of cases. This is characterised by multiorgan involvement, and >50% of cases have myocardial dysfunction and require critical care admission for supportive care. Neurological, cardiac, gastrointestinal, renal and dermatological symptoms are all reported in acute and post-acute SARS-CoV-2 infection. To date, there is no evidence of a benefit from remdesivir, steroids or other investigative treatment in children during acute infection, and their use is recommended only on a case-by-case compassionate basis. Management of PIMS-TS is based on evidence from Kawasaki disease with immunomodulation and cardiac protection, and urgent RCT data are required. The collateral effects of the pandemic are likely to have long-term effects on children's physical and mental health.

    Cite as: Longbottom K, Whittaker E, Penner J. Clinical features and acute management in children. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 144–161 [].

  13. Page 162
    Christian Laursen (

    Thoracic imaging is an important cornerstone in the diagnosis, monitoring and follow-up of admitted patients with pneumonia associated with COVID-19 caused by SARS-CoV-2. The most commonly used forms of thoracic imaging, encompassing lung ultrasound, chest radiography and CT, all possess acceptable sensitivities for the detection of COVID-19 with lung involvement but are flawed, with the typical findings being unspecific. As such, imaging results should always be critically appraised and correlated into the given clinical context. None of the thoracic imaging modalities is optimal for any given clinical scenario or setting, as what is practically feasible in one context may not be feasible in another. Local logistical factors, available healthcare resources, limitation of disease spread and safety of healthcare staff also need to be considered when determining the optimal choice of thoracic imaging. Hence, additional studies are warranted, especially assessing the optimal use of thoracic imaging for monitoring patients with COVID-19 during admission, but also for assessment of possible pulmonary COVID-19 sequelae.

    Cite as: Laursen CB, Prosch H, Harders SMW, et al. Imaging. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 162–179 [].

  14. Page 180
    Francesco Blasi (

    This chapter explores the currently available knowledge (as at October 2021) about the long-term clinical consequences of COVID-19. Distinction between cardiorespiratory and extra-cardiorespiratory sequelae can facilitate understanding of the post-COVID sequelae problem and may aid the clinical management of patients. The strength of the recommendations is highlighted at the end of each paragraph.

    Cite as: Gramegna A, Mantero M, Amati F, et al. Post-COVID-19 sequelae. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 180–196 [].

  15. Page 197
    Sally Singh (

    The long-term problems for survivors of SARS-CoV-2 infection are not fully understood; data indicates a complex range of symptoms that initially appeared to focus on the respiratory system but now appear to be multisystem and wide ranging. The most frequently reported symptoms appear to be breathlessness, muscle weakness and fatigue. A proportion of individuals have persistent problems that would be amenable to a rehabilitation programme. The programme needs to have a much wider scope and remit than that of conventional pulmonary rehabilitation but this service model may form the foundation of a holistic programme to support the recovery of these individuals. Data from the SARS/MERS pandemic would support this initial approach. Rehabilitation teams need to collaborate to develop a wider interdisciplinary team to offer the best service to patients with post-COVID-19 symptoms.

    Cite as: Singh S. Post-COVID-19 rehabilitation. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 197–213 [].

  16. Page 214
    James D. Chalmers (

    The COVID-19 pandemic has required a substantial coordinated international effort to develop effective treatments and vaccines, which has led to an acceleration in innovation in clinical research with the rapid adoption of pragmatic, open, adaptive platform trials for new therapeutics. Large platform trials such as RECOVERY, SOLIDARITY and REMAP-CAP have demonstrated the ability to recruit thousands of patients across multiple sites in a short period of time, resulting in therapies that have now been adopted into clinical practice. Therapies tested for COVID-19 include repurposed antivirals, immunomodulatory drugs, convalescent plasma and, more recently, novel therapeutics developed specifically to target SARS-CoV-2. Challenges have included ethical and practical issues of delivering clinical research during a pandemic, some duplication of effort and the testing of some therapies with a low likelihood of success. COVID-19 has required acceleration of the process of clinical trial conduct, from grant funding to approvals and simplification of trial processes. Many of the innovations and simplifications to clinical trial conduct that have featured so prominently during the COVID-19 pandemic are likely to be just as valuable in a post-pandemic world. An important legacy of the pandemic may be a more efficient and effective way of delivering clinical research in the future.

    Cite as: Abo-Leyah H, Chalmers JD. Clinical trials during the pandemic: research design and lessons. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 214–231 [].

  17. Page 232
    Roger McIntyre (

    The COVID-19 pandemic is an unprecedented global public health crisis with respect to its effects on economic, physical and mental health. While early lockdown guidelines may have been effective for reducing viral transmission, prolonged quarantine and physical distancing measures may have augmented the disparities underlying the determinants of health. The aggregate effects of rapid and significant economic downturn, as well as physical and mental morbidity and mortality, are reported to increase the risk of suicide. Furthermore, students, females and individuals with pre-existing mental health illness(es) are at an increased risk for poor mental health outcomes as a result of decreased social support and gaps in healthcare access. Individuals with a mood disorder are at a greater risk for COVID-19 hospitalisation. Additionally, international collaboration addressing underlying social and economic inequities across high-, middle- and low-income countries is critical for managing infection rates. Taken together, public health policies should target upstream factors that affect the determinants of ill health.

    Cite as: Lui LMW, Lee Y, McIntyre RS. Economic, physical and social determinants of health during lockdown: a call for renewed societal responses. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 232–243 [].

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    Anita K. Simonds (

    The pandemic has facilitated an explosion in the development of new platforms for vaccines and rapid regulatory approval systems. The COVID-19 vaccines have been produced in record time and have proved far more effective than expected. In many countries, the roll out of vaccination initially proved effective in reducing severe disease, but there are major concerns following the emergence of SARS-CoV-2 variants, especially omicron, where vaccine boosting is required to maximise effect. Vaccine hesitancy, the spread of disinformation and the equitable delivery of vaccines worldwide remain significant challenges.

    Cite as: Simonds AK, Boyton RJ. Vaccines: immunology, regulation and clinical management. In: Fabre A, Hurst JR, Ramjug S, eds. COVID-19 (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 244–260 [].