Monograph: - COVID-19

ERS monograph
COVID-19
ERS monograph
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clinicians and scientists were at the forefront of delivering
healthcare for people with COVID-19, leading efforts to understand Edited by Aurelie Fabre,
this novel virus and disease, and developing and testing strategies
to better prevent and treat it. These endeavours extended not only John R. Hurst and
to the acute illness, but also to understanding the longer-term
consequences. The pace of knowledge acquisition was rapid but Sheila Ramjug
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.
ERS monograph 94
ISBN 978-1-84984-148-1
Print ISSN: 2312-508X
Online ISSN: 2312-5098
Print ISBN: 978-1-84984-148-1
Online ISBN: 978-1-84984-149-8
December 2021
€60.00
9 781849 841481
COVID-19
Edited by
Aurelie Fabre, John R. Hurst and
Sheila Ramjug
Editor in Chief
John R. Hurst
This book is one in a series of ERS Monographs. Each individual issue

provides a comprehensive overview of one specific clinical area of
respiratory health, communicating information about the most advanced
techniques and systems required for its investigation. It provides factual and
useful scientific detail, drawing on specific case studies and looking into
the diagnosis and management of individual patients. Previously published
titles in this series are listed at the back of this Monograph.
ERS Monographs are available online at books.ersjournals.com and print

copies are available from www.ersbookshop.com
Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia),
Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda),
Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK).
Managing Editor: Rachel Gozzard

European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK
Tel: 44 114 2672860 | E-mail: monograph@ersnet.org
Production and editing: Caroline Ashford-Bentley, Claire Marchant, Catherine Pumphrey, Kay Sharpe and
Ben Watson
Published by European Respiratory Society ©2021

December 2021
Print ISBN: 978-1-84984-148-1
Online ISBN: 978-1-84984-149-8
Typesetting by Nova Techset Private Limited

All material is copyright to European Respiratory Society. It may not be reproduced in any way including
electronic means without the express permission of the company.
Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory
Society, editors or publishers.
ERS monograph
Contents
COVID-19 Number 94
December 2021
Preface i
Guest Editors iii
Introduction v

List of abbreviations ix
1. Respiratory failure: a patient’s perspective and clinical cases 1

Francesco Amati, Annalisa Vigni, Sofia Misuraca, Francesco Bindo,
Andrea Gramegna, Antonio Voza, Francesco Blasi and Stefano Aliberti
2. Epidemiology: global spread, risk factors for disease incidence, 14

severity and mortality
Joan B. Soriano and Alberto Infante
3. Historical perspective: other human coronavirus infectious diseases, 28

SARS and MERS
David S. Hui and Alimuddin Zumla
4. Drug repurposing and other strategies for rapid antiviral 39

development: lessons from the early stage of the pandemic
Sophie O’Reilly, Matthew Angeliadis, Ross Murtagh and Virginie W. Gautier
5. Can the immune system be targeted to treat COVID-19? 69

Sarah Abdelhafeez and Derek Doherty
6. Lung pathology 86
Marie-Christine Copin, Jean-Baptiste Gibier, Véronique Hofman and Paul Hofman
7. Clinical features and acute management in adults 101

Nuzhath Khan, Lucy Lamb and Rachel Moores
8. Management in the ICU 124

Sachin Ananth, Avinash Aujayeb, Shari B. Brosnahan, Lieuwe D. Bos,
Rebecca F. D’Cruz, Daniel López-Padilla, Anthony Lubinsky,
Hrishikesh S. Kulkarni, Toni Marín and Ema Swingwood
9. Clinical features and acute management in children 144

Katherine Longbottom, Elizabeth Whittaker and Justin Penner
10. Imaging 162
Christian B. Laursen, Helmut Prosch, Stefan M.W. Harders, Casper Falster,
Jesper R. Davidsen and Ádám D. Tárnoki
11. Post-COVID-19 sequelae 180

Andrea Gramegna, Marco Mantero, Francesco Amati, Stefano Aliberti and
Francesco Blasi
12. Post-COVID-19 rehabilitation 197

Sally Singh
13. Clinical trials during the pandemic: research design and lessons 214
Hani Abo-Leyah and James D. Chalmers
14. Economic, physical and social determinants of health during lockdown: 232
a call for renewed societal responses
Leanna M.W. Lui, Yena Lee and Roger S. McIntyre
15. Vaccines: immunology regulation and clinical management 244

Anita K. Simonds and Rosemary J. Boynton
ERS | monograph
Preface
Anh Tuan Dinh-Xuan
Even though SARS-CoV-2 can theoretically infect a variety of

organs after binding to the ubiquitous ACE2 cell membrane
receptor, the respiratory system is still the most frequently
impacted due to the airborne nature of the infective agent. The
clinical picture is very heterogeneous, but the potential for
severe life-threatening conditions in adults comes from lung
injury, as inflammatory processes causing airways, alveolar and
vascular dysfunction and damage can lead to rapidly progressive
acute hypoxaemic respiratory failure. Since its appearance in
December 2019, it has become rapidly apparent that this new
disease behaves very differently from previously known viral
pneumonias in terms of risk factors and clinical, radiological
and biological presentations. It has challenged, and continues to
challenge, our knowledge whilst also urging in-depth basic
research and rapidly evolving clinical guidance, both of which
are mandatory to improve patient care and support public
health decisions.
Adaptive mutations of the SARS-CoV-2 genome alter its

pathogenic potential, which in turn increases the already
significant obstacles to drug and vaccine development. As with
other RNA viruses, the rate of nucleotide substitution in the
SARS-CoV-2 genome is fast, and this rapid evolution is mainly
shaped by natural selection. Despite the extraordinary speed of
vaccine development against COVID-19 and >8 billion vaccine
doses administered to date, the very recent emergence of
omicron, yet another variant of concern which threatens to
supersede the already dreadful delta variant, highlights the
ongoing difficulties of achieving global control of the pandemic.
Nevertheless, at the time of writing in December 2021, 2 years

after the pandemic outbreak, we can state that much has been
learned about the pathogenesis, epidemiology and clinical
management of COVID-19. No other medical condition has
ever had such a “high speed” dynamic in the emergence of
medical knowledge, as reflected by the unprecedented
exponential rise in scientific publications over the past 2 years.
Copyright ©ERS 2021. Print ISBN: 978-1-84984-148-1. Online ISBN: 978-1-84984-149-8. Print ISSN: 2312-508X. Online ISSN: 2312-5098.
https://doi.org/10.1183/2312508X.10021321 i
In my position as European Respiratory Society (ERS)
Publications Committee Chair, I am pleased to introduce this
latest issue of the ERS Monograph. With 15 chapters entirely
dedicated to COVID-19, written by 50 leading experts in the
field, it reflects the relentless efforts of the ERS and its members
to add another stone to fortify the scientific compendium
against past, current and future pandemic waves.
Disclosures: A.T. Dinh-Xuan's institution is supported by a research grant

from the "Fondation Air Liquide" related to lung function in COVID-19.
A.T. Dinh-Xuan reports receiving ad hoc honoraria for lectures in pharmaceutical-
sponsored symposia: AstraZeneca, Chiesi, Circassia, GSK, Novartis and
Sanofi-Genzyme.
ii https://doi.org/10.1183/2312508X.10021321
ERS | monograph
Guest Editors
Aurelie Fabre
Aurelie Fabre is a Consultant Histopathologist and Full Clinical

Professor at St Vincent’s University Hospital (Dublin, Ireland)
and the School of Medicine at University College Dublin (UCD)
(Dublin), with a special interest in thoracic pathology (lung and
cardiac). She provides national expertise on interstitial and
cystic lung diseases, participating in various multidisciplinary
meetings. She is an active member of the UCD lung research
group, supervises research projects and collaborates with
national and international groups on lung fibrosis and
COVID-19 research.
Aurelie was Chair of the European Respiratory Society (ERS)

Group for Molecular Pathology and Functional Genomics
(2018–2021). She is a member of various ERS task forces:
genetics in pulmonary fibrosis; the ERS/European Society for
Thoracic Surgeons (ESTS)/European Society for Radiotherapy
and Oncology (ESTRO)/European Society of Radiology (ESR)/
European Society of Thoracic Imaging (ESTI) statement on
management of incidental findings from low-dose CT screening
for lung cancer; the ERS/European Alliance of Associations for
Rheumatology (EULAR) guidelines on connective tissue
disease-associated interstitial lung disease (ILD); and the ERS
task force on optimising experimental research in respiratory
diseases. She is also a member of the Irish Thoracic Society
(ITS) lung fibrosis ILD/idiopathic pulmonary fibrosis subgroup.
John R. Hurst
John R. Hurst is Professor of Respiratory Medicine at University

College London (London, UK), where he has worked since
2007. He has a particular research and clinical interest in COPD
but, like most respiratory healthcare professionals, he found
himself facing the clinical challenge of acute and later
post-COVID-19 as waves of the pandemic unfolded from the
first quarter of 2020. He is Chief Editor of the ERS Monograph.
https://doi.org/10.1183/2312508X.10016621 iii
Sheila Ramjug
Sheila Ramjug is a Consultant Pulmonologist with a specialist

interest in pulmonary vascular and interstitial lung disease,
working in Wythenshawe Hospital, Manchester University NHS
Foundation Trust (Manchester, UK).
She obtained her first consultant position at the start of the

COVID-19 pandemic and due to her previous cardiothoracic
intensive care experience, she initially worked in the COVID-19
intensive care unit, after which she transitioned to care for
patients on the acute COVID-19 wards. During this time, Sheila
had the opportunity to develop local venous thromboembolism
guidance in COVID-19 in relation to national and international
standards, as well as reviewing discharged COVID-19 patients
with evidence of venous thromboembolism.
Sheila is part of the ERS Monograph editorial board as the

previous early career member representative for the Pulmonary
Vascular Disease Assembly of the European Respiratory Society.
iv https://doi.org/10.1183/2312508X.10016621
ERS | monograph
Introduction
1 2
Aurelie Fabre , John R. Hurst and Sheila Ramjug3
@ERSpublications
The COVID-19 ERS Monograph details the immense achievement of the respiratory community in
this evolving area. It offers a comprehensive understanding of the virus, its pathological
consequences, potential long-term sequelae, and current best practice. https://bit.ly/3Efam73
In March 2020, Sheila distinctly remembers sitting in a hospital lecture theatre in

Lausanne, Switzerland, for a European Respiratory Society (ERS) masterclass on pulmonary
vascular disease, where the course facilitator announced, “it is unfortunate that the Chinese
delegates are unable to attend”. This was the last face-to-face conference Sheila attended. At
the time of writing, 265 million people had been affected worldwide by the COVID-19
virus and 5.2 million people had died.
At the start of the pandemic, there was an overwhelming amount of information, especially
on social media, about: the different methods countries were employing to help reduce
transmission of the virus; asymptomatic carriers; which countries had the lowest rates of
morbidity and mortality; and the best strategies to help manage patients with COVID-19.
For clinicians, in the initial stages of the pandemic, it seemed very unnatural to be relying
solely on supportive measures, without evidence-based, disease-modifying interventions.
There was an eagerness for knowledge and to be informed of other health professionals’
experiences with this unknown entity.
This Monograph is a reflection of the immense work the respiratory and wider medical
community has achieved in this ever-evolving area. It aims to give the reader a
comprehensive understanding of the virus itself, its pathological consequences, current best
clinical practice, and the potential long-term consequences not only for the patient but for
society as a whole, concluding with strategies to combat the virus.
The first section of the Monograph explores the history of coronavirus [1], the virus itself [2],
its effects upon the immune system [3] and the pathological consequences of infection [4].
Coronaviruses are a common cause of upper respiratory tract infections, particularly in
children. Historically though, it was not until 2002 (with SARS-CoV-1) and again in 2012
(with MERS) that the virus developed severe and potentially lethal capabilities. The
COVID-19 virus is a positive-sense, single-stranded RNA virus. Both the innate and adaptive
immune system are affected by the virus, but it is an impaired host immune response that is
1
Dept of Histopathology, St Vincent’s University Hospital and School of Medicine, University College Dublin, Dublin, Ireland. 2Centre
for Inflammation and Tissue Repair, University College London, London, UK. 3Respiratory Medicine, Wythenshawe Hospital,
Manchester University NHS Foundation Trust, Manchester, UK.
Correspondence: Sheila Ramjug (sheilaramjug@hotmail.com)
https://doi.org/10.1183/2312508X.10017521 v
associated with more severe forms of the disease. By exploring the immunological responses,
the reader will understand the deleterious effects of a maladaptive immune response to
COVID-19 and how various pathways can be targeted for therapies such as immune
modulation (for example, IL-6 inhibitors), as well as vaccine development (for example,
spike protein).
With COVID-19 infection, a variable pathological process occurs in the lung. In those who are
critically ill, it is now well-established from post mortem examinations that the lungs have
evidence of diffuse alveolar damage with lymphoid infiltration of the interstitium and capillary
or arteriolar microthromboses. In those with less respiratory compromise, this is reflected in the
lung tissue by lymphocytic-type pneumonia with atypical hyperplasia of type II pneumocytes.
Describing the variety of patterns of lung injury helps respiratory teams appreciate the likely
severity of the disease, the benefits of suggested therapeutics and the potential long-term
consequences, such as lung fibrosis in those who have been ventilated for longer periods.
Another fundamental chapter of this Monograph is the patient perspective, which presents the
powerful narrative of a COVID-19 survivor [5]. They detail their hospital experience in the
general ward as well as in the ICU. At the start of the pandemic, many advocated early
intubation and some clinicians were reticent to consider high-flow oxygenation or noninvasive
measures for respiratory support, partly due to the fear of aerosolisation of the COVID-19
virus. More recent observational studies have demonstrated the utility of high-flow oxygenation
and perhaps even noninvasive therapy to help reduce the need for invasive ventilation [6].
Proning has been a central part of our supportive therapy for awake and ventilated patients,
and thanks to trial data [7–11], we are now equipped with therapeutics [12].
The rapid response to the virus in terms of the design and swift implementation of large
international clinical trials to ascertain the effects of differing therapeutics was a major
accomplishment and success [13]. Barriers that prevented collaborative work disappeared,
and respiratory scientists and clinicians around the world worked as one. Currently, we are
able to offer: dexamethasone, which RCTs have shown to have mortality benefits;
remdesivir, an anti-viral drug that inhibits viral RNA transcription; and tocilizumab and
sarilumab, which are monoclonal antibodies that block the IL-6 receptor, thus instigating a
reduction in pro-inflammatory cytokines [7–11, 14].
With the advent of large, adaptive platform trials, recommendations have been made pertaining
to the role of therapeutic versus prophylactic anticoagulation in COVID-19 patients [15]. The
suggestion is that therapeutic anticoagulation should be strongly considered in moderately unwell
general ward patients with a low risk of bleeding. Patients receiving high-flow oxygenation,
NIV or invasive ventilation should, conversely, be offered prophylactic anticoagulation.
For those who survive COVID-19, there is emerging evidence of the persistence of diverse
symptoms after the acute phase of the disease. These enduring symptoms may be respiratory
in nature but many patients also suffer from extra-respiratory post-COVID sequelae. This
chapter of the Monograph offers a comprehensive guide to post-COVID sequelae, together
with the rationale and benefits of rehabilitation in this typically younger cohort of patients, in
order to support their return to being productive members of society [16].
Predictably, the COVID-19 pandemic has had a detrimental effect on society, not only on the
physical health of some of those significantly affected but also upon mental and economic
vi https://doi.org/10.1183/2312508X.10017521
health. Health inequalities in society in terms of viral transmission, access to healthcare as
well as the ability to access digital health have also never been as apparent [17].
The final chapter is written by Professor Anita K. Simmonds, the ERS President during
part of the pandemic. The chapter covers the development of COVID-19 vaccines. It details
how it was possible for vaccines to be developed rapidly using prior knowledge of
coronaviruses and existing vaccines, alongside immense collaborative work.
We would like to thank all invited authors and reviewers for their willingness to make time
in their busy clinical and research schedule to write and review each chapter published
in this Monograph, and for the high quality of their content thanks to their knowledge of
the field.
The COVID-19 pandemic has devasted our way of life and some have sorrowfully
experienced their loved ones and colleagues losing their lives or livelihood to the virus. We
believe COVID-19 survivors are a testament to the phenomenal work of the global medical
and scientific communities who, in these unprecedented times, have come together to
openly share findings and discuss potential therapies to combat the virus. This edition of
the Monograph is dedicated to the entire respiratory community, and serves as a testament
to their endeavours and sacrifices that have allowed us to acquire so much knowledge about
a new disease in such a short space of time.
References
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Perkins GD, Ji C, Connolly BA, et al. An adaptive randomized controlled trial of non-invasive respiratory strategies
in acute respiratory failure patients with COVID-19. medRxiv 2021; preprint [https://doi.org/10.1101/2021.08.02.
21261379].
7. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19.
N Engl J Med 2021; 384: 693–704.
8. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – final report. N Engl J Med
2020; 383: 1813–1826.
9. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-
controlled, multicentre trial. Lancet 2020; 395: 1569–1578.
10. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a
randomised, controlled, open-label, platform trial. Lancet 2021; 397: 1637–1645.
11. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill
patients with Covid-19. N Engl J Med 2021; 384: 1491–1502.
12. 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.
13. 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.
https://doi.org/10.1183/2312508X.10017521 vii
14. 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.
15. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic anticoagulation
with heparin in noncritically ill patients with Covid-19. N Engl J Med 2021; 385: 790–802.
16. Gramegna A, Mantero M, Amati F, et al. Post-COVID-19 sequelae. In: Fabre A, Hurst JR, Ramjug S, eds.
17. 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.
Disclosures: A. Fabre has nothing to declare. J.R. Hurst reports receiving the following, outside the submitted
work: support to attend meetings, and payment for educational and advisory work, both to him and his
employer (University College London, London, UK), from pharmaceutical companies that make medicines to
treat respiratory disease. S. Ramjug reports receiving the following, outside the submitted work: honoraria
from Janssen and Bayer.
viii https://doi.org/10.1183/2312508X.10017521
List of abbreviations
ACE angiotensin-converting enzyme

AGP aerosol-generating procedure
ARDS acute respiratory distress syndrome
CPAP continuous positive airway pressure
CRP C-reactive protein
CT computed tomography
DVT deep vein thrombosis
FIO2 fractional inspired oxygen
FVC forced vital capacity
HCoVs human coronaviruses
HFNC high-flow nasal cannula
ICU intensive care unit
IFN interferon
IL interleukin
LDH lactate dehydrogenase
LMWH low-molecular-weight heparin
MERS Middle East respiratory syndrome
MERS-CoV MERS coronavirus
NIV noninvasive ventilation
PPE personal protective equipment
PTSD post-traumatic stress disorder
RCT randomised controlled trial
SARS severe acute respiratory syndrome
SARS-CoV-1 SARS coronavirus
SARS-CoV-2 SARS coronavirus 2
SpO2 oxygen saturation
TNF tumour necrosis factor
WHO World Health Organization
| Chapter 1
Respiratory failure: a patient’s
perspective and clinical cases
Francesco Amati 1,2, Annalisa Vigni3,4, Sofia Misuraca3,4,
Francesco Bindo3,4, Andrea Gramegna3,4, Antonio Voza5,
Francesco Blasi 3,4 and Stefano Aliberti 1,2
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 [https://doi.org/10.1183/2312508X.10025320].
@ERSpublications
Up to 20% of COVID-19 patients develop acute respiratory failure and acute respiratory
distress syndrome with the need for oxygen therapy delivered through high-flow nasal
cannula, noninvasive ventilation or invasive mechanical ventilation https://bit.ly/3sYBXEZ
U p to 20% of COVID-19 patients develop acute respiratory failure (ARF) and ARDS
with the need for oxygen therapy delivered through HFNC, NIV and invasive
mechanical ventilation (IMV) [1–4]. Hospitals have had to reorganise their logistical
structures to optimise the care of COVID-19 patients and ensure infection control [5, 6].
The rapid spread of multidisciplinary units specifically dedicated to COVID-19 patients has
characterised the public health scenario worldwide [5]. COVID-19 patients may also be
affected by extrarespiratory involvement, including cardiac, renal, neurological and vascular
complications [7–14]. The extremely stressful experience of some patients with COVID-19
may also impact their mental status after discharge [15]. Psychological problems and
1
Dept of Biomedical Sciences, Humanitas University, Milan, Italy. 2IRCCS Humanitas Research Hospital, Milan, Italy. 3Dept of
Pathophysiology and Transplantation, University of Milan, Milan, Italy. 4Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy. 5Emergency Dept, Humanitas Clinical and Research Center, IRCCS,
Milan, Italy.
Correspondence: Stefano Aliberti (stefano.aliberti@hunimed.eu)
https://doi.org/10.1183/2312508X.10025320 1
ERS MONOGRAPH | COVID-19
mental health consequences that COVID-19 patients have could be due to different factors
including psychological stressors (e.g. social isolation), the psychological impact of a novel
and potentially fatal illness, concerns about infecting other people, stigma and, ultimately,
the immune response to the virus itself [16]. In this chapter, we report 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 ARF due to
COVID-19 will also be discussed.
Case 1: criteria and time to intubation and the role of prone

positioning in severe ARF due to COVID-19 pneumonia
A 60-year-old man was admitted to the emergency room because of fever and dyspnoea
for 1 week. His past medical history was unremarkable. A nasopharyngeal swab was
positive for SARS-CoV-2. The arterial blood gas (ABG) analysis showed acute
hypoxaemic respiratory failure ( pH 7.51, carbon dioxide tension (PCO2) 29 mmHg, oxygen
tension (PO2) 54 mmHg, bicarbonate (HCO− −1 −1
3 ) 23 mEq·L , lactate 1.1 mmol·L , in room
−1
air) and his respiratory rate was 22 breaths·min without the use of respiratory accessory
muscles. Blood tests revealed that his white blood cell (WBC) count, CRP and
procalcitonin were within the normal range. The CT findings were typical for COVID-19
pneumonia (figure 1). The patient was hospitalised in our high-dependency unit at the
Policlinico Hospital in Milan, Italy, and was initially treated with a Venturi mask with an
FIO2 of 0.50 with no improvement of either respiratory rate or gas exchange. He
subsequently underwent helmet CPAP treatment with a positive end-expiratory pressure
(PEEP) of 5 cmH2O and an FIO2 of 0.50. A lung recruitability test was performed to
optimise PEEP values [17]. The patient also underwent prone positioning (PP) during
helmet CPAP in order to improve oxygenation (table 1). Concomitant medications
included methylprednisolone (20 mg twice daily) and LMWH. The patient was evaluated
on a daily basis by a multidisciplinary team composed of pulmonologists, intensive care
physicians, infectious disease specialists and respiratory physiotherapists. After 10 days of
treatment with helmet CPAP, a new chest CT scan was ordered because of the absence of
clinical improvement and worsening of gas exchange. The CT scan showed subpleural
consolidations in the posterior lower lobes (figure 2, table 1). Helmet CPAP and PP were
both continued up to day 15 of hospitalisation when a gradual improvement of gas
exchange was documented. The patient was discharged after 30 days of hospitalisation
with no supplemental oxygen therapy.
Figure 1. Case 1: CT scan at emergency room admission. The scan revealed scattered parenchymal
thickening with a ground-glass appearance associated with thickening in the right lung parenchyma of the
pulmonary interstitium, in part confluent with each other.
2 https://doi.org/10.1183/2312508X.10025320
https://doi.org/10.1183/2312508X.10025320
Table 1. Arterial blood gas (ABG) analysis and respiratory rates (RR) before and after the prone positioning (PP) cycle
Day in FIO2, RR ABG pre-PP RR ABG post-PP

HDU % pre-PP, post-PP,
bpm bpm
pH PCO2, PO2, Lactate, PO2/FIO2, pH PCO2, PO2, Lactate, PO2/FIO2,
mmHg mmHg mmol·L−1 mmHg mmHg mmHg mmol·L−1 mmHg
4 50 24 7.47 39 136 1.0 272 20 7.51 34 200 0.9 400

5 50 25 7.50 35 115 1.1 230 18 7.48 35 183 1.0 366
PATIENT PERSPECTIVE AND CLINICAL CASES | F. AMATI ET AL.

6 50 22 7.51 37 90 1.2 180 16 7.49 36 150 1.0 300
7 50 24 7.47 36 68 1.4 136 17 7.48 38 145 1.2 290
8 50 26 7.48 35 80 1.1 160 20 7.50 37 203 0.8 406
9 50 25 7.46 34 95 1.5 190 18 7.47 36 187 1.3 374
10 50 24 7.45 37 100 1.3 200 19 7.52 37 204 0.9 408
11 50 22 7.48 40 94 1.6 188 16 7.51 41 230 1.2 460
12 50 25 7.46 38 80 1.8 160 20 7.46 41 189 1.6 378
13 50 26 7.51 37 69 1.4 138 18 7.50 38 193 1.0 386
14 50 23 7.47 41 91 0.9 182 20 7.46 40 180 0.9 360
15 45 25 7.46 38 112 0.6 248 21 7.44 40 178 0.6 396
16 45 26 7.45 38 103 0.8 228 20 7.45 37 150 0.7 333
17 40 26 7.50 41 98 1.3 245 19 7.51 40 130 1.0 325
18 40 25 7.48 39 111 0.9 277 16 7.50 41 137 0.8 343
19 40 23 7.45 40 100 1.0 250 16 7.46 39 129 0.8 323
20 40 20 7.47 41 110 0.9 275 18 7.48 41 142 1.0 355
The duration of each cycle was at least 4 h. HDU: high-dependency unit; bpm: breaths·min−1; PCO2: carbon dioxide tension; PO2: oxygen tension.
3
Figure 2. Case 1: CT scan after 10 days of treatment with helmet CPAP. The scan revealed extensive and
confluent subpleural parenchymal consolidations affecting the lower lobes. Some areas of “ground glass”
and “crazy paving” were evident in the right upper lobe and middle lobe. The middle lobe was characterised
by small parenchymal consolidation. Filling defects attributable to pulmonary thromboembolism were absent.
Patient’s perspective
At the beginning of my hospitalisation, I was angry. I have been always respectful of COVID-19 rules
and restrictions to avoid the risk of infection. I couldn’t understand how I could have contracted the
virus.
During hospitalisation, the state of my mind was dominated by fear because the prolonged stay in the
hospital kept me away from all the different commitments my life has. I live alone with no close
familiar member who could have helped me.
My feeling was also characterised by confidence. I was confident in the doctors, nurses, respiratory
physiotherapists and all medical staff. And my only thought was to cooperate with them to the best of
my ability.
At the beginning of the hospitalisation, I felt fine. I had just a few symptoms and sometimes some
shortness of breath. Wearing the helmet during CPAP treatment was a shock for me because I
couldn’t see my cell phone very well, the only tool I had to communicate with the world outside the
hospital. Furthermore, staying in a prone position was hard to tolerate, and I had to invent new forms
of distractions for as long as necessary. When the treatment with helmet CPAP was discontinued, I
had the feeling that I was doing fine. However, when I stood up, I noticed that I had very unstable
balance. After a few steps, I felt my legs were empty and my lungs heavy.
It was tough, but I was not alone. On the one hand, I socialised with other patients sharing the room
with me, and on the other hand, my family and friends were keeping me company through social
media. These helped me to move forward through the hospitalisation period.
Generally speaking, I am open to relationships and therefore I had a great time with all the staff, who
were always kind and professional with me. I used to travel a lot for work and I speak several
languages. As a matter of fact, I tried to share some of my travel memories with the staff.
What about the future? I’m not worried at all. I feel good and I’m very happy I went through COVID-19
with a reasonably good outcome, unlike many other patients.
Discussion
One of the main characteristics of COVID-19 pneumonia is dissociation between the severity
of the hypoxaemia and the relatively preserved respiratory mechanics [5]. Patients with severe
COVID-19 pneumonia tend to have hypoxaemic–hypocapnic respiratory failure with a highly
variable respiratory rate [18, 19]. Two distinct respiratory phenotypes have been suggested
based on different pathophysiology: the “non-ARDS” or type 1 phenotype, and the ARDS or
type 2 phenotype [20]. In type 1 patients, severe hypoxaemia is associated with high
respiratory system compliance, high tidal volume and lung recruitability that is preserved
with small efforts. In type 2 patients, severe hypoxaemia is associated with compliance values
<40 mL·cmH2O−1 and a reduction in lung recruitability; an increase in lung weight and
4 https://doi.org/10.1183/2312508X.10025320
oedema might also be present. In COVID-19 patients who are breathing spontaneously,
CPAP is a way of delivering PEEP. PEEP maintains the set pressure throughout the
respiratory cycle, during both inspiration and expiration, to constantly open the airways.
Thus, the application of CPAP in COVID-19 patients can reduce atelectasis, increases the
alveolus area, and improves ventilation/perfusion matching and oxygenation [21]. In these
patients, a cautious gradual increase of PEEP up to 14–15 cmH2O could be beneficial [20]. In
spontaneously breathing patients with an exorbitant respiratory drive that leads to increased
minute ventilation and/or high tidal volume, a goal of therapy should be to minimise the
so-called pulmonary self-inflicted lung injury. Endotracheal intubation (ETI) and a
lung-protective ventilatory strategy guided by lung injury severity may be the easiest and
most effective way to achieve this goal, while medications can treat the cause of respiratory
failure [22–24]. Unfortunately, no specific treatments for the different SARS-CoV-2
pathophysiologies exist, with the duration of the disease and length of hospitalisation being
longer in SARS-CoV-2 than in non-SARS-CoV-2 pneumonia [1, 25, 26]. Notably, both ETI
and IMV expose patients to several risks including ventilator-associated pneumonia, airway
injury, ventilator-associated lung injury and haemodynamic disturbances caused by
positive-pressure ventilation. Thus, the time to intubation can be prolonged and based on the
patient’s characteristics, as well as on available resources [27, 28]. The COVID-19 pandemic
caused a shortage of hospital and ICU beds, and even ventilators [29]. The identification of
specific criteria and the exact time for ETI are key challenges in patients with severe
COVID-19. One of the strategies used to gain time, improve gas exchange and avoid ETI in
some COVID-19 patients might be PP [30, 31]. PP may improve gas exchange through
different mechanisms, including recruitment and aeration of perfused and previously
degassed ventral lung regions, diversion of blood flow from gasless regions to aerated ones,
reduction of lung compression, improved secretion clearance and reduction of regional
transpulmonary force disparities [32, 33]. PP might provide a robust advantage in patients
with high lung compliance and should be considered in the early phase of the disease [33,
34]. The patient’s tolerance and comfort are crucial in PP. Although several studies have
shown benefits of PP in patients undergoing IMV, few are available in spontaneously
breathing, nonintubated patients [30, 33, 35–37]. Awake, early self-proning in the
subintensive wards has demonstrated improved SpO2 in COVID-19 patients [31, 37–39]. A
success of PP in COVID-19 patients undergoing helmet CPAP has recently been defined by
at least one of the following criteria: a decrease in the alveolar–arterial gradient of ⩾20%, an
equal or reduced respiratory rate, and equal or reduced dyspnoea [38]. An increase in
respiratory rate or in the alveolar–arterial gradient occurring during a PP session and
compared with the supine position led to its interruption [38]. According to these criteria,
only a small proportion of PP tests succeeded in COVID-19 patients undergoing helmet
CPAP [38]. These findings are in line with others with different experiences [37].
Furthermore, the beneficial improvement of gas exchange during PP vanishes after
resupination in half of patients [38]. Thus, it remains unclear whether pronation averts
intubation and accelerates recovery. RCTs are needed to evaluate the efficacy of PP on both
the need for intubation and the mortality rate in awake, spontaneously breathing,
nonintubated COVID-19 patients.
Case 2: pulse steroid treatment as rescue therapy to prevent

lung fibrosis
A 64-year-old man with no comorbidity and an active lifestyle was admitted to the
emergency room after a 10-day history of cough, fever and asthenia. Before hospital
https://doi.org/10.1183/2312508X.10025320 5
Figure 3. Case 2: CT scan after 10 days of hospitalisation. The parenchyma was strongly affected by
interstitial septal thickening and a micronodular pattern with diffuse ground-glass alteration. The scan
showed a minimal pneumomediastinal flap extending to the neck base with s.c. emphysema.
admission, he was treated with clarithromycin with no clinical improvement. He then

tested positive for SARS-CoV-2. His ABG showed a severe hypoxaemic respiratory failure
with a pH of 7.48, PCO2 of 37 mmHg, lactate level of 1.4 mmol·L−1 and a PO2/FIO2 ratio of
70. His blood samples showed an increase in both WBC count with leucocytosis and CRP.
A chest radiograph showed confluent parenchymal consolidations in the middle-inferior
area of both lungs. The patient was admitted to our high-dependency unit and treated with
helmet CPAP with a PEEP of 7.5 cmH2O and an FIO2 of 0.60. He was also treated with
methylprednisolone (40 mg twice daily). Five days after hospital admission, he underwent
ETI and IMV because of a rapid deterioration of gas exchange. After 2 days of intubation,
the patient’s condition improved and he was extubated. He continued supplemental oxygen
therapy through both HFNC with a flow of 40 L·min−1 and an FIO2 of 0.60, and helmet
CPAP with a PEEP of 7.5 cmH2O and an FIO2 of 0.60. After 10 days of treatment with no
further clinical improvement, a chest CT was performed showing signs of massive
interstitial involvement with no pulmonary embolism (figure 3). A second chest CT scan
was performed 15 days after treatment with methylprednisolone (40 mg twice daily) and
documented signs of severe interstitial pneumonia along with initial fibrotic signs
(figure 4). Blood tests at that point documented increasing levels of CRP, D-dimer, LDH
and ferritin with no microbiological and clinical evidence of either bacterial or fungal
infection. With this new information, a pulse methylprednisolone intravenous therapy
(10 mg·kg−1·day−1 i.v.; 750 mg for 3 days) was ordered. The patient’s lung gas exchange
gradually improved over a few days and he was then transferred to specialist rehabilitation
on low-flow oxygen therapy. Three months after being discharged from the pulmonary
rehabilitation, a third chest CT showed regression of the interstitial involvement of the
parenchyma (figure 5).
Figure 4. Case 2: CT scan after 25 days of hospitalisation. The scan showed reduction of the
pneumomediastinal flap and bilateral consolidations with several signs of fibrotic evolution, such as traction
bronchiectasis and parenchymal bands.
6 https://doi.org/10.1183/2312508X.10025320
Figure 5. Case 2: CT scan 3 months after discharge. The scan showed almost complete regression of the
fibrotic aspect of the parenchyma.
Discussion
Corticosteroids are, so far, the only treatment that has shown an improvement in overall
survival in patients with ARF due to COVID-19 pneumonia who do not require
mechanical ventilation or extracorporeal membrane oxygenation [40]. The RECOVERY
(Randomised evaluation of COVID-19 therapy) trial showed that dexamethasone can lower
28-day mortality among COVID-19 patients undergoing either IMV or oxygen therapy
alone [41]. However, different disease phenotypes should be considered to better shape a
personalised approach with corticosteroids for COVID-19 patients. Recent data stratify
patients’ risks by distinct immunophenotypes. DUPONT et al. [42] identified three
phenotypes bearing distinct immunological features that were associated with different
outcomes. The first cluster was a “humoral immunodeficiency” phenotype with predominant
B-lymphocyte defects, relative hypogammaglobulinaemia and moderate inflammation; the
second was a “hyperinflammatory” phenotype with high cytokine levels (IL-6, IL-1α, IL-8,
TNF-α) associated with CD4+ and CD8+ T-lymphocyte defects; and the third was a
“complement-dependent” phenotype with terminal complement activation markers
(elevated C3 and soluble C5b-9). The hyperinflammatory phenotype seems to be
characterised by a higher ICU mortality compared with the complement-dependent
phenotype. CHEN et al. [43] used an unsupervised machine-learning approach to identify
two different phenotypes of COVID-19 patients: the hyperinflammatory and the
hypoinflammatory phenotypes. The hyperinflammatory phenotype was characterised by
elevated levels of pro-inflammatory cytokines, a higher sequential organ failure assessment
score and higher rates of complications in comparison with the hypoinflammatory
phenotype. Corticosteroid therapy was associated with reduced 28-day mortality in patients
with a hyperinflammatory phenotype, regardless of the baseline SpO2/FIO2 ratio and the use
of IMV. Notably, 28-day mortality was reduced in patients with D-dimer >2.0 μg·mL−1 or a
neutrophil/lymphocyte ratio >6.9 [43]. From a pathophysiological point of view, the
hyperinflammatory phenotypes among COVID-19 patients could justify a corticosteroid-
based approach, even in the absence of ARF [44, 45]. Thus, the subgroup of patients with
markedly elevated levels of inflammatory markers could mostly benefit from corticosteroids.
Few data are currently available concerning possible sequelae of COVID-19 such as
long-term fibrotic complications [46–48]. Virus eradication per se does not preclude the
development of progressive and irreversible fibrotic changes in COVID-19 [47]. Pulmonary
fibrosis induced by SARS-CoV-2 infection seems to be induced by the combination of
direct damage by the virus along with an aberrant local immune response in a predisposed
patient [48]. Furthermore, even a relatively small degree of residual (although nonprogressive)
fibrosis could result in considerable morbidity and mortality in COVID-19 survivors, many
https://doi.org/10.1183/2312508X.10025320 7
of whom will have pre-existing pulmonary conditions. Other coronaviruses, namely SARS-
CoV-1 and MERS-CoV, are genetically similar to SARS-CoV-2 and cause pulmonary
syndromes (SARS and MERS, respectively) similar to COVID-19 [47]. A study enrolling 71
patients with SARS showed that interstitial abnormalities and functional decline recovered
over the first 2 years after infection and then remained stable. In this study, after 15 years
of follow-up, only 4.6% of the lungs showed interstitial abnormalities in patients who had
been infected with SARS-CoV-1 [49]. In a study of 36 patients who had recovered from
MERS, chest radiographs obtained after a median period of 43 days from hospital discharge
showed lung fibrosis in about one-third of the patients [50]. To date, there are very few
studies that have tried to identify predictors of pulmonary fibrosis as a complication of
COVID-19 by combining follow-up thin-section CT findings, clinical features and
biomarkers [51]. YU et al. [52] found interstitial thickening, an irregular interface, a coarse
reticular pattern and parenchymal bands manifested in the process of the disease as
predictors of pulmonary fibrosis. An irregular interface and parenchymal bands could
predict the early evolution of pulmonary fibrosis. A retrospective study conducted in
COVID-19 survivors found that patients with pulmonary fibrosis on follow-up CT scans
had higher levels of neutrophils, CRP and LDH, and a higher neutrophil/lymphocyte ratio,
compared with patients without pulmonary fibrosis at CT scan [53]. The peak LDH level
during acute illness was found to correlate significantly with the risk of pulmonary fibrosis
following both SARS-CoV-1 and MERS-CoV infection [50, 54]. Moreover, there are no
data concerning the treatment of patients with high-dose corticosteroids to prevent fibrotic
changes in this subgroup of patients. The choice to treat our patient with high-dose
corticosteroids was supported by different evidence including the lack of improvement after
weeks of treatment, the elevated inflammatory markers and the CT appearance, and the
absence of clinical and microbiological evidence of infection. This treatment is administered
in acute exacerbation of interstitial lung diseases (ILDs), such as acute exacerbation of
idiopathic pulmonary fibrosis, in pneumonia due to Mycoplasma pneumoniae or acute
exacerbation of connective tissue disease-associated ILDs, although conflicting results exist
in the literature [55–57]. Moreover, the hyperinflammatory phenotypes of COVID-19 could
justify our approach with high doses of corticosteroids [44]. Characterising COVID-19
patients in terms of clinical phenotypes or specific endotypes is crucial to design RCTs on
corticosteroid treatment and to explore other therapeutic strategies that can help in reducing
the risk of serious life-threatening COVID-19 sequelae such as pulmonary fibrosis.
Case 3: is pneumomediastinum in a COVID-19 patient treated with

helmet CPAP a marker of severe disease or an iatrogenic
complication?
A 53-year-old man without comorbidity presented to the emergency room for persistent
fever and progressive dyspnoea in the last week. He tested positive for SARS-CoV-2. His
ABG showed acute hypoxaemic–hypocapnic respiratory failure ( pH 7.46, PCO2 33 mmHg,
PO2/FIO2 ratio 110, HCO− −1 −1
3 25 mEq·L , lactate 1.2 mmol·L ). His blood tests on arrival
showed an increase in inflammatory biomarkers (WBC 18 300 cells·μL−1 and CRP
24 mg·dL−1). A chest radiograph showed bilateral interstitial pneumonia. Given the
patient’s clinical status and the positive test for SARS-CoV-2, he was hospitalised in a
high-dependency unit and was put on i.v. dexamethasone 6 mg daily, anticoagulant
prophylaxis, and helmet CPAP with a PEEP of 8 cmH2O and an FIO2 of 0.60. On day 5 of
treatment, he developed localised chest pain. He underwent a chest CT scan that showed
evidence of pneumomediastinum (PNM) and diffused s.c. emphysema extending to the
8 https://doi.org/10.1183/2312508X.10025320
Figure 6. Case 3: CT scan after 5 days of CPAP treatment. The scan showed pneumomediastinum and
diffused s.c. emphysema extending to the cervical region. The parenchyma was affected by diffused
alveolar–interstitial infiltrates with a crazy-paving pattern, involving all lobes.
cervical region (figure 6). Respiratory support with helmet CPAP was discontinued and
HFNC was started. The patient’s haemodynamics always remained stable, and both the
PNM and s.c. emphysema were monitored clinically and radiologically. Complete resolution
of the s.c. emphysema and improvement of the PNM were documented at a CT scan
performed after 7 days (figure 7). The patient was put on low-flow oxygen therapy and
transferred to the ward with no other complications.
Discussion
One of the main risk factors for PNM is the presence of pre-existing lung parenchymal and
airways diseases (in particular, asthma, emphysema and cystic diseases), along with
smoking status [58, 59]. Pneumothorax (PNX) is more frequent than PNM, and rarely both
complicate a viral lower respiratory tract infection [60]. When they occur in the context of
interstitial pneumonia, rupture of the alveolar wall due to an increased pressure gradient
between the alveoli and the lung interstitium seems to be the main aetiology [61, 62]. Air
accumulates in the interstitium, determines pulmonary interstitial emphysema and spreads
out to the mediastinum via perivascular and peribronchial fascial sheets as described by the
so-called Macklin effect [59]. In some cases, it can extend further to the pleura, s.c. tissue,
pericardium, peritoneal cavity and epidural space [59, 62]. Two different mechanisms
underlie the increased pressure gradient: the increase in intra-alveolar pressure, which can
be generated by coughing, sneezing and other situations associated with the Valsalva
manoeuvre, and/or the decrease in perialveolar interstitial pressure, observed during
extreme respiratory effort, marijuana smoking, diabetic ketosis or a rapid reduction in
atmospheric pressure. In the case of pneumonia due to influenza virus, the alveolar rupture
is caused by a sudden and repetitive increase in alveolar pressure through coughing [63–65].
Figure 7. Case 3: CT scan at day 15 after the complication. The scan showed complete regression of the s.c.
emphysema and almost complete regression of the pneumomediastinum.
https://doi.org/10.1183/2312508X.10025320 9
In the case of COVID-19 pneumonia, the virus itself seems to play a pathogenic role.
Members of the family Coronaviridae infect both type I and type II pneumocytes by
entering the target cells via the ACE2 receptor, and damage the alveolar membrane both
indirectly, impairing the lung compliance by compromising surfactant production, and
directly [65, 66]. This process eventually results in rupture of the alveolar membrane.
Consequently, when the alveolar damage is more severe and more extensive, the risk of
PNM/PNX increases [67]. With these premises, the occurrence of these complications
could represent a potential indicator of disease progression and poor prognosis. However,
this correlation is yet to be defined [68].
As SARS-CoV-2 damage of the lung parenchyma is often severe, either IMV or NIV are
frequently needed in the hospital setting to support respiratory failure. However, both IMV
and NIV (including CPAP) cause an increase in intra-alveolar pressure with the risk of
barotrauma. From the beginning of the COVID-19 outbreak, few cases of PNM/PNX
associated with COVID-19 pneumonia have been described, either spontaneous or
secondary to positive airway pressure during mechanical ventilation [69–72]. Most cases
have occurred during ETI. However, several cases have been also described during NIV [70,
71]. In some cases, PNM can be identified by a plain chest radiograph, although a CT scan
is the gold standard in small PNM/PNX or in case of complications [58, 61]. On a chest
CT scan, the Macklin effect usually appears as linear collections of air contiguous with the
bronchovascular sheaths [62]. Given the usually self-limiting nature of PNM, a close
follow-up with frequent chest radiographs is usually required. When PNM/PNX is
secondary to mechanical ventilation, ventilator strategies should be modified, lowering
positive pressures or switching treatment to oxygen therapy (e.g. HFNC). Indeed,
retrospective multicentre studies have showed that PNM does not seem to be an
independent marker of poor prognosis in COVID-19 patients, and continuation of active
treatment should be encouraged where clinically possible [72].
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of-novel-coronavirus-(2019-ncov) Date last accessed: 3 September 2021. Date last updated: 30 January 2020.
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70. Kolani S, Houari N, Haloua M, et al. Spontaneous pneumomediastinum occurring in the SARS-COV-2 infection.
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non-intubated patients with COVID-19. Clin Imaging 2020; 67: 207–213.
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Disclosures: None declared.
https://doi.org/10.1183/2312508X.10025320 13
| Chapter 2
Epidemiology: global spread, risk
factors for disease incidence,
severity and mortality
1,2,3
Joan B. Soriano and Alberto Infante4
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 [https://doi.org/10.1183/2312508X.10025420].
@ERSpublications
New evidence derived from epidemiology remains necessary to help end the COVID-19
pandemic https://bit.ly/3sYBXEZ
Background
The COVID-19 pandemic has literally changed our lives and those of our patients. The
first alert was received on 31 December 2019 in Wuhan, Hubei Province, China, due to a
cluster of 27 hospitalised patients with pneumonia of unknown aetiology [1]. Most initial
1
Servicio de Neumología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain. 2Centro de
Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 3COVID-19
Clinical Management Team, WHO Health Emergency Programme, World Health Organization HQ, Geneva, Switzerland. 4National
School of Public Health/Institute of Health Carlos III, Madrid, Spain.
Correspondence: Joan B. Soriano ( jbsoriano2@gmail.com)
14 https://doi.org/10.1183/2312508X.10025420
EPIDEMIOLOGY | J.B. SORIANO AND A. INFANTE
cases were epidemiologically linked to the Huanan Seafood Wholesale Market, a wet market
located in Wuhan, which sold seafood and live animals, including poultry and wildlife.
However, according to a retrospective study, the onset of the first known case dated back to 8
December 2019 [2]. Whatever the origin of the pandemic [3], it took 10 days (9 January
2020) for the Chinese Centre for Disease Control and Prevention to report that a novel
coronavirus, later called SARS-CoV-2, was the causative agent of that local outbreak [4].
SARS-CoV-2 belongs to the broad coronavirus family. It is a positive-sense single-stranded

RNA (+ssRNA) virus with a single linear RNA segment. Other coronaviruses cause
illnesses ranging from the common cold to MERS. SARS-CoV-2 is the seventh known
coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV and
SARS-CoV-1. Overall, SARS-CoV-2 has a proclivity for epithelial cells in general and the
respiratory system in particular.
Globally, as of 9 December 2021 (nearly 2 years after onset), there have been >266 million
confirmed cases of COVID-19 and 5.2 million deaths reported to WHO (figure 1) [5].
Nearly 4 billion vaccine doses, and counting, have been administered, though with uneven
distribution in low- and middle-income countries [6]. Questions are still being asked about
the origin of the virus, although both bats and pangolin are suspected. But the level of
disinformation has been unprecedented [7], and lessons from history are yet to be learnt, as
elegantly stated elsewhere [8].
The natural history of SARS-CoV-2
The natural history of SARS-CoV-2 and the time course of COVID-19 and its
determinants from infection to final outcome, are still being unravelled. One of the many
challenges when facing COVID-19 is the heterogeneity of its acute presentation and early
natural history of all severities, from utterly asymptomatic, to mild, moderate, severe and
critical COVID-19 in apparently similar types of patients. It is thought that the incubation
period is also highly variable: an infected person can transmit the virus to another person
up to 5 days before they themselves show symptoms, as can people who do not experience
symptoms. People remain infectious for up to 10 days after symptom onset in moderate
cases and up to 20 days in severe cases. These characteristics differentiate the transmissibility
Cases n
>5 000 000
500 001–5 000 000
50 001 –500 000
5001–50 000
1–5000
0
Not applicable
Figure 1. COVID-19 spread by country. Globally, as of 18:08 h CEST on 5 August 2021, the number of confirmed
cases of COVID-19 was 200 174 883, including 4 255 892 deaths reported to WHO. As of 5 August 2021, a total
of 3 984 596 440 vaccine doses had been administered. Reproduced and modified from [5] with permission.
https://doi.org/10.1183/2312508X.10025420 15
of SARS-CoV-2 from SARS-CoV-1 and seasonal flu (figure 2) [9], making COVID-19
much more difficult to control with universal hygiene interventions. To date, most natural
history information comes from hospitalised patients with COVID-19, and little is known
about those seen exclusively in primary care, underprivileged minorities, or those in low-
and middle-income countries, among other subgroups of interest. The natural history of
SARS-CoV-2 is likely to expand with forthcoming results from either animal models [10]
or human challenge studies [11].
Case definitions of COVID-19
Case definitions of COVID-19 surveillance – suspected, probable, confirmed [12] – need to

be followed up by the development of working case definitions – healing, re-infection and
post-COVID-19, among others (table 1).
The severity of COVID-19
Assessing the severity stages of COVID-19 has evolved since the onset of the outbreak, and a
number of societies and authors have proposed domains and thresholds that should be used
universally. Current staging is likely to be updated once more evidence appears (table 2).
Epidemiology estimators and determinants
There are many epidemiological estimators that are used to quantify the population burden
of COVID-19. A combination of three basic estimators has been used to alert the
population and promote public health interventions: cumulative incidence, PCR positivity
and the percentage use of ICU.
Cumulative incidence
The cumulative incidence in the last 14 days is calculated as the moving average number of
new cases of COVID-19 divided by the total number of individuals in the population at risk,
Peak before or within the first 5 days
Peak 1–2 days after onset Peak in second week
SARS-CoV-2
Seasonal influenza
SARS-CoV-1
–5 –4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Presymptomatic phase Time from symptom onset, days
Figure 2. Transmissibility of SARS-CoV-2 versus SARS-CoV-1 and seasonal flu. Transmissibility may vary in
SARS-CoV-2 variants. Data from [9].
16 https://doi.org/10.1183/2312508X.10025420
Table 1. Case definitions for COVID-19 surveillance
Domain Definition
WHO COVID-19 case Case definitions for COVID-19 surveillance for the categories of
definitions suspected, probable and confirmed can be found in figure 3 [12]
Healed/cured Not only a negative RT-PCR test or development of IgG, but a
recovery to full health as before acute COVID-19 infection
Re-infection Confirmed re-infection:
Samples available for both episodes allowing for genomic
sequencing, showing evidence of differing clades (as defined
by Nextstrain (https://nextstrain.org/) or GISAID
(https://www.gisaid.org/)) of SARS-CoV-2 between the
first and second infection, ideally coupled with other evidence
of actual infection (e.g. high viral titres in each sample or
positive for sgRNA, and culture)
Probable re-infection:
Positive PCR test for both episodes (Ct <33) or antigen-positive
tests with criteria for a COVID-19 confirmed case, with a
significant number of days (⩾90 days) between both suspected
episodes
Suspected re-infection:
If samples are available for both illness episodes, antibody testing:
A negative test at first infection and a positive test at the start of
the second episode
Antibody titre has risen between episodes or IgM may have
developed
Virus neutralisation titre increase between first and second
infection may also provide confirmation
If no samples are available for the two different illness episodes:
A positive PCR (Ct <33) and positive serology performed while
the suspected second infection is ongoing (e.g. symptomatic
or <14 days after initial PCR)
Ongoing symptomatic Signs and symptoms of COVID-19 at 4–12 weeks.
COVID-19
Post-COVID-19 To be developed using a formal Delphi methodology
Definitions of infection and timings for re-infection also need to achieve wider consensus. Ig:
immunoglobulin; Ct: cycle threshold.
expressed per 100 000 inhabitants in the previous 2 weeks. It has the advantage of smooth
shorter periods, as it includes weekends (when some health systems do not function or report
cases) and is considered a fine indicator for predicting risk trends in COVID-19.
PCR positivity
This is the percentage of all PCR tests conducted in a region/country that is positive.
The percentage use of ICU
This is the proportion of ICU beds occupied by COVID-19 patients. It is considered a

critical indicator when it exceeds 30%.
https://doi.org/10.1183/2312508X.10025420 17
18

Suspected case of SARS-CoV-2 infection Probable case of SARS-CoV-2 infection
A person who meets the clinical AND epidemiological criteria: A patient who meets the clinical criteria above AND is a contact of a probable or confirmed case, or
Clinical criteria: linked to a COVID-19 cluster+
• Acute onset of fever AND cough; OR A suspect case with chest imaging showing findings suggestive of COVID-19 disease§
• Acute onset of ANY THREE OR MORE of the following signs or A person with recent onset of anosmia (loss of smell) or ageusia (loss of taste) in the absence of any
symptoms: fever, cough, general weakness/fatigue#, headache, other identified cause
myalgia, sore throat, coryza, dyspnoea, anorexia/nausea/vomiting#, Death, not otherwise explained, in an adult with respiratory distress preceding death AND was a
diarrhoea, altered mental status. contact of a probable or confirmed case or linked to a COVID-19 cluster+
AND
Epidemiological criteria:
• Residing or working in an area with high risk of transmission of Confirmed case of SARS-CoV-2 infection
virus: closed residential settings, humanitarian settings such as
camp and camp-like settings for displaced persons; any time within
the 14 days prior to symptom onset; or
A person with a positive nucleic acid amplification test
• Residing or travel to an area with community transmission
any time within the 14 days prior to symptom onset; or A person with a positive SARS-CoV-2 antigen rapid diagnostic test AND meeting either the probable
• Working in any healthcare setting, including within health facilities case definition or suspect criteria A OR B
or within the community; any time within the 14 days prior to An asymptomatic person with a positive SARS-CoV-2 antigen rapid diagnostic test who is a contact
symptom onset. of a probable or confirmed case
A patient with severe acute respiratory illness: (SARI: acute

+ A group of symptomatic individuals linked by time, geographic location and common exposures, containing
respiratory infection with history of fever or measured fever of ≥38°C;
and cough; with onset within the last 10 days; and requires at least one nucleic acid amplification test-confirmed case or at least two epidemiologically linked,
hospitalisation). symptomatic (meeting clinical criteria of Suspect case definition A or B) persons with positive antigen
https://doi.org/10.1183/2312508X.10025420
rapid diagnostic tests (based on ≥97% specificity of test and desired >99.9% probability of at least one
Asymptomatic person not meeting epidemiological criteria with a
positive result being a true positive)
positive SARS-CoV-2 antigen rapid diagnostic test¶
§ Typical chest imaging findings suggestive of COVID-19 include the following:
Chest radiography: hazy opacities, often rounded in morphology, with peripheral and lower lung
# Signs separated with slash (/) are to be counted as one sign. distribution
¶ nucleic acid amplification test required for confirmation, see Diagnostic Chest CT: multiple bilateral ground-glass opacities, often rounded in morphology, with peripheral and
testing for SARS-CoV-2 [13] lower lung distribution
See Antigen detection in the diagnosis of SARS-CoV-2 infection using rapid Lung ultrasound: thickened pleural lines, B lines (multifocal, discrete or confluent), consolidative patterns
immunoassays [14] with or without air bronchograms
Note: Clinical and public health judgement should be used to determine the need for further investigation in patients who do not strictly meet the clinical or epidemiological criteria.
Surveillance case definitions should not be used as the sole basis for guiding clinical management.
Figure 3. WHO COVID-19 case definitions. Reproduced and modified from [12] with permission.
Table 2. Severity staging of COVID-19
Category Definition Clinical criteria
Asymptomatic No symptoms An individual with an ongoing (within 20 days

of diagnosis) SARS-CoV-2 infection but
without symptoms
Mild Minor symptoms A patient meeting the case definition for
COVID-19 with minor symptoms and no
limitations on daily function
Moderate Moderate symptoms (low risk of Moderate symptoms with some limitations on
poor outcome) daily function but no signs of severe
disease
Severe Hypoxia or vital organ Hypoxia. Any of the following:
dysfunction (high risk of poor SpO2 <90% on room air
outcome) Respiratory rate >30 breaths·min−1
Signs of severe respiratory distress
(accessory muscle use, inability to
complete full sentences)
OR: receiving <10 L·min−1 oxygen and
SpO2 ⩾90%
Vital organ dysfunction defined as any
severely deranged vital sign#
Critical Severe hypoxia or vital organ Severe hypoxia defined as either:
failure (very high risk of poor SpO2 <80% on room air; OR
outcome) SpO2 <90% on ⩾10 L·min−1 oxygen via
facemask (equivalent of SpO2/FIO2<180¶
or PaO2/ FIO2 <120 (note with or without
CPAP/PEEP)+
Vital organ failure defined as either of the
following:
Clinical judgement that advanced organ
support is the ideal therapy for the
patient (e.g. invasive ventilation or NIV,
vasopressors, dialysis, emergency
endoscopy, etc.), irrespective of
whether that is provided
Receiving invasive mechanical
ventilation§
PaO2: arterial oxygen tension; PEEP: positive end-expiratory pressure. #: Glasgow Coma Scale 3–8,
respiratory rate <8 or >30 breaths·min−1, SpO2 <90%, heart rate <40 or >130 beats·min−1 and systolic
blood pressure <90 mmHg, as used in [15]. ¶: a 10 L·min−1 face mask is the equivalent of FIO2 of
∼50%, according to [16] and the formula that FIO2 increases by 3% for every additional litre of oxygen
flow. +: an SpO2 of 90% corresponds to a PaO2 of 59 mmHg, according to [17]. §: a patient receiving
mechanical ventilation is regarded as critical due to very high risk of a poor outcome, even if their
underlying condition may not put them at a very high risk per se.
Some countries have used a traffic light system to graphically display risk. Unfortunately, it
seems lockdowns and de-escalation from different phases of lockdown using such
thresholds have failed and no consensus is yet available (table 3).
The basic reproductive number
The basic reproductive number (R0) of SARS-CoV-2, which measures the average number
of new cases generated per typical infectious case, was initially reported to be 1.2. However,
https://doi.org/10.1183/2312508X.10025420 19
Table 3. The traffic light system of population estimators for COVID-19 risk
Colour Thresholds
Red Regions with >50 new infections per 100 000 incidents and test positivity >4%; or
incidence is >150 per 100 000 in the past 14 days
Orange Regions reporting <50 new infections per 100 000 and test positivity >4%; or an
incidence of 25–150 and test positivity <4%
Green Regions reporting <25 new infections per 100 000 inhabitants and test positivity <4%
it is now thought to be much greater. A meta-analysis reported an average R0 of 2.87

(95% CI 2.39–3.44) [18]. The highest R0 reported was 14.8 during the Diamond Princess
Cruise Ship incident in Japan [19]. The R0 of the new variants of concern might even be
higher [20].
Other epidemiological determinants
Initial reports indicated that RNA traces could be identified in objects, on surfaces and
elsewhere [21], raising concerns that have caused havoc and created panic. Later reports
identified that the inoculum of the virus is higher than that received from physical contact
with objects, meaning both droplets and aerosols are now considered the main source [22].
Ongoing advice regarding hydrogel, shoe cleaning and salutations are now disproportionate
and mostly unnecessary, and should soon be reconsidered. In contrast, room ventilation
and outdoor activities are recommendations that are easy to implement to avoid airborne
transmission and contagion, and should be enforced.
Although the virus has been identified in many biological fluids, airborne transmission is
paramount. Yet investigations have identified SARS-CoV-2 in nearly all biological fluids,
meaning they are both a potential source of infection and can be used as clinical specimens
for diagnostics [23]. These fluids include: nasal mucus, sputum and saliva as major
components of the respiratory droplets by which the transmission of SARS-CoV-2
predominantly occurs; tears, ocular liquid and conjunctivitis; urine, faeces and the
wastewater system; blood, breast milk and semen.
For any new disease, collecting new data in a harmonised way is key to establishing
guidance for treatment, management and prevention. Based on tools created by the
International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and
others, WHO proposed a case report form designed to report standardised clinical data
from individuals after hospital discharge or after the acute illness to examine determinants
during the acute infection of any medium- and long-term consequences of COVID-19
(figure 4) [25]. The forms are available in multiple languages. Initiatives to collect and pool
diverse sets of data from many sources while fulfilling all safety and data protection
standards are under way [26].
It is important to consider terminology and coding, as there are already

WHO-recommended ICD-10 (International Statistical Classification of Diseases and
Related Health Problems, version 10) and ICD-11 codes referring to all aspects of
COVID-19 (figure 5) [25]. The following codes are of note: U08 Personal history of
20 https://doi.org/10.1183/2312508X.10025420
MODULE 1. Complete on hospital admission (within 24 hrs from hospital admission)

Facility name Country
Date of enrolment [_D_][_D_]/[_M_][_M_]/[_2_][_0_][_Y_][_Y_]

1a. CLINICAL INCLUSION CRITERIA
One or more | A history of self-UHSRUWHGIHYHULVKQHVVRUPHDVXUHGIHYHURI 38ºC տYes տNo
of these | Cough տYes տNo
during this | Dyspnoea (shortness of breath) OR Tachypnoea* տYes տNo
illness | Clinical suspicion despite not meeting criteria above տYes տNo
5HVSLUDWRU\UDWHEUHDWKVPLQIRU\HDUIRU–\HDUVIRU–\HDUVIRU years
1b. DEMOGRAPHICS
Sex at birth տMale տFemale տNot specified Date of birth [_D_][_D_]/[_M_][_M_]/[_Y_][_Y_][_Y_][_Y_]
If date of birth is unknown, record: Age [ ][ ][ ] years OR [_ ][ _] months OR [_ ][ _] days
Health care worker? տYes տNo տUnknown Laboratory worker? տYes տNo տUnknown
Pregnant?* տYes տNo տUnknown տN/A If yes: Gestational weeks assessment [___][ _] weeks
If currently pregnant or recently pregnant (delivery within 21 days of symptom onset), complete Pregnancy CRF
1c. DATE OF ONSET AND ADMISSION VITAL SIGNS ILUVW DYDLODEOH data at SUHVHQWDWLRQDGPLVVLRQ
Symptom onset (date of first/earliest symptom) [_D_][_D_]/[_M_][_M_]/[_2_][_0_][_Y_][_Y_]
Admission date at this facility [_D_][_D_]/[_M_][_M_]/[_2_][_0_][_Y_][_Y_]
Temperature [_ ][ ].[_ ]°C Heart rate [___][___][_ ]beats/min
Respiratory rate [_ ][___]breaths/min
BP [_ ] [_ ] [_ ](systolic) [___][_ ][_ ](diastolic) mmHg Severe dehydration տYes տNo տUnknown
Sternal capillary refill time > 2 seconds տYes տNo տUnknown
Oxygen saturation: [__][ ][__]% on տRoom air տOxygen therapy տUnknown A V P U (circle one)
Glasgow Coma Score (GCS/15) [_ ][_ ] Malnutrition տYes տNo տUnknown
Mid-upper arm circumference [_ ][_ ][___]mm Height [___] [___] [___]cm Weight [_ ][_ ][___]kg
1d. CO-MORBIDITIES H[LVWLQJat DGPLVVLRQ8QN 8QNQRZQ

Chronic cardiac disease տYes տNo տUnk Diabetes տYes տNo տUnk
QRW K\SHUWHQVLRQ
Hypertension տYes տ No տUnk Current smoking տYes տNo տUnk
Chronic pulmonary disease տYes տ No տUnk Tuberculosis (active) տYes տNo տUnk
Asthma տYes տ No տUnk Tuberculosis (previous) տYes տNo տUnk
Chronic kidney disease տYes տ No տUnk Asplenia տYes տNo տUnk
Chronic liver disease տYes տ No տUnk Malignant neoplasm տYes տNo տUnk
Chronic neurological disorder տYes տ No տUnk Other տYes տNo տUnk
If yes, specify: _______________
HIV տYes (on ART) տ<HVQRWRQ$57տ1Rտ8QNQRZQ$57UHJLPHQBBBBBB
1e. PRE-ADMISSION AND CHRONIC MEDICATION Were any of the following taken within 14 days of admission
Angiotensin converting enzyme inhibitors (ACE inhibitors)? տYes տNo տUnknown
Angiotensin II receptor blockers (ARBs)? տYes տNo տUnknown
Non-steroidal anti-inflammatory (NSAID)? տYes տNo տUnknown
Antiviral? տChloroquine/hydroxychloroquine տAzithromycin տLopinavir/Ritonavir տOther:
Figure 4. WHO COVID-19 case report form (CRF). BP: blood pressure; ART: antiretroviral therapy.
Reproduced and modified from [24] with permission.
COVID-19 and optional code U08.9 Personal history of COVID-19, unspecified, to record
an earlier episode of COVID-19, confirmed or probable, that influences the person’s health
status, where the person no longer suffers from COVID-19; U09 Post-COVID-19
condition; and U10 Multisystem inflammatory syndrome associated with COVID-19 or
U10.9 Multisystem inflammatory syndrome associated with COVID-19, unspecified,
temporally associated with COVID-19 – cytokine storm, Kawasaki-like syndrome,
https://doi.org/10.1183/2312508X.10025420 21
ICD-10 ICD-11
COVID-19 virus
U07.2 Need for immunisation
not identified U11
against COVID-19
RA01.1 QC01.9
+vaccine code
ICD codes for

U07.2
COVID-19 virus COVID-19 Adverse reaction to a
U12
not identified COVID-19 vaccine
Adverse reaction/PL00
RA01.1
+vaccine code
U10 Multisystem
inflammatory Post-COVID-19
U09 + specific condition
syndrome condition
associated Personal history
U08 QC42.0
RA03 with COVID-19 of COVID-19
RA02 + specific condition
Figure 5. WHO Emergency use ICD (International Statistical Classification of Diseases and Related Health
Problems) codes for COVID-19 disease outbreak. Reproduced and modified from [25] with permission.
paediatric inflammatory multisystem syndrome, multisystem inflammatory syndrome in

children, excluding mucocutaneous lymph node syndrome (Kawasaki) (M30.3).
Risk factors and protective factors
The identification of risk factors linked with COVID-19 infection, severity and mortality
has evolved since disease onset, and several lists are available. A summary is presented in
tables 4 and 5. In all likelihood, this list is neither exhaustive nor independent, as several
factors either interact synergistically or affect modifiers in different time windows, making
Table 4. Sociodemographic characteristics associated with COVID-19 incidence, severity

and mortality
Advanced age
Male sex
Comorbidities
Heart conditions (hypertension and cardiovascular disease)
Chronic neurological disorders (stroke)
Chronic respiratory diseases (COPD)
Diabetes
Chronic kidney disease
Some conditions causing patients to be immunocompromised (cancer,
transplanted, HIV, AIDS)
Smoking
Obesity
Ethnic origin
African-American and Latin-American in the US
Blood type
Type A increases risk
All these risk and protective factors interact in the three levels of prevention of COVID-19.
22 https://doi.org/10.1183/2312508X.10025420
Table 5. Lab findings associated with COVID-19 incidence, severity and mortality
Product line Parameter Lab abnormalities
Haemostasis D-dimer ↑
Prothrombin time ↑
Haematology White blood cell count ↑
Neutrophil count ↑
Lymphocyte count ↓
Clinical chemistry CRP ↑
Albumin ↓
LDH ↑
Alanine aminotransferase ↑
Aspartate aminotransferase ↑
Total bilirubin ↑
Creatinine ↑
Cardiac Cardiac troponin ↑
Inflammation Procalcitonin ↑
All these risk and protective factors interact in the three levels of prevention of COVID-19.
their effect and magnitude variable in similar individuals at different times within the
clinical course of COVID-19. Similarly, protective factors, or determinants associated with
reduced risk of COVID-19 infection, severity and mortality, are an unchartered territory
beyond universal hygiene measurements.
Primary prevention of COVID-19
Primary prevention refers to universal hygiene measurements to reduce the transmission of

SARS-CoV-2. They include the following.
1) Face masks. Masks and other protective devices protect the wearer from infection and
others from being infected when they are properly worn. There should be no exemptions in
respiratory or psychiatric patients [27, 28].
2) Handwashing and hand hygiene. Hands must be washed regularly with soap and water,
or cleaned with alcohol-based hand rub. People should avoid touching their face, and
should cover their mouth and nose when coughing or sneezing.
3) Social distancing. A distance of ⩾1 m should be maintained between people indoors, in

poorly ventilated places. People coughing, sneezing, singing, etc. should be avoided.
Physical distancing should be practiced by avoiding unnecessary travel and staying away
from large groups.
4) Common sense. People should stay at home if they feel unwell, and refrain from
smoking and other activities that weaken the lungs.
Some of these primary preventive strategies have been publicly questioned and challenged
by population groups and political leaders, particularly the use of face masks and social
distancing [29]. At the same time, technical organisations such as WHO and the European
https://doi.org/10.1183/2312508X.10025420 23
Centre for Disease Prevention and Control (ECDC) have been modifying their criteria as
the pandemic progresses. Two examples are recommendations for the use of face masks
and the causative role of airborne transmission [30, 31].
Secondary prevention of COVID-19
Secondary prevention refers to screening and case finding. As previously discussed, the
intrinsic characteristics of SARS-CoV-2 require active screening strategies in community
settings where there is broad transmission, as well as case finding of contacts of newly
infected individuals, whether they are relatives or close contacts through work, leisure or
travel. Different tests have been developed for screening and clinical purposes [32].
Seroprevalence studies, particularly when serially conducted in defined populations and
settings [33], are fundamental to determining herd immunity achieved via natural infection
or vaccination.
Tertiary prevention of COVID-19
Finally, tertiary prevention refers to any action in COVID-19 patients that aims to reduce
their severity and eventual adverse outcomes, up to death. Earlier identification and
commencement of preventative treatment reduces the use of health services and mortality
in those at risk. It is premature to identify determinants and modifiers of post-COVID-19
condition, referred next. Vaccinations, initially approved with 50% efficacy, are good news,
and there is a growing list of vaccines in the portfolio that have excellent efficacy and
effectiveness and are mostly safe, although pharmacovigilance reports have identified rare
events that require close monitoring. No doubt the implementation of these vaccines will
help to set a level of herd immunity.
Post-COVID-19 condition
Among the many unresolved issues surrounding COVID-19, the sequelae and long-term
medical consequences of survivors of acute SARS-CoV-2 infection are being unravelled [34],
Clade
20H (Beta, V2) 21H (Mu)
20I (Alpha, V1) 21K (Omicron)
20J (Gamma, V3) 19A
21A (Delta) 19B
21I (Delta) 20A
21J (Delta) 20C
21B (Kappa) 20G
21C (Epsilon) 20B
21D (Eta) 20D
21F (Iota) 20F
21G (Lambda) 20E (EU1)
21J (Delta)
21A (Delta)
21B (Kappa) 21I (Delta)
20E (EU1) 21D (Eta)
20F
20J (Gamma, V3)
21G (Lambda) 21K (Omicron)
20D 20I (Alpha, V1)

20A 20B
20H (Beta, V2) 21C (Epsilon)
20G 21F (Iota)
20C 21H (Mu)
19B
2020-Feb 2020-Apr 2020-Jun 2020-Aug 2020-Oct 2020-Dec 2021-Feb 2021-Apr 2021-Jun 2021-Aug 2021-Oct 2021-D
Date
Figure 6. Genomic epidemiology of novel coronavirus: global subsampling. Showing 3643 of 3643 genomes
sampled between December 2019 and December 2021. Reproduced and modified from [45] with permission.
24 https://doi.org/10.1183/2312508X.10025420
and emerging evidence warns of the concerning long-term effects of SARS-CoV-2 [35].
Further evidence and the consensus of WHO [36], the ECDC [37], the European
Respiratory Society (ERS) [38], and others, is required to inform terminology use, the
definition of post-COVID-19 condition, how long patients should be tracked, and which
tests should be used to assess it. SARS-CoV-2 is not the first virus to cause long-lasting
symptoms or newly associated syndromes. Previous viral outbreaks, such as Zika,
Chikungunya, SARS and MERS – and before those, the 1918 flu (misnamed Spanish flu) –
left many people weakened for months, sometimes years [39].
There is as yet no consensus on terminology for this condition, with authors using
different terms, such as chronic COVID-19 syndrome, late sequelae of COVID-19, long
COVID, long haul COVID, post-COVID syndrome, post-acute COVID-19 and post-acute
sequelae of SARS-CoV-2 infection, among others. However, a definition by WHO, using a
modified Delphi method, has been just released: “post-COVID-19 condition occurs in
individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3
months from the onset, with symptoms that last for at least 2 months and cannot be
explained by an alternative diagnosis. Common symptoms include, but are not limited to,
fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on
everyday functioning. Symptoms might be new onset following initial recovery from an
acute COVID-19 episode or persist from the initial illness. Symptoms might also fluctuate
or relapse over time. A separate definition might be applicable for children” [40].
Post-COVID sequelae are discussed further elsewhere in this Monograph [41].
Projections and variants
There are several initiatives that project epidemiological estimators for weeks and even
months with remarkable accuracy [42, 43]. They all appear to produce a bleak scenario; an
endgame in which COVID-19 goes from pandemic to endemic appears likely [44]. Close
monitoring of population trends, particularly of any new variants of concern (figure 6),
and reinforced efforts and resources are an asset to identifying the individual and
population modulators of COVID-19 [45, 46]. Major COVID-19 research advances are
needed to provide useful information for global pandemic control [47–49]. New research
must include not only “classical” biological and epidemiological dimensions, but also focus
on economic, social and political domains [50], particularly where they hamper population
interventions and people’s confidence to comply with public health recommendations [51].
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https://doi.org/10.1183/2312508X.10025420 27
| Chapter 3
Historical perspective: other
human coronavirus infectious
diseases, SARS and MERS
David S. Hui1,2 and Alimuddin Zumla3,4
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 [https://doi.org/10.1183/2312508X.10025620].
@ERSpublications
Alpha- and betacoronaviruses are common causes of human upper respiratory tract
infection. SARS-CoV-1 and MERS-CoV emerged in 2002 and 2012, respectively, and can
cause severe disease. MERS remains a threat to global health security. https://bit.ly/
3sYBXEZ
H istorically, coronaviruses have been well known to veterinarians, as they can cause a
wide range of diseases of the respiratory, gastrointestinal and central nervous systems
in a large number of animal host species. Coronaviruses were initially reported as causative
pathogens in humans in the 1960s, causing predominately upper respiratory tract
infections, particularly in children and the elderly. The potential of coronaviruses to cause
deadly outbreaks in humans has only come to the fore in the last 20 years. Since the end of
1
Dept of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. 2Stanley Ho Center
for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. 3Dept of Infection,
Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, UK. 4National Institute for
Health Research Biomedical Research Centre, University College London Hospitals, London, UK.
Correspondence: David S. Hui (dschui@cuhk.edu.hk)
28 https://doi.org/10.1183/2312508X.10025620
HISTORICAL PERSPECTIVE | D.S. HUI AND A. ZUMLA
2002, three novel zoonotic coronaviruses have emerged and crossed the species barrier,
resulting in lethal disease in humans: SARS-CoV-1, which emerged in Guangdong, China,
in November 2002, leading to the SARS epidemic in 2003, and vanished by 2004;
MERS-CoV causing MERS, which was first identified in Jeddah, Saudi Arabia, in
September 2012 and has continued to cause sporadic and localised outbreaks; and
SARS-CoV-2, the aetiology of the ongoing global COVID-19 pandemic [1]. In this chapter,
SARS and MERS are reviewed from a historical perspective, focusing on the important
timeline events and disease transmission.
Classification and phylogenetics
Coronaviruses (order Nidovirales, family Coronaviridae, subfamily Coronavirinae) are a group

of enveloped, single-stranded, positive-sense, highly diverse RNA viruses that can cause
respiratory disease with involvement of other organ systems of varying severity in many
animal species, including humans. The subfamily Coronavirinae is classified into four genera:
Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus [2]. Previously,
the genus Betacoronavirus was subdivided into lineages A, B, C and D. Recently, these
lineages have been classified into subgenera of Betacoronavirus as Embecovirus (lineage A),
Sarbecovirus (lineage B), Merbecovirus (lineage C) and Nobecovirus (lineage D).
The main coronaviruses causing respiratory tract infection in humans well before the onset
of the SARS epidemic in 2003 were two alphacoronaviruses (HCoV-229E and
HCoV-NL63) and two betacoronaviruses (HCoV-OC43 and HCoV-HKU1, which was
discovered in January 2004). A novel group 2b betacoronavirus (SARS-CoV-1) was
discovered in March 2003 as the causative agent responsible for SARS [3]. SARS-CoV-1,
SARS-CoV-2 and MERS-CoV are betacoronaviruses. SARS-CoV-1 and SARS-CoV-2
belong to lineage B, while MERS-CoV belongs to lineage C [4].
SARS
Epidemiology
SARS-CoV-1 first emerged as a human pathogen in Guangdong in the southern part of

China in November 2002 before spreading to Singapore, Canada, Vietnam and other
countries via international travellers through Hong Kong in February and March 2003 [5, 6].
There was an unusual outbreak of “atypical pneumonia” in at least five municipalities
including Foshan in Guangdong Province in China in November 2002, with a significant
component of nosocomial transmission to healthcare workers (HCWs), who accounted for
24% of cases [7, 8]. Using serological tests, virus isolation and molecular assays in a
retrospective analysis, the nasopharyngeal aspirates of 55 patients with “atypical
pneumonia” hospitalised in Guangzhou between January and February 2003 were found to
be positive for SARS-CoV-1, while 48 of the patients (87%) had SARS-CoV-1-positive
antibody in their convalescent sera. Genetic analysis of the SARS-CoV-1 isolates from the
patients in Guangzhou showed the same origin as those from other countries, with a
phylogenetic pathway matching the spread of SARS-CoV-1 to other parts of the world [9].
In March 2003, a novel coronavirus was confirmed as the causative agent of SARS, and is
now referred to as SARS-CoV-1. A retrospective serological study suggested that
https://doi.org/10.1183/2312508X.10025620 29
cross-species transmission of SARS-CoV-1 or its variants from animal species to humans

may have occurred frequently in the wet market, as a high seroprevalence (16.7%) was
found among asymptomatic animal handlers [10]. Masked palm civets were initially
thought to have accounted for transmission of SARS-CoV-1 to humans after the detection
of a close variant of SARS-CoV-1 in palm civets in Dongmen Market, Shenzhen, in 2003
[11]. It was also shown that three out of the four patients had had direct or indirect contact
with palm civets during the small-scale SARS outbreaks that occurred in China in late 2003
and early 2004 [12, 13]. However, analysis of viral genomic sequences showed that the
SARS-CoV-like virus had not been circulating among masked civets in markets for that
length of time. Coronaviruses with high similarity to SARS-CoV-1 were later isolated in
horseshoe bats in 2005 [14, 15] and were found to share 88–92% sequence identity with
human or civet isolates, suggesting that bats could well be a natural reservoir of a close
ancestor of SARS-CoV-1 [16].
A 64-year-old nephrologist who had travelled from southern China to Hong Kong for his
nephew’s wedding reception on 21 February 2003 was the index patient causing subsequent
major outbreaks of SARS in Hong Kong, Singapore, Vietnam and Canada (table 1) [5, 6,
17–19]. He infected 16 hotel guests and visitors who were staying or visiting friends on the
ninth floor of the Metropole Hotel, where the physician had stayed briefly. These visitors
spread the infection to 29 countries/regions via international air travel, resulting in 8098
cases in total with a case fatality rate of 774 (9.6%) by the end of the epidemic in July 2003 [20].
Transmission
SARS-CoV-1 appears to have spread by person-to-person close contact by respiratory

droplet transmission or by contact with fomites [21]. Such superspreading events were a
hallmark of SARS, such as the major nosocomial outbreak at the Prince of Wales Hospital,
a major teaching hospital in Hong Kong, where 138 subjects (many of whom were
previously healthy HCWs) were infected within 14 days of exposure to a patient (who was
visiting the Metropole Hotel), who was hospitalised with “community-acquired
pneumonia” on a general medical ward without negative-pressure isolation facilities [5, 22].
This superspreading event was probably caused by multiple risk factors including
overcrowding, poor ventilation in the hospital ward and the use of a jet nebuliser for
delivering salbutamol to the index case [5, 22]. Using computational fluid dynamics
modelling analysis of the normalised concentration of virus-laden aerosols at different
locations of the ward, the temporal–spatial spread of SARS among inpatients in the index
medical ward of the hospital in Hong Kong was consistent with airborne transmission [23].
In addition, SARS-CoV-1 may have spread by opportunistic airborne transmission in a

major community outbreak in a private residential complex, Amoy Gardens in Hong Kong,
involving over 300 residents [24, 25]. It is possible that drying up of the U-shaped
bathroom floor drains together with backflow of contaminated sewage (from a SARS
patient with end-stage renal failure and diarrhoea) linked with negative pressure generated
by the toilet exhaust fans in these high-rise apartments created infectious aerosols that were
able to move upwards through the warm airshaft of the building. After analysis of the
distribution of all confirmed cases, it was thought that airborne spread was the most likely
explanation in the Amoy Gardens outbreak, and that SARS-CoV-1 could also have spread
over a distance of 200 m to nearby residential complexes [26]. An environmental study of
air samples from a hospital room occupied by a patient with SARS and swab samples taken
from frequently touched surfaces in rooms and in the nurses’ station in Toronto were
30 https://doi.org/10.1183/2312508X.10025620
Table 1. Timeline of the spread of SARS from mainland China to Canada, Vietnam and
Singapore via Hong Kong
16 November 2002 First known case of atypical pneumonia in Foshan City, Guangdong Province,
China, but aetiology not identified until much later.
11 February 2003 The WHO received reports from the Chinese Ministry of Health of an
outbreak of acute respiratory syndrome with 300 cases and five deaths in
Guangdong Province.
21 February 2003 A 64-year-old medical doctor from Zhongshan University in Guangzhou
(Guangdong Province) arrived in Hong Kong to attend a wedding and
checked into the ninth floor of the Metropole Hotel (room 911).
22 February 2003 The Guangdong doctor was admitted to the ICU at Kwong Wah Hospital in
Hong Kong with respiratory failure (he had previously treated patients with
atypical pneumonia in Guangdong). He warned medical staff that he might
have contracted a “very virulent disease” with onset of symptoms on 15
February 2003.
26 February 2003 A 48-year-old Chinese–American businessman was admitted to the French
Hospital in Hanoi (Vietnam) with a 3-day history of fever and respiratory
symptoms. He travelled to Hong Kong on 17 February, departed for Hanoi
on 23 February and fell ill there. Shortly before his departure from Hong
Kong, he had stayed on the ninth floor of the Metropole Hotel in a room
across the hall from the Guangdong doctor.
1 March 2003 A 26-year-old woman was admitted to a hospital in Singapore with
respiratory symptoms. A resident of Singapore, she was a guest on the
ninth floor of the Metropole Hotel in Hong Kong from 21 to 25 February.
4 March 2003 The Guangdong doctor died of atypical pneumonia at Kwong Wah Hospital.
5 March 2003 In Hanoi, the Chinese–American businessman, in a stable but critical
condition, was evacuated by air to the Princess Margaret Hospital in Hong
Kong. Seven healthcare workers who had cared for him in Hanoi became ill.
A 78-year-old woman from Toronto (Canada), who had checked out of the
Metropole Hotel in Hong Kong on 23 February, died at Toronto’s Scarborough
Grace Hospital. Five members of her family were found to be infected and
admitted to the hospital.
7 March 2003 Healthcare workers at Hong Kong’s Prince of Wales Hospital started to
complain of respiratory tract infection, progressing to pneumonia. All had
an identifiable link with Ward 8A.
12 March 2003 The WHO issued a global alert about cases of severe atypical pneumonia
following mounting reports of spread among staff at hospitals in Hong
Kong and Hanoi.
At the French Hospital in Hanoi, 26 staff had symptoms. Of these, 25 had
either pneumonia or acute respiratory syndrome, and five were in a
critical condition. The hospital was closed to new admissions.
Hong Kong health authorities formally reported an outbreak of unidentified
flu-like illness among hospital staff at the Prince of Wales Hospital. As of
midnight on 11 March, 50 healthcare workers had been screened; 23 were
found to have febrile illness and eight showed early chest radiograph
signs of pneumonia. A 26-year-old man, who had visited an acquaintance
staying on the ninth floor of the Metropole Hotel from 15 to 23 February,
was the source of this hospital outbreak following subsequent
epidemiological investigation.
13 March 2003 The Ministry of Health in Singapore reported three cases of atypical pneumonia in
young women who had recently returned to Singapore after travelling to Hong
Kong. All had stayed on the ninth floor of the Metropole Hotel in late February.
15 March 2003 The WHO issued a travel advisory as evidence mounted that SARS was spreading
by air travel along international routes. The WHO named the mysterious
illness SARS after its symptoms, and declared it “a worldwide health threat”.
https://doi.org/10.1183/2312508X.10025620 31
Table 2. Independent factors associated with increased risk of superspreading events of SARS
in the healthcare setting#
Risk factor OR (95% CI) p-value
Performance of resuscitation 3.81 (1.04–13.87) 0.04

Staff working while experiencing symptoms 10.55 (2.28–48.87) 0.003
SARS patients requiring oxygen therapy of ⩾6 L·min−1 4.30 (1.00–18.43) 0.05
SARS patients requiring positive-pressure NIV 11.82 (1.97–70.80) 0.007
Minimum distance between beds of <1 m 6.94 (1.68–28.75) 0.008
Washing or changing facilities for staff 0.12 (0.02–0.97) 0.05
#
: a superspreading event was defined as one patient who could infect at least three others.
found to be positive for the virus by PCR testing [27]. Taken together, these data suggested
the possibility of airborne transmission and highlighted the importance of appropriate
respiratory protection, as well as implementing strict surface hygiene practices.
Asymptomatic transmission
Asymptomatic SARS-CoV-1 infection was rather uncommon, as a meta-analysis has shown
overall seroprevalence rates of 0.1% for the general population and 0.23% for HCWs,
although the true incidence of asymptomatic infection remains unknown [28].
Nosocomial transmission
A case–control study involving 124 medical wards in 26 hospitals in Guangzhou and Hong
Kong identified six independent factors for superspreading nosocomial outbreaks of SARS:
performance of resuscitation, a minimum distance between beds of <1 m, SARS patients
requiring oxygen therapy or NIV, and staff working while experiencing symptoms all
caused spread of the virus, while the availability of washing or changing facilities for staff
was found to be a protective factor (table 2) [29]. A systematic review highlighted four
AGPs that increased the risk of nosocomial SARS-CoV-1 transmission to HCWs: tracheal
intubation, manual ventilation before intubation, NIV and tracheotomy (table 3) [30].
Thus, before carrying out AGPs, it is important for HCWs to implement appropriate
airborne precaution measures.
Table 3. Respiratory procedures reported to present an increased risk of transmission of SARS

to healthcare workers
Procedures Studies OR (95% CI)
Tracheal intubation 4 cohort studies Pooled OR 6.6 (2.3–18.9)

4 case–control studies Pooled OR 6.6 (4.1–10.6)
NIV 2 cohort studies Pooled OR 3.1 (1.4–6.8)
Tracheotomy 1 case–control study OR 4.2 (1.5–11.5)
Manual ventilation before intubation 1 cohort study OR 2.8 (1.3–6.4)
32 https://doi.org/10.1183/2312508X.10025620
MERS
Epidemiology
MERS-CoV was first identified in September 2012 with the isolation of a novel betacoronavirus
from a 60-year-old male patient who had died in June 2012 of acute severe pneumonia and
renal failure in Jeddah, Saudi Arabia [31]. MERS-CoV infection has since spread to 27
countries. Globally, between September 2012 and July 2021, the WHO was informed of 2576
laboratory-confirmed cases of MERS, with at least 927 deaths [32]. Countries that have
reported human MERS cases are: Jordan, Saudi Arabia, Qatar, United Arab Emirates, Oman,
Kuwait, Yemen, the UK, France, Germany, Italy, Tunisia, Malaysia, the Philippines, USA,
Egypt, Lebanon, the Netherlands, Iran, Algeria, Turkey, Austria, Greece, Republic of Korea,
China, Thailand and the Kingdom of Bahrain. The timelines of first human case detection and
the latest reported cases globally for each country are summarised in table 4.
Table 4. Timelines and global spread of MERS-CoV cases in humans by country and dates of
first and most recent cases (as of 21 July 2021)
Region Country Cumulative Date of first Date of last

cases, n# observation observation
Middle East Saudi Arabia 2 176 13 June 2012 8 June 2021

United Arab 92 19 March 2013 18 January 2021
Emirates
Jordan 28 2 April 2012 26 September 2015
Qatar 23 15 August 2013 18 February 2020
Oman 24 26 October 2013 20 February 2019
Iran (Islamic 6 11 May 2014 18 March 2015
Republic of)
Kuwait 4 30 October 2013 8 September 2015
Lebanon 2 22 April 2014 8 June 2017
Yemen 1 17 March 2014 17 March 2014
Bahrain 1 4 April 2016 4 April 2016
(Kingdom of)
Asia Republic of Korea 186 11 May 2015 28 August 2018
Philippines 2 15 April 2014 30 June 2015
Thailand 3 10 June 2015 25 July 2016
China 1 21 May 2015 21 May 2015
Malaysia 2 8 April 2014 24 December 2017
Europe UK 5 3 September 2012 16 August 2018
Germany 3 5 October 2012 7 March 2015
Netherlands 2 1 May 2014 5 May 2014
France 2 23 April 2013 27 April 2013
Austria 2 22 September 2014 8 September 2016
Turkey 1 25 September 2014 25 September 2014
Italy 1 25 May 2013 25 May 2013
Greece 1 8 April 2014 8 April 2014
Americas USA 2 14 April 2014 1 May 2014
Africa Tunisia 3 1 May 2013 17 June 2013
Algeria 2 23 May 2014 23 May 2014
Egypt 1 22 April 2014 22 April 2014
#
: cumulative confirmed MERS-CoV human cases. Reproduced and modified from [32] with
permission.
https://doi.org/10.1183/2312508X.10025620 33
The natural reservoir of MERS-CoV remains unclear, but dromedary camels are an
important intermediary natural host for the diversification and maintenance of MERS-CoV
and are the major known source of zoonotic human infection [33]. MERS-CoV has been
isolated from dromedary camels in the Arabian Peninsula and across East, West, North and
Central Africa; however, it has not been found in dromedary camels in other countries
such as Kazakhstan [34], or in Bactrian camels in Mongolia [35]. Nevertheless, only a
minority of human cases with MERS have reported direct camel exposure [36].
Transmission
Although MERS-CoV was first officially described in September 2012 [31], a retrospective
study of a cluster of hospital cases dating back to April 2012 in the city of Zarqa, Jordan,
using reverse transcriptase PCR and serology, confirmed MERS-CoV as the aetiological
agent of the outbreak, which involved at least 10 HCWs and two family members [37]. The
epidemiology of MERS-CoV is characterised by sporadic primary zoonotic transmission
events, which can be followed by nosocomial outbreaks in healthcare settings due to a
failure in infection control and preventative measures. Saudi Arabia has the largest MERS
case load to date, followed by the Republic of Korea as the country with the highest case
load outside the Arabic Peninsula [32].
Risk factors
A case–control study analysed the risk factors for primary MERS-CoV infection in 30
primary MERS-CoV cases reported between March and November 2014 in Saudi Arabia,
with two to four controls matched by age, sex and neighbourhood for each case patient
[38]. Using multivariate analyses, the investigators found that direct dromedary exposure in
the 2 weeks before symptom onset was strongly associated with MERS-CoV illness
(adjusted OR 7.45, 95% CI 1.57–35.28), together with having heart disease (adjusted OR
6.87, 95% CI 1.81–25.99) or diabetes mellitus (adjusted OR 6.99, 95% CI 1.89–25.86), and
being a current tobacco smoker (adjusted OR 6.84, 95% CI 1.68–27.94) [38]. The risk of
Table 5. Risk factors for primary and household transmission of MERS-CoV
Risk factors Adjusted OR/risk ratio

(95% CI)
Independent factors associated with primary MERS-CoV illness

(Saudi Arabia) [38]
Direct dromedary exposure in the 2 weeks before illness onset Adjusted OR 7.45 (1.57–35.28)
Diabetes mellitus Adjusted OR 6.99 (1.89–25.86)
Heart disease Adjusted OR 6.87 (1.81–25.99)
Currently smoking tobacco Adjusted OR 6.84 (1.68–27.94)
Direct physical contact with dromedaries in the previous Adjusted OR 14.59 (2.38–89.55)
6 months
Risk factors for household transmission [40]
Sleeping in an index patient’s room Risk ratio 4.1 (1.5–11.2)
Removing patient’s waste (urine, stool and sputum) Risk ratio 3.2 (1.2–8.4)
Touching respiratory secretions from an index patient Risk ratio 4.0 (1.6–9.8)
34 https://doi.org/10.1183/2312508X.10025620
secondary transmission from patients to household contacts was estimated at ∼4% [39].
The household transmission risk factors included touching respiratory secretions from the
index patient and sleeping in the index patient’s room, while simple proximity and casual
contact were not associated with transmission (table 5) [40].
Asymptomatic or mild infections
A cross-sectional serosurveillance study of 10 009 healthy individuals in Saudi Arabia found

evidence of positive MERS-CoV serology in 0.15%, suggesting that the number of mild or
asymptomatic infections far exceeds those that are recognised [42]. Seropositivity was found
to be more common in males than in females, in central than in coastal provinces, and in
camel shepherds (2.3%) and slaughterhouse workers (3.6%) than in other workers [42].
Since 2012, 298 laboratory-confirmed cases have been reported as asymptomatic to the
WHO, and among these, 164 were HCWs. The potential to transmit MERS-CoV to others
has been shown in viral-shedding studies of subjects with asymptomatic MERS infections.
The results suggest the possibility for onward transmission of MERS-CoV from
asymptomatic individuals. Thus, screening of HCW contacts of patients with confirmed
MERS is essential, while systematic screening of non-HCW contacts outside of healthcare
facilities should be encouraged [43]. Cases specifically reported as “asymptomatic” or “mild
disease” in Saudi Arabia occurred only among secondary cases [44, 45], while most (90%)
of index or sporadic cases had severe disease [44].
Nosocomial transmission
Similar to SARS, nosocomial transmission is a hallmark of MERS. Superspreading events

involving MERS have been reported in Jordan [37], Al Hasa [44], Jeddah [45] and Abu
Dhabi [46], while the major 2015 outbreak in the Republic of Korea resulted from a
Table 6. Risk factors for MERS-CoV infection and transmission
Indirect or direct contact with MERS-CoV-infected camels and camel products (nasal secretions,
urine, faeces, milk, meat, other)
Exposure to and/or contact with MERS patients (home, compound, community, hospitals/clinics)
Delayed implementation of infection control measures
Overcrowded or contaminated hospitals (emergency departments, dialysis units and crowded
inpatient wards)
Exposure to or contact with asymptomatic hospital staff or patients with MERS
Poor compliance with MERS-specific infection control guidelines (hand hygiene, droplet contact
precautions, environmental cleaning and inadequate PPE when assessing patients with febrile
respiratory illness or MERS)
AGPs and invasive procedures on MERS patients (e.g. nebulisers, resuscitation, intubation
and ventilation)
Lack of proper isolation room facilities
Distance between inpatient beds of <1 m
Friends and family members staying as caregivers in overcrowded healthcare facilities
Increased risk of mortality in MERS patients with underlying chronic comorbidities, the elderly
and those who are immunosuppressed
Data from [38–40, 44–50]. Reproduced and modified from [41] with permission.
https://doi.org/10.1183/2312508X.10025620 35
number of superspreading events in hospital settings [47]. Failures in infection control and
prevention measures in healthcare facilities have resulted in large numbers of secondary
cases of MERS involving HCWs, existing patients and visitors in Saudi Arabia [44, 45] and
in several other countries in recent years [37, 46, 47]. Common predisposing factors
included the following: exposure to contaminated and overcrowded healthcare facilities,
suboptimal compliance with appropriate PPE during assessment of patients with febrile
respiratory illness, the application of potentially AGPs (resuscitation, nebulised medications,
CPAP) and lack of proper negative-pressure isolation room facilities [37, 44–48]. Factors
unique to the Republic of Korea were the tradition of “doctor shopping” (where patients seek
care at different healthcare facilities) and using family members as caregivers to look after the
patients at already overcrowded healthcare facilities [49, 50]. Table 6 summarises risk factors
for MERS-CoV infection and transmission.
Conclusion
SARS-CoV-1 and MERS-CoV emerged in 2002 [9] and 2012 [31], respectively, causing
severe and lethal infection in humans. Bats appear to be the common natural source of
SARS, while more research is needed to examine their role in MERS. Civet cats [10, 11]
and dromedary camels [38] are the intermediary animal sources for SARS and MERS,
respectively. The sale and consumption of the intermediary source of SARS-CoV-1 (civet
cats) have been banned in China since 2003, and the transmission chain was cut. In the
Middle East, the intermediary reservoir for MERS (camels) is still widely available and
there is sporadic spillover infection from camels to humans through close contact.
Nosocomial outbreaks are hallmarks of SARS [5–8] and MERS [37, 43–46]. Nosocomial
transmission of MERS has become less frequent in the Middle East due to improvements
in hospital infection control and prevention measures in recent years. MERS, SARS and
now COVID-19 present unique opportunities for all stakeholders involved in human and
animal health systems to take forward a “One Health” approach to monitor new zoonotic
pathogens with epidemic potential [51].
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38 https://doi.org/10.1183/2312508X.10025620
| Chapter 4
Drug repurposing and other
strategies for rapid antiviral
development: lessons from the
early stage of the pandemic
Sophie O’Reilly1,2,3, Matthew Angeliadis1,2,3, Ross Murtagh1,2 and
Virginie W. Gautier1,2
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 [https://doi.org/10.
1183/2312508X.10024020].
@ERSpublications
The development of new SARS-CoV-2 antivirals will rely on innovative strategies, a
deeper understanding of the molecular virology of coronaviruses and on pre-clinical
models to select potential antivirals to be evaluated in clinical trials https://bit.ly/
3sYBXEZ
C oronaviruses, in the order Nidovirales, belong to the family Coronaviridae and are
divided into four genera: Alphacoronvirus, Betacoronavirus, Gammacoronavirus and
1
Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin, Dublin, Ireland. 2Conway
Institute, University College Dublin, Dublin, Ireland. 3These authors contributed equally.
Correspondence: Virginie Gautier (virginie.gautier@ucd.ie)
https://doi.org/10.1183/2312508X.10024020 39
Genus Subgenus Species

SARS-CoV PC4-227 (palm civet)
Sarbecovirus SARS-CoV-1
SARSr-CoV BtKY72 (bat)
SARSr-CoV RaTG13 (bat)
SARS-CoV-2
Hibecovirus Bat Hp-BetaCoV (bat)
Ro-BatCoV GVVDC1 (bat)

Nobecovirus Ro-BatCoV HKU9 (bat)
Ei-BatCov C704 (bat)
Merbecovirus Pi-BatCoV HKU5 (bat)

Ty-BatCoV HKU4 (bat)
Betacoronavirus MERS-CoV
EriCoV (hedgehog)
MHV (rodent)
HCoV-HKU1
Embecovirus
ChRCoV HKU (rodent)
HCoV-OC43
MrufCoV 2JL14 (rodent)
Setracovirus
Alphacoronavirus HCoV-NL63
Duvinacovirus HCoV-229E
Gammacoronavirus
Deltacoronavirus
Figure 1. Taxonomy of the family Coronaviridae. Shown are single virus representatives of 13 species of the
genus Betacoronavirus, together with five representatives of the SARS-related coronavirus species, and their
relative genetic distance (not drawn to scale). The human alphacoronaviruses HCoV-NL63 and HCoV-229E
are also shown. HCoVs are indicated in bold text. The animal reservoir is shown in parentheses. Data
from [1].
Deltacoronavirus (figure 1). Because of their high adaptive capacity, these enveloped,
positive-sense, single-stranded RNA viruses present a great zoonotic potential, causing
significant concerns for both animal and human health. The immediate and global
COVID-19 threat has stressed the importance of pandemic preparedness and the prompt
development of vaccines and therapeutic interventions [2–4].
Although vaccines are the cornerstone of controlling epidemics and saving lives, antivirals
also have a key role to play in controlling the progression of disease by reducing viral loads
and by breaking SARS-CoV-2 community transmission chains through limiting virus
shedding levels and duration. In this chapter, we describe the virological features of
SARS-CoV-2 and review the unprecedented international efforts and strategies that took
place over the first 12 months of the pandemic to screen and identify new antiviral
treatments against SARS-CoV-2 replication for inclusion in COVID-19 clinical trials. We
discuss the importance of long-range planning and sustaining our translational research
focus to deepen our understanding of HCoVs and their molecular pathogenesis. The latter is
crucial to identify and validate novel targets for therapeutic interventions, in particular those
commonly shared by HCoVs, and to expand the repertoire of broad-spectrum antiviral
agents, enabling prompt deployment for current and future pandemics. Here, we will focus
specifically on antiviral agents and not on immunomodulating therapies such as monoclonal
antibodies and corticosteroid treatments. These have been reviewed elsewhere [5–7].
40 https://doi.org/10.1183/2312508X.10024020
VIROLOGY | S. O’REILLY ET AL.
Understanding the molecular virology and zoonotic origins of

emerging coronaviruses
The first description of a HCoV dates back to 1965, with the isolation of HCoV-229E from
individuals with a common cold [8]. Among the seven betacoronaviruses currently described
as infecting humans are four endemic HCoVs (HCoV-229E, HCoV-NL63, HCoV-OC43 and
HCoV-HKU1) currently circulating throughout the world. These are associated with mild
upper respiratory tract (URT) infections and are responsible for 20% of common colds during
the winter season. The remaining three, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, recently
emerged in the human population as a result of independent zoonotic transmissions and are
thought to have originated from bats, which are the natural reservoirs of alpha- and
betacoronaviruses (figure 1). However, they have probably been transmitted to humans via
intermediate reservoirs such as palm civets in the case of SARS-CoV-1 and dromedary camels
for MERS-CoV [2, 9, 10]. The search for possible intermediate hosts for SARS-CoV-2 is still
ongoing. Despite similarities between pangolin betacoronavirus isolates and SARS-CoV-2,
their role in the zoonotic transmission of SARS-CoV-2 is still being debated [11–13].
These emerging HCoVs are phylogenetically related. SARS-CoV-2 shares 79% genome
sequence identity with SARS-CoV-1 and 50% with MERS-CoV (figure 1) [3]. Their genome
of ∼30 kb is the largest of all RNA viruses and presents a highly conserved genomic
organisation (figure 2). It encodes four structural proteins. The nucleocapsid (N) protein
multimerises to form a helical capsid that surrounds the viral genome and is essential for
viral genome packaging and viral particle assembly and release [14]. The envelope (E),
membrane (M) and spike (S) proteins are present in the viral envelope [15]. The trimeric
transmembrane glycoprotein S has two subunits: S1, comprising the receptor-binding
domain, and S2, the fusion peptide. The S proteins mediate virus docking and entry into
host target cells via membrane fusion at the cell surface or following virus entry via the
endosomal pathway (figure 2) [16, 17]. MERS-CoV S protein recognises the human
dipeptidyl peptidase 4 (DPP4) as a functional receptor, while SARS-CoV-1 and SARS-CoV-2
S proteins both recognise the human ACE2 protein. In addition, neuropilin 1 (NRP1) has
been identified as an additional host factor for SARS-CoV-2 entry [18]. All three coronavirus
infections are enhanced by expression of transmembrane serine protease 2 (TMPRSS2) [19].
Interestingly, SARS-CoV-2 S protein displays a distinct feature compared with SARS-CoV-1,
as its sequence includes a polybasic cleavage site present at the S1–S2 boundary, which is
thought to be cleaved by furin in order to prime SARS-CoV-2 S protein for TMPRSS2
processing, the latter event releasing the fusion peptide [17, 20]. Genomes of HCoVs also
include two large open reading frames (ORF1a and ORF1b) encoding polyprotein precursors
(pp1a and pp1ab) that are proteolytically cleaved into 16 nonstructural proteins (NSP1–16),
including papain-like protease (PLpro) and 3C-like protease (3CLpro), and form the RNA
replicase–transcriptase complex comprising the RNA-dependent RNA polymerase (RdRp),
helicase (Hel) and exonuclease (ExoN) (figure 2). Finally, there are nine additional smaller
ORFs for SARS-CoV-1 and SARS-CoV-2 and five for MERS-CoV encoding accessory factors
acting as mediators of the host–virus interface [15].
Following virus entry, viral genome replication and transcription take place in virus-
induced double-membrane vesicles derived from the endoplasmic reticulum (ER), where
the RNA replicase–transcriptase complex generates full-length viral genomic RNA and a set
of subgenomic RNA copies encoding the viral structural proteins and accessory factors.
The structural proteins and viral genome are assembled into the nucleocapsid and viral
https://doi.org/10.1183/2312508X.10024020 41
a) b) 0 5000 10 000 15 000 20 000 25 000 30000

S
ORF6 ORF10
N ORF7b
5'UTR ORF1a ORF1b S EM N 3'UTR

M
E ORF3a ORF8
pp1a ORF7a
Single-stranded pp1ab
genomic RNA
c) Receptor binding Exocytosis

and virus entry
Cytoplasm ACE2 TMPRSS2
Uncoating
Hydroxychloroquine
Azithromycin
Endocytosis Camostat Formation
Imatinib
Nafamostat of progeny Exocytic
virion vesicle
Translation of
polypeptide
Assembly
Autoproteolysis
Lopinavir–ritonavir ERGIC
Danoprevir pp1a
pp1ab Cleavage of Nucleocapsid
polypeptide to
generate NSPs gRNA
N
Remdesivir Translation into

RdRp complex
Favipiravir structural and
sgRNA accessory proteins
ER
RNA replication
and transcription
Figure 2. Potential antiviral target key steps of the SARS-CoV-2 replication cycle. a) Coronavirus virion
structure. The main structural proteins are the spike (S), nucleocapsid (N), membrane (M) and envelope (E)
proteins. b) Genomic structure of SARS-CoV-2. The genome comprises genes encoding the four main
structural proteins. It also comprises two large open reading frames (ORF1a and ORF1b) that encode 16
nonstructural proteins (NSP1–16) and six accessory genes (ORF3a, ORF6, ORF7a, ORF7b, ORF8 and ORF10).
c) SARS-CoV-2 replication cycle. Entry of SARS-CoV-2 into host cells involves attachment of the S
glycoprotein receptor-binding domain (S1 subunit) to host-cell ACE2 receptors. Upon binding of the S
protein to ACE2, the receptor complex undergoes proteolytic cleavage by transmembrane serine protease 2
(TMPRSS2), allowing S2-mediated fusion of viral and cellular membranes. Upon entry, SARS-CoV-2 uncoats
and releases its RNA genome (gRNA) into the host cell cytoplasm. Positive-sense viral RNA is translated by
the host translational machinery. ORF1a and ORF1b are translated into two polyproteins ( pp1a and pp1ab),
which are further processed into individual NSPs that form the RNA-dependent RNA polymerase (RdRp)
complex. The remaining components of the genome are transcribed into subgenomic mRNAs (sgRNAs) for
production of the structural and accessory proteins. Following translation, the four structural proteins enter
the secretory pathway of the endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC). In the
ERGIC, viral genomes are encapsidated by the N protein. Structural proteins subsequently interact with the
encapsidated viral genomes and assemble into enveloped virions by budding. These mature progeny virions
are released from the cell by exocytosis. Figure created using BioRender.com
42 https://doi.org/10.1183/2312508X.10024020
membrane at the ER–Golgi intermediate compartment, followed by exocytosis and release

of virions from the infected cell (figure 2) [21].
Virus dynamics and COVID-19 disease trajectories are key to inform

antiviral interventions
Viral load dynamics are the result of an intricate balance between virus replication and host
responses, and can be used as a biomarker of clinical progression in COVID-19, as well as
to monitor the impact of antiviral treatments (figure 3, table 1) [34]. Importantly, temporal
viral load dynamics may differ between anatomical sites and according to disease
progression and patient profiles, and therefore should be used with caution as a predictive
biomarker of disease severity [34–39]. Like MERS-CoV and SARS-CoV-1, SARS-CoV-2 has
a broad tissue tropism, determined by the expression and distribution of ACE2 and
TMPRSS2, and targets the respiratory tract, where it infects type I and II pneumocytes and
airway epithelial cells, and enterocytes in the intestinal tract (table 2) [42]. SARS-CoV-2
dynamics can be monitored by quantifying its genomic material in nasopharyngeal swabs,
sputum, saliva, bronchial lavages, stool and serum samples with quantitative reverse
transcriptase PCR (RT-qPCR) (figure 3) [27].
The initial peak of nasopharyngeal viral loads for all three emerging HCoVs can be
associated with clinical severities [43, 44]. While SARS-CoV-1 and MERS-CoV viral peaks
occur 7–10 days after symptoms onset [35], the SARS-CoV-2 peak is observed earlier, at
or within 5 days of symptom onset (figure 3). Initial infection triggers activation of
intrinsic cellular and innate immune responses including the IFN pathway, which
suppresses virus replication, resulting in a lower viral peak, and supports the development
of an adaptive immune response. Over the next 14 days, nasopharyngeal viral loads
decrease overtime until virus clearance [36]. Of note, early infection with SARS-CoV-1,
SARS-CoV-2 and MERS-CoV is associated with a delayed or suppressed IFN response
[45]. This phenotype is further accentuated in severe cases of COVID-19, where the
type I IFN response is highly impaired with low levels of type I IFN and/or
IFN-stimulated genes [32, 46]. In the absence of effective antiviral activities mediated by
the host cell, the virus is able to replicate to high titres, resulting in a high viral peak in
nasopharyngeal samples [47]. Viral loads in the URT are maintained over time in
COVID-19 patients with severe disease due to sustained residual virus replication and
delayed virus clearance. These can drive a state of systemic inflammation with higher
levels of pro-inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, IL-10,
IL-18 and CXC motif chemokine ligand 10 (CXCL10) and even the elevation of type I
IFN in the late stage of disease [32, 48–50]. Ultimately, this hyperinflammation phenotype
can then affect distal tissues, cause multiple organ dysfunction and lead to increased
COVID-19 clinical severity [51].
While nasopharyngeal sampling has been the standard practice for diagnosis of
COVID-19, monitoring saliva viral loads is now being considered as an alternative due to
its high sensitivity and reproducibility [23]. Saliva viral loads peak in the week following
symptom onset before declining over time [25, 36]. Similar to SARS and MERS, the
progression of the infection to the lower respiratory tract (LRT) is critical for COVID-19
pathology, and increased and sustained LRT viral loads are observed in severe COVID-19
cases [52–55]. The detection of SARS-CoV-2 RNA in plasma samples, or “RNAaemia”, is
distinct from viraemia, which indicates the presence of infectious viral particles [56].
https://doi.org/10.1183/2312508X.10024020 43
44

b) URT virus dynamics
a)
Presymptomatic Early infection Late infection
SARS-CoV-1
SARS-COV-2
MERS-CoV
Viral load
Upper Nasopharnygeal
respiratory Saliva
tract
Oropharyngeal
2–14 days 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Endotracheal aspirate Days from symptom onset
Lower
respiratory Sputum c) SARS-CoV: viral load in the URT according to disease severity
tract Bronchoalveolar lavage Presymptomatic Early infection Late infection
Asymptomatic
Plasma/serum Mild
Severe
Viral load
Urine
Stool
https://doi.org/10.1183/2312508X.10024020
2–14 days 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days from symptom onset
d) PEP Early intervention Late intervention
Treated Treated Treated

Untreated Untreated Untreated
Viral load
Viral load
Viral load
Time Time Time
Figure 3. Legend overleaf.

Figure 3. Virus dynamics and COVID-19 disease trajectories. a) SARS-CoV-2 can be detected in the upper
and lower respiratory tracts, plasma/serum, urine and stool across the course of infection. b) SARS-CoV-2
peaks early in the course of infection, at symptom onset or within 5 days. By contrast, SARS-CoV-1 and
MERS-CoV peak later in infection. c) SARS-CoV-2 viral load dynamics can vary according to disease
severity, with asymptomatic and mild cases having lower peak viral loads and shorter duration of shedding
than severe cases. Severe cases may display prolonged virus shedding (>28 days, dashed line). d) Timing of
antiviral interventions include but are not limited to post-exposure prophylaxis (PEP), early in infection
(<5 days post-symptom onset) and late in infection (>5 days post-symptom onset). The black dotted line
indicates the time of treatment initiation. URT: upper respiratory tract. Figure created using BioRender.com
RNAaemia is significantly associated with the inflammatory markers CRP and IL-6, and
inflammatory cytokines including IL-8, CXCL10 and monocyte chemoattractant protein 1
(MCP-1), as well as with disease severity and mortality [30, 57]. The source of viral
RNA in the blood remains to be identified but could reflect a route of virus
dissemination leading to multisystem involvement, or may reflect the breakdown of
damaged lung tissue, allowing leakage of viral particles or viral RNA into the
bloodstream [30, 56, 57]. The association with inflammatory markers and clinical
deterioration makes RNAaemia a valuable prognostic biomarker when monitoring the
efficacy of antivirals [58].
Development of gastrointestinal symptoms during the course of COVID-19 is associated

with disease severity [59], increased risk of ICU admission and the requirement for
ventilation support [60]. Nevertheless, the presence and levels of SARS-CoV-2 viral RNA in
stool can be inconsistent and are not associated with gastrointestinal symptoms or disease
severity [33, 61]. Of interest, faecal shedding leads to SARS-CoV-1 and SARS-CoV-2 being
detectable in sewage, which can prove useful for reflecting case load in the local population,
providing early warning of outbreaks or peaks in transmission [62, 63]. Sequencing of
sewage samples can also track the emergence of genetic variants in a population [64], which
is particularly relevant for the identification of potentially more transmissible variants [65].
Overall, the features of virus dynamics suggest that the therapeutic window for antiviral
treatment is limited in COVID-19 patients (figure 3). To maximise their impact, early
treatment intervention, within 3–5 days of symptoms onset, could be aimed at controlling
the initial stages of SARS-CoV-2 infection and flattening the viral peak in the URT to limit
Table 1. Viral antigens and host biomarkers that can be detected from different anatomical sites
Source Viral Host biomarkers First author [ref.]

biomarker(s)
Nasopharyngeal gRNA, S, N MARTY [22], WYLLIE [23]

Saliva gRNA, S, N IgA, IgG, IgM WYLLIE [23], MACMULLAN [24]
Oropharyngeal gRNA, S, N TO [25], NSOGO [26]
Endotracheal gRNA TO [25]
Sputum gRNA, S, N TRYPSTEEN [27], YAMAYOSHI [28]
Bronchoalveolar gRNA TRYPSTEEN [27]
lavage
Urine gRNA PENG [29]
Plasma/serum gRNA IgG, IgM, VEYER [30], MAZZINI [31],
cytokines HADJADJ [32]
Stool gRNA CHEN [33]
https://doi.org/10.1183/2312508X.10024020 45
Table 2. Comparison of relative SARS-CoV-2 infection and ACE2 expression, and

transmembrane protease serine 2 (TMPRSS2) expression positivity, in human tissues
Organ/region Cell/structure Relative infection/ TMPRSS2

expression level expression
SARS-CoV-2 ACE2
Upper airway Mucus ++++ NA NA

Nasopharynx ++++ NA Yes
Trachea ciliated epithelial cells ++++ +++ Yes
Mucosal epithelial cells NA +++ Yes
Olfactory sustentacular cells NA +++ NA
Mouth Sputum ++++ NA NA
Oropharynx ++++ NA NA
Mucosal epithelial cells NA ++++ NA
Tongue keratinocytes NA ++++ NA
Lungs Bronchoalveolar lavage ++++ NA NA
Ciliated/secretory ++++ +++ Yes
epithelial cells
Type I pneumocytes ++++ +++ No
Type II pneumocytes ++++ NA Yes
Alveolar macrophages ++++ NA Yes
Cardiovascular Heart interstitial fibroblasts ++ +++ NA
system Vessel endothelial cells ++ +++ Yes
Cardiomyocytes NA +++ NA
Immune system Blood +++ + NA
Lymph nodes +++ + Yes
Spleen +++ + NA
Liver/gallbladder/ Liver cholangiocytes + +++ Yes
pancreas Gallbladder epithelial cells + +++ NA
Pancreas acinar/ductal cells + +++ NA
Gastrointestinal tract Stool ++++ NA NA
Stomach ++++ NA Yes
Enterocytes ++++ ++++ Yes
Urinary system Urine +++ NA NA
Kidney tubular epithelial/ +++ +++ Yes
podocyte cells
Female reproductive NA + ++ NA
tract
Male reproductive Testicular spermatogenic/ ++ ++++ Yes
tract Sertoli/Leydig cells
Nervous system Brain (non-neuronal) ++ +++ Yes
Cerebrospinal fluid ++ NA NA
Spinal cord (non-neuronal) NA +++ NA
Eye Tears ++ NA NA
Cornea/conjunctiva/retina ++ +++ NA
epithelial cells
Mammary glands Breast milk ++ NA NA
Mammary epithelial cells NA +++ NA
Skin/adipose tissue Skin epithelial cells + +++ NA
NA: not applicable. Data from [27, 40, 41].
46 https://doi.org/10.1183/2312508X.10024020
virus propagation to the LRT. Later or delayed antiviral treatments in patients with
moderate and severe COVID-19 would typically be less effective but could then target virus
persistence and help accelerate virus clearance. Both strategies could contribute to reduce
viral loads, limit systemic inflammation, shorten time to resolution and mitigate the risk of
progression to severe disease for individuals at risk of developing severe symptoms.
Alternative strategies include pre- or postexposure prophylactic administration of antiviral
drugs to control viral loads and limit outbreaks or prevent transmission in particular
settings with high-risk populations, such as residential care facilities.
Clinical trials with repurposed antiviral drugs for COVID-19
Pandemic preparedness should include the ability to promptly select and evaluate antivirals
against emerging viruses in clinical trials with the goal of suppressing viral loads and
reducing transmission, time/duration of hospitalisation and/or mortality, so that those
antivirals with optimum clinical efficacy can be rapidly deployed globally (figure 4).
Despite the previous emergence of MERS-CoV and SARS-CoV-1, there were no antivirals
available against HCoVs in early 2020.
Antiviral therapies can broadly be classified into direct-acting antivirals (DAAVs) or

host-directed therapy (HDT) targeting cellular proteins and pathways utilised by the virus
for its replication. DAAVs target viral enzymatic activities and can be associated with lower
toxicity if the viral target has no cellular homologue [66]. To limit the risks of emergence
of antiviral drug-resistant variants, combination therapy is strongly advised, where two or
more different classes of antivirals are used. HDT can target and inhibit host cellular
factors required for virus replication or persistence, enhance protective immune responses
or modulate pathogenic immune responses. HDT is less prone to the development of
resistance and can also be effective across different groups of viruses once they rely on the
same cellular pathways. Therapeutic agents in clinical use against cancers and metabolic
diseases have often been repurposed as HDT [67].
Initial strategies developed to select antiviral compounds for inclusion in COVID-19

clinical trials were based on repurposed antiviral drugs including broad-spectrum antiviral
agents displaying antiviral activities across more than one group of viruses and/or DAAVs
targeting common viral enzymatic functions essential for virus replication (figure 2).
Additional selection criteria included their safety profile and bioavailability, as well as
previous records of good efficacy against SARS-CoV-1 or MERS-CoV in cell-based assays
or animal models. In particular, priority was given to the following repurposed antivirals
(table 3): 1) remdesivir (RDV; GS-5734, Gilead Sciences), a DAAV and a prodrug
nucleoside analogue originally developed for Ebola virus and shown to target and inhibit
SARS-CoV-1 and MERS-CoV RdRp in vitro and in animal models [84–86]; 2) favipiravir
(FPV), another DAAV also targeting RdRp, with a broad-spectrum activity against RNA
viruses including influenza, norovirus and flaviviruses [87]; 3) lopinavir–ritonavir (LPV/r),
a DAAV and protease inhibitor currently used in combination antiretroviral therapy against
HIV; LPV/r was also tested in vitro against SARS-CoV, MERS and HCoV-229E and in
animal models (ferrets) where a combination of LPV/r with hydroxychloroquine lowered
the overall clinical score but did not affect viral load [88–92]; 4) hydroxychloroquine
(HCQ), an HDT and widely used antimalarial and autoimmune disease drug displaying
broad-spectrum antiviral activities against HIV-1, influenza virus H5N1 and SARS-CoV-1
in vitro and believed to block virus–cell fusion by increasing the endosomal pH [93].
https://doi.org/10.1183/2312508X.10024020 47
48

a) In vitro/ex vivo antiviral screening
Cellular models Workflow End-point assays Analysis
100
Virus inhibition, %
75
Dose-dependent
Fluorescent microscopy Flow cytometry 50
quantification
antiviral activity
Infected cell
1000 (EC50)
Viability marker (PE)

25
800 EC50 EC90
Immortalised cell lines, e.g. 600
0
10–10 10–9 10–8 10–7 10–6
Vero E6, Calu-3, A549/ACE2 400 Concentration, μM
Ciliated epithelial cells 200 100
Virus inhibition, %
SARS-CoV-2 0
0 200 400 600 800 1000 75
nucleocapsid- Dose-dependent
Goblet cells
2–8 h 8–72 h positive cells SARS-CoV-2 nucleocapsid 50 drug toxicity
(FITC) (CC50)
Basal cells 25
0
2D models: pseudo-stratified RT-qPCR TCID50 assay
10–10 10–9 10–8 10–7 10–6
50% infectious dose
quantification
epithelium in ALI Pretreatment SARS-CoV-2 High
Concentration, μM
Viral load
with drugs infection
Fluorescence
Moderate
100 Drug A+B
Virus inhibition, %
Low
(MOI 0.05–1) Threshold 75 Drug B
Synergistic drug
50 combinations
Drug A
Cycles SARS-CoV-2 log dilution 25
3D models: airway organoids Infected cells
0
10–10 10–9 10–8 10–7 10–6
Uninfected cells
Concentration, μM
b) Preclinical models of SARS-CoV-2 infection c) COVID-19 clinical trials

Animal models Transmission studies Study design Time of administration Route of administration
Fatal
Ferrets
https://doi.org/10.1183/2312508X.10024020
Physical distance Severe

PEP
Moderate PrEP
Infected animal Healthy animal Early infection (<5 days PSO)
Mice Nonhuman primates Late infection (>5 days PSO)
Mild/asymptomatic
Challenge studies Clinical monitoring
Clinical monitoring
Viral loads and
dissemination Symptoms/ Inflammation and Viral loads and
Infection coagulation markers dissemination
Resolution side-effects
Tissue pathology
(imaging, biopsy,
Treatment
Pre-exposure autopsy) Tissue pathology Time to recovery,

Early infection Inflammation and (imaging, biopsy, supplementary oxygen,
Late infection coagulation markers autopsy) ventilation or death

Figure 4. Screening, preclinical tools and clinical studies for SARS-CoV-2 antiviral therapeutics. a) Cell-
based SARS-CoV-2 infection models and high-throughput screening platforms before SARS-CoV-2 infection
at a multiplicity of infection (MOI) of 0.05–1. End-point assays are performed at 8–72 h post-infection to
measure the percentage of inhibition of viral infection. Dose–response assays can estimate the 50% or 90%
effective concentration of a drug (EC50/EC90) and the 50% cytotoxic concentration (CC50). b) Preclinical
animal models of SARS-CoV-2 include mice, ferrets and nonhuman primates. c) Study design of clinical
trials. 2D: two-dimensional; ALI: air–liquid interface; 3D: three-dimensional; MOI: multiplicity of infection;
RT-qPCR: quantitative reverse transcriptase PCR; PE: phycoerythrin; FITC: fluorescein isothiocyanate;
TCID50: 50% tissue culture infectious dose; PEP: post-exposure prophylaxis; PrEP: pre-exposure
prophylaxis; PSO; post-symptom onset. Figure created using BioRender.com
Clinical efficacy of HCQ
Early, small-scale clinical trials of HCQ in February and March 2020 showed promising
data for its efficacy in treating COVID-19 (figure 5). A randomised, controlled, unblinded
trial including 62 COVID-19 PCR-positive patients in Wuhan, China, reported that
patients on 200 mg HCQ twice daily for 5 days had increased remission of fever (average
2.2 versus 3.2 days) and improved pneumonia (80.6% versus 54.8%) compared with the
standard of care (antibiotics, corticosteroids, oxygen and immunoglobulin) [68].
Subsequently, a single-arm, open-label study in France enrolled 36 patients positive for
SARS-CoV-2 including a majority of asymptomatic and symptomatic patients with mild
COVID-19. This study showed that significantly more HCQ-treated patients tested negative
for nasopharyngeal RT-qPCR by day 6 compared with controls (70% versus 12.5%;
p = 0.0001). It also suggested that the combination therapy of HCQ (600 mg·day−1 for
10 days) and azithromycin (AZM; 500 mg on day 1, then 250 mg·day−1 for 4 days) for six
patients was beneficial, as all patients on the combination therapy had a negative PCR test
by day 6 of the study [69].
An observational study of 1438 COVID-19 patients in New York City identified no

difference in mortality in patients treated with HCQ alone or in combination with AZM
(HCQ+AZM 25.7%, HCQ 19.9%, AZM 10%) [70]. Another observational study of 1446
COVID-19 patients in New York City showed no association between HCQ (600 mg twice
on day 1, then 400 mg·day−1 for a median of 5 days) and prevention of intubation (hazard
ratio 1.04, 95% CI 0.82–1.32) [71].
Finally, HCQ did not show efficacy as a therapeutic treatment of COVID-19 in

international large-scale multicentre RCT studies. The WHO SOLIDARITY trial, which
coordinated the testing of COVID-19 treatments in RCTs across 30 countries and 11 330
patients, showed no efficacy of HCQ in the treatment of COVID-19 [73]. The RCT
compared the oral therapeutic administration of HCQ (800 mg at 0 h post-inclusion,
800 mg at 6 h post-inclusion, and from 12 h post-inclusion onward, 400 mg twice daily for
10 days). HCQ showed no effect on mortality (HCQ rate ratio 1.19), initiation of
ventilation or length of hospitalisation when compared with patients receiving the general
standard of care for COVID-19. Consequently, the HCQ arm of the trial was discontinued
on 17 June 2020, shortly following the revoked Emergency Use Authorisation (EUA) of
HCQ from the US Food and Drug Administration (FDA) on 15 June 2020 [104, 109].
Similarly, the RECOVERY (Randomised evaluation of COVID-19 therapy) trial of HCQ
(800 mg at 0 and 6 h post-inclusion, then 400 mg at 12 h post-inclusion and every 12 h
after for 9 days or until discharge) coordinated by the University of Oxford, UK,
demonstrated no effect on mortality (HCQ 26.8%, n=1561; control 25.0%, n=3155) or
progression to mechanical ventilation [110].
https://doi.org/10.1183/2312508X.10024020 49
Table 3. Early clinical studies of SARS-CoV-2 antiviral treatments
First author Study type Participants, Antiviral(s) Dosage Outcome

[ref.] n
CHEN [68] RCT, no blinding 62 HCQ 400 mg·day−1, Reduced

5 days average time
to fever
resolution
(2.2 versus
3.2 days);
improved
pneumonia
(80.6% versus
54.8%)
GAUTRET [69] Nonrandomised, 36 HCQ HCQ: Increased
open label, AZM 600 mg·day−1, virus
controlled 10 days; clearance
AZM: 500 mg (70% versus
(L), 12.5%)
250 mg·day−1
(M), 4 days
ROSENBERG [70] Observational 1438 HCQ NA None
study HCQ+AZM
GELERIS [71] Observational 1446 HCQ 1200 mg (L), None
study 400 mg·day−1
(M), ∼5 days
BOULWARE [72] Post-exposure, 1446 HCQ 1400 mg (L), None
placebo 600 mg·day−1
(M), 4 days
WHO Multicentre RCT 11 330 HCQ HCQ: 1600 mg None for all
Solidarity RDV (L),
Trial 800 mg·day−1
Consortium (M), 10 days
[73] RDV: 200 mg
(L),
100 mg·day−1
(M), 9 days
HORBY [74, 75] Multicentre RCT 4716 HCQ HCQ: 1600 mg None for all
LPV/r (L), 400 mg
every 12 h
(M), 9 days
LPV/r: 400/
100 mg·day−1
(M), for 10
days
GREIN [76] Cohort, no 53 RDV 200 mg (L), Clinical
control 100 mg·day−1 improvement
(M), 9 days (68%
improved)
SPINNER [77] Controlled 596 RDV 200 mg (L), Clinical
100 mg·day−1 improvement
(M), 5 or 10
days
WANG [78] RCT, placebo, RDV 200 mg (L), None
double blind 100 mg·day−1
(M), 10 days
Continued
50 https://doi.org/10.1183/2312508X.10024020
Table 3. Continued
First author Study type Participants, Antiviral(s) Dosage Outcome

[ref.] n
BEIGEL [79] RCT, placebo, 1062 RDV 200 mg (L), Decreased

double blind 100 mg·day−1 median time
(M), 10 days to clinical
recovery (10
versus
15 days)
CAO [80] RCT, open label 199 LPV/r 800/200 mg None
daily, 14 days
CAI [81] Nonrandomised, 80 FPV 1200 mg daily Increased
open label, virus
controlled clearance;
chest CT
improvement
KHAMIS [82] Randomised, 89 FPV FPV: 1600 mg None
open label +IFN-β1b (L), 1200·day−1
(M), 10 days
IFN:
nebulised,
16×106 IU,
5 days
MCCULLOUGH Randomised, 89 FPV 1800 mg (L), Reduced fever
[83] open label 1600 mg (M),
10 days
HCQ: hydroxychloroquine; AZM: azithromycin; L: loading dose; M: maintenance dose; NA: not
applicable; RDV: remdesivir; LPV/r: lopinavir/ritonavir; FPV: favipiravir.
In a post-exposure prophylaxis treatment trial of HCQ including 1446 patients with a

reported high-risk exposure to a COVID-19-positive individual, HCQ (800 mg loading
dose, 600 mg 6–8 h later, 600 mg·day−1 for 4 days) showed no significant difference in the
incidence of COVID-19 compared with placebo (11.8%, n=414, versus 14.3%, n=407) [72].
Collectively, these large observational studies and multicentre trials failed to show evidence
of HCQ efficacy as a prophylactic or therapeutic in the treatment of COVID-19.
Clinical efficacy of RDV
The Washington State 2019-nCoV Case Investigation Team reported the first USA
confirmed case of COVID-19 (19 January 2020), a 35-year-old man who subsequently
received treatment with intravenous RDV for compassionate use 7 days following
admission because of worsening clinical status (figure 5). The team noted that the patient’s
clinical condition improved the following day [94]. In April 2020, a Gilead study on the
efficacy of compassionate use of RDV (200 mg i.v. on day 1 and 100 mg daily for 9 days)
in a small cohort of 53 patients showed that 68% of patients had clinical improvement
including improvement in oxygen-support class or extubation; however, the study did not
measure viral load and had no control group [76]. This was followed up in another Gilead
study of 596 patients treated with RDV (200 mg on day 0, then 100 mg·day−1) for 5 and
https://doi.org/10.1183/2312508X.10024020 51
52

December 2020
• SOLIDARITY trial demonstrates
April 2020 November 2020 no efficacy of RDV for the
• Inconclusive small cohort study • 106-patient trial shows RDV treatment of COVID-19 [73]
of RDV by Gilead [76] decreases time to patient
January 2020 • In vitro data showing increased recovery [79]
• Compassionate use of RDV to RDV potency in primary HAE cells • US FDA grants EUA for the 2021
treat first USA COVID-19 patient compared with Vero E6 [96] combination use of RDV and • Update to the DisCOVeRy arm
[94] • Animal model data showing October 2020 baricitinib for the treatment of of the SOLIDARITY trial shows
• In vitro cell data established EC50 efficacy of RDV in rhesus • US FDA approves RDV for the COVID-19 no efficacy for RDV in trial that
macaques [97]
RDV
of RDV [95] treatment of COVID-19 • WHO publicly recommends measured effect on viral load
against the use of RDV for the • Early RDV treatment in
treatment of COVID-19 symptomatic patients shows
• RDV shows efficacy in hPSC significant decrease in time to
February 2020 May 2020 organoid models [99] clinical recovery [100, 101]
• Small RCT shows decreased • US FDA grants EUA for RDV in the while late treatment shows no
patient recovery time with RDV treatment of severe COVID-19 [98] clinical benefit [102]
[78]
January February March April May June July August September October November December 2021
February 2020 April 2020 July 2020 October 2020

• In vitro cell data established • 62-patient RCT in Wuhan showing • RECOVERY trial shows no efficacy • Animal model data show no
EC50 of HCQ [103] decrease in clinical recovery time of HCQ [75] efficacy of HCQ or HCQ+AZM in
with HCQ treatment [68] • HCQ shows no inhibitory effect in Syrian hamsters [107]
HAE-ALI models or rhesus
https://doi.org/10.1183/2312508X.10024020
March 2020 macaques [106]

• Small uncontrolled trial in May 2020 December 2020
France shows potential efficacy • Observational study shows no • SOLIDARITY trial demonstrates no
HCQ
for HCQ and HCQ+AZM [69] effect on mortality of HCQ or efficacy of HCQ for the treatment
• US FDA grants EUA for HCQ in HCQ+AZM [70] August 2020
of COVID-19 [73]
the treatment of COVID-19 [104] • Animal model data show no • 1446-patient trial shows no
efficacy of HCQ in ferrets [105] efficacy of HCQ [72]
• Animal model data show no January 2021
efficacy of HCQ in syrian hamsters • In vitro cell data show that HCQ
June 2020 or rhesus macaques [106] mechanism of action is irrelevant
• FDA revokes EUA for HCQ to in vivo SARS-CoV-2 infection
treatment of COVID-19 [108]
• Observational study shows no
efficacy of HCQ on mortality or
intubation [71]
• HCQ arm of the SOLIDARITY trial
is discontinued

Figure 5. Remdesivir (RDV) and hydroxychloroquine (HCQ) evaluation timeline. Trajectory of published
research for RDV in blue and HCQ in pink contrasted over 2020 and 2021. HAE: human airway epithelial;
EUA: Emergency Use Authorisation; FDA: US Food and Drug Administration; hPSC: human pluripotent
stem cell; EC50: 50% effective concentration; AZM: azithromycin; ALI: air–liquid interface. Figure created
using BioRender.com
10 days, where the 5-day group showed improved clinical status compared with the
standard of care, but, unexpectedly, the 10-day group did not [77].
A randomised, double-blind, placebo-controlled study in Hubei, China, showed that

patients on daily infusions of RDV (200 mg on day 0, then 100 mg·day−1 for 10 days) were
not associated with a difference in time to clinical improvement (hazard ratio 1.23, 95% CI
0.87–1.75) [78]. Early (<10 days post-symptom onset) or late (>10 days post-symptom
onset) treatment had no effect on clinical improvement or mortality compared with
placebo. A similar double-blinded, placebo-controlled study of 1062 COVID-19 patients by
the US National Institutes of Health, given the same dosing regimen of RDV, showed a
median recovery time of 10 days compared with 15 days in the placebo group, providing
data that RDV may shorten the time to recovery [79]. Another study showed that patients
treated with RDV on a 5-day regimen (200 mg i.v. on day 1, then 100 mg·day−1 for 4 days)
showed a higher chance of improved clinical status by day 11 than those treated with the
standard of care [77]. A retrospective cohort study funded by Gilead showed that RDV
gives a modest decrease in 14- and 28-day mortality in patients on nonsupplemental,
low-flow and high-flow oxygen therapy compared with patients who did not receive RDV
treatment [111].
Finally, the benefit of decreased time to clinical recovery was not recapitulated by the
SOLIDARITY trial results, where RDV (200 mg on day 0, then 100 mg·day−1 for 9 days)
showed no effect on mortality (RDV rate ratio 0.95), initiation of ventilation or length of
hospitalisation when compared with patients receiving the general standard of care for
COVID-19 [73].
The FDA issued an EUA for RDV use in nonsevere patients on 28 August 2020 [98]. The
WHO released a conditional recommendation against the use of RDV in COVID-19
patients on 20 November 2020, due to its lack of efficacy on reducing mortality, the need
for ventilation and recovery time.
Clinical efficacy of LPV/r
Although LPV/r treatment was used in the first patients of the COVID-19 pandemic, LPV/r
combination therapy in clinical trials was met with disappointing results. An open-label
RCT showed no benefit in 28-day mortality of 199 LPV/r-treated patients compared with
control (19.2% versus 25%) [80]. The 1616-participant LPV/r arm of the SOLIDARITY
trials shows no benefit in decreased time to discharge (median 11 days for all groups) or
progression to mechanical ventilation [75]. The dosage for LPV/r was based on the 50%
effective concentration (EC50) for HIV, which is 200–1000-fold lower than the comparable
EC50 in SARS-CoV-2 [112]. Thus, the dosage given clinically probably does not inhibit
virus replication of SARS-CoV-2 and the projected dosage from SARS-CoV-2 EC50 is
not feasible.
https://doi.org/10.1183/2312508X.10024020 53
Clinical efficacy of FPV
Early clinical observations of FPV treatment showed evidence of efficacy when FPV was
used to treat patients in Wuhan, China, at the epicentre of the pandemic [113]. A case
series of 11 COVID-19 patients in Japan suggested early efficacy of FPV in combination
with methylprednisolone, where 10 of the patients were removed from ventilation and
supplemental oxygen [114]. In an open-label, nonrandomised study, 80 COVID-19 patients
who received 600 mg FPV twice daily showed faster virus clearance (nasopharyngeal swab
PCR test) and chest CT improvement compared with patients on a 400 mg lopinavir/50 mg
ritonavir regimen of the same length [81]. Two studies of 89 COVID-19 patients, a
randomised, open-label study of FPV in combination with IFN-β1b and a randomised,
open-label trial of FPV early and late treatment in asymptomatic and mild COVID-19,
showed that FPV did not affect clinical outcome and inflammatory markers, or time to
virus clearance (nasopharyngeal swab PCR test), respectively [82, 84]. In the second study,
it was shown that FPV treatment did decrease time to fever resolution; however, neither
study showed that FPV reduced time to virus clearance. Large-scale clinical trials that look
at FPV as well as combination treatments in a blinded RCT would be better suited to
identify the efficacy of FPV as a treatment for COVID-19.
Ongoing clinical studies with RDV, HCQ, FPV and LPV/r
Despite the disappointing outcomes of these large clinical trials in 2020 showing no or
limited antiviral activities or clinical benefits, the potential antiviral activities of RDV,
HCQ, FPV and LPV/r against SARS-CoV-2 were still investigated in clinical studies in 2021
(available at https://clinicaltrials.gov/]. Some of them propose alternative strategies and are
evaluating whether earlier interventions could achieve maximum treatment effects or
whether different routes and modes of administration such as aerosolised products directly
targeting the URT and LRT could increase the bioavailability of the drugs in the lungs and
be a more effective approach (e.g. Gilead study GS-US-553-9018, ClinicalTrials.gov
identifier NCT04539262) [115–117].
Expanding the repertoire of potential HCoV antivirals with screening

strategies
To address their limited availability, it is critical to fast track the development of novel
antivirals using innovative high-throughput strategies such as unbiased large-scale library
screening. Alternatively, it is important to characterise SARS-CoV-2 molecular pathogenesis
and dissect the host–virus interface to identify new targets for therapeutic intervention.
Such strategies rely on in vitro cell-based and animal models of SARS-CoV-2 infection. Of
note, the isolation and propagation of Risk Group 3 biological agents such as pathogenic
HCoVs for research purposes require access to Biosafety Level 3 containment facilities.
Cell-based SARS-CoV-2 infection models
There is a large collection of cellular systems permissive for SARS-CoV-2 replication

including target cells from various tissues relevant to COVID-19 pathogenesis (table 4)
[119]. The Vero E6 cell line (African green monkey (Chlorocebus aethiops) kidney epithelial
cells) is widely used for the isolation and propagation of viral clinical isolates. As these cells
express high levels of ACE2 but low levels of TMPRSS2, new clones (e.g. Vero
54 https://doi.org/10.1183/2312508X.10024020
https://doi.org/10.1183/2312508X.10024020
Table 4. Tissue tropism of SARS-CoV-1 and SARS-CoV-2 in various cell lines
Cell line Cell description CPE ATCC no./supplier WT Permissibility First author [ref.]
expression
Vero E6 (Vero E6/ African green monkey kidney Yes CRL-1586 ACE2+ SARS-CoV-1 MATSUYAMA [19],
TMPRSS2) # epithelial cells TMPRSS2− SARS-CoV-2 HOFFMANN [20]
Continuous IFN−
Caco-2 Human colorectal Yes HTB-37 ACE2+ SARS-CoV-1 HOFFMANN [20],
adenocarcinoma epithelial cells TMPRSS2+ SARS-CoV-2 KRUGER [99]
Cancer
Calu-3 Human lung adenocarcinoma Yes HTB-55 ACE2+ SARS-CoV-1 HOFFMANN [20],
epithelial cells SARS-CoV-2 PRUIJSSERS [96]
Cancer
HEK-293T Human fetal kidney epithelial cells Yes CRL-11268 ACE2− SARS-CoV-1 HOFFMANN [20]
(HEK-293T/ Immortalised TMPRSS2− SARS-CoV-2
hACE2) ¶ CatB/L+
Huh-7 Human liver carcinoma Yes Thermo Fisher ACE2+ SARS-CoV-1 HOFFMANN [20]
differentiated hepatocytes Scientific SARS-CoV-2
Cancer
HAE Human airway epithelial cells Yes NA ACE2+ SARS-CoV-1 HOFFMANN [20],
Primary TMPRSS2+ SARS-CoV-2 PRUIJSSERS [96]
16HBE Human bronchial epithelial cells No Sigma-Aldrich: ACE2+ SARS-CoV-1 LIAO [118]
1-year old male patient SCC150 TMPRSS2+ SARS-CoV-2
Immortalised
H1299 Human lung carcinoma Not CRL-5803 SARS-CoV-2 HOFFMANN [20]

epithelial cells known
Cancer
A549 (A549/hACE2) ¶ Human lung carcinoma No CCL-185 ACE2+ SARS-CoV-1 HOFFMANN [20],
epithelial cells TMPRSS2+ SARS-CoV-2 BLANCO-MELO [46]
Cancer
TMPRSS2: transmembrane protease serine 2; hACE2: human ACE2; CPE: cytopathic effect; ATCC: American Type Culture Collection; WT: wild type;
CatB/L: cathepsin B and L; NA: not applicable. #: Vero E6 cells must be transfected with TMPRSS2 to support coronavirus infection; ¶: HEK-293T and
A549 cells must be transduced with ACE2 to support coronavirus infection.
55
E6/TMPRSS2) have been engineered to overexpress TMPRSS2, which is important for

SARS-CoV-2 fusion at the plasma membrane and to maximise virus replication [19]. Of
note, when passaged in Vero E6 cells and in the absence of TMPRSS2, SARS-CoV-2 can
adapt and acquire deletions or mutations in its polybasic cleavage motif, also described as
the furin cleavage site, located at the S1/S2 junction, which can reduce its capacity to
replicate in other cellular models and may attenuate virus pathogenicity in animal models
[120–123]. This highlights the importance of the choice of cell line and the importance of
sequencing newly amplified viral stocks. Other cellular models of choice include Huh7,
Calu-3, A549/ACE2 and 293T/ACE2 and support varying levels of SARS-CoV-2 replication
(table 4). These monolayer cultures have high propagative capacity, are amenable to genetic
manipulation and are well-adapted for high-throughput screening.
Other relevant and more complex systems include primary human bronchial epithelial
(HBE) cells, which, when grown at an air–liquid interface, differentiate into
pseudo-stratified epithelium or airway organoids both including basal stem cells, ciliated
cells and mucus-producing goblet cells [124–126]. These ex vivo preclinical models express
ACE2 and TMPRSS2 and recapitulate well the three-dimensional architecture of lung
structure, and are better suited to characterise host responses and validate the efficacy of
selected antiviral drugs.
Target cells are plated into 96- or 384-well plates and incubated with antivirals before being
infected with SARS-CoV-2 clinical isolates at low viral input with a multiplicity of infection
ranging from 0.01 to 1 (figure 4). These can be cultured for 8–72 h after virus challenge to
enable one or multiple rounds of virus replication. To facilitate high-throughput screening,
readout strategies include high-content screening technologies using microscopy or flow
cytometry to monitor the percentage of infected cells with intracellular SARS-CoV-2
N protein immunofluorescent staining or virus-induced cytopathic effect [127–131].
Alternatively, viral loads or viral particles released by the infected cells into the supernatant
can be quantified using RT-qPCR. More classical approaches to measure infectious viral
titres rely on serial dilution of viral supernatants and estimation of the 50% tissue culture
infectious dose (TCID50) or plaque-forming units; however, these have limited throughput.
Evaluating in vitro antiviral efficacy
The activity of antiviral agents is measured as the percentage of virus inhibition and should
aim to achieve high potency at a low micromolar or submicromolar concentration (figure 4).
Dose–response analysis of the antiviral activities of drugs provides the EC50, which needs to
be well outside the 50% cytotoxic or cytostatic concentration (CC50), which can influence
viral growth. The relationship between EC50 and CC50 is represented by the selectivity
index (SI=EC50/CC50), where higher SI can support progression into preclinical testing.
Although the clinical relevance of these measures is unclear, they can suggest an achievable
concentration in patients according to pharmacokinetics data. Of note, observed EC50 can
vary due to intrinsic differences in SARS-CoV-2 isolates, quantification methods, cellular
models and assay conditions, such as incubation period and virus input. For reference,
HCQ and RDV displayed potent SARS-CoV-2 antiviral activities in Vero E6 cells with
reported EC50 values of 0.7–4 μM [95, 103] and 0.77–1 μM [95], respectively, while the
EC50 of FPV was higher at 61.88 to >100 μM [95, 132]. Subsequent studies testing RDV
antiviral activities against SARS-CoV-2 in primary human airway epithelial (HAE) cells
showed an ∼160-fold reduction in EC50 compared with Vero E6 cells [96]. These
56 https://doi.org/10.1183/2312508X.10024020
differences were attributed to cell-type specific metabolism of the prodrug RDV in its active
form (GS-441524) [96]. In contrast, another study showed no significant antiviral activities
for HCQ when tested against SARS-CoV-2 in bronchial and nasal HAE cells [133]. These
studies underline the importance of validation of antiviral drugs across different cell
models, including primary human cell models.
Unbiased large-scale library drug screening to identify novel antiviral options

against SARS-CoV-2
Cell-based SARS-CoV-2 models are essential to facilitate high-throughput screening using

unbiased libraries of approved repurposed drugs with known pharmacological and human
safety profiles and to identify new classes of antiviral compounds for accelerated preclinical
and clinical evaluation [131, 134]. A study by RIVA et al. [131] screened the ReFRAME
library (https://reframedb.org/) including 12 000 clinical-stage or FDA-approved small
molecules to identify candidate therapeutic drugs for COVID-19. They first identified 100
molecules inhibiting SARS-CoV-2 and, following a series of characterisation and validation
studies, focused on 13 compounds with submicromolar EC50 and antiviral efficacy in
primary human cell models and/or a lung explant model including apilimod (a PIKfyve
kinase inhibitor), and MDL-28170 and ONO5334, two cysteine proteases inhibitors.
System-wide strategies to identify host–virus junctions as new therapeutic targets

for antiviral intervention
Strategies to dissect the host–virus interface include omics approaches enabling the
comprehensive mapping of physical protein–protein interactions mediated by viral proteins
or genetic screening with CRISPR (clustered regularly interspaced short palindromic
repeats) genome-wide knockout to identify host factors and the cellular pathway highjacked
by SARS-CoV-2 [127, 128, 130, 135]. Such studies can identify essential virus–host
junctions, which can then be targeted by drug repurposing strategies to accelerate their
translation into the clinic. This approach is well illustrated by two consecutive studies,
which generated the comparative interactome of SARS-CoV-1, SARS-CoV-2 and MERS-
CoV and identified common pathways targeted by HCoVs including the eukaryotic
translational machinery, and revealed host-dependency factors essential for SARS-CoV-2
replication [122, 124]. In a follow-up study, the authors further explored the therapeutic
potential of eukaryotic elongation factor 1α1 (eEF1A) and characterised its inhibitor
plitidepsin (Aplidin) as a potent antiviral drug using primary human lung cells and mouse
models [136]. In silico screens using approved drug libraries and public databases (LOPAC,
The Cancer Genome Atlas, Gene Expression Omnibus) can complement cell-based
screening approaches by rapidly identifying suitable drug candidates. In silico screens of
antivirals were analysed for strong binding energy and molecular docking dynamics against
the SARS-CoV-2 receptor-binding domain and ACE2 binding pocket [137], and protein–
protein interaction maps of ACE2-related genes of known drug targets have identified
several drug compounds with potential antiviral activity against SARS-CoV-2 infection [138].
Preclinical evaluation of SARS-CoV-2 antivirals
Animal models provide essential in vivo systems to evaluate the efficacy, toxicity and
pharmacokinetics of SARS-CoV-2 antivirals (figure 4) [139]. These preclinical models
should recapitulate the main aspects of SARS-CoV-2 dynamics and pathogenesis (table 5).
https://doi.org/10.1183/2312508X.10024020 57
58

Table 5. Animal models supporting SARS-CoV-1, SARS-CoV-2 and MERS-CoV infection
Animal Model type Symptoms/ Severity/site of Length Permissive First author [ref.]
traits infection
Human (Homo sapiens) NA Fever Asymptomatic to 7–14 days SARS-CoV-2 YUKI [140]
Nasal discharge severe Peak: SARS-CoV-1
Laboured Respiratory tract: 5–7 dpi MERS-CoV
breathing upper and lower
Seroconversion
nAb
T-cell response
Inflammatory
cytokines
ARDS
Pneumonia
Inflammation
Mouse (Mus musculus) Transgenic# Seroconversion Mild to severe¶ Varies SARS-CoV-2¶ TSENG [141], BAO [142],
Humanised nAb Respiratory tract: SARS-CoV-1 JIANG [143], WANG [144],
Sensitised T-cell immunity upper and lower MERS-CoV SUN [145], RATHNASINGHE
Inflammatory [146], SINGH [147]
cytokines
https://doi.org/10.1183/2312508X.10024020
Ferret (Mustela putorius furo) Therapeutic Fever Asymptomatic to 6–14 days SARS-CoV-2 BLANCO-MELO [46],
Transmission Nasal discharge mild Peak: SARS-CoV-1 KIM [148], RYAN [149],
Seroconversion Respiratory tract: 2–6 dpi KAPTEIN [107], CHU [150]
nAb upper and lower
T-cell immunity
Pneumonia
Inflammation
Syrian hamster (Mesocricetus Therapeutic Laboured Mild to moderate 2–14 days SARS-CoV-2 CHAN [151], DRIOUICH [152]
auratus) Transmission breathing Respiratory tract: Peak: SARS-CoV-1
Seroconversion upper 2–3 dpi
nAb
Pneumonia
Inflammation
Continued
https://doi.org/10.1183/2312508X.10024020
Table 5. Continued
Animal Model type Symptoms/ Severity/site of Length Permissive First author [ref.]
traits infection
Rhesus macaque (Macaca Therapeutic Seroconversion Mild to moderate 7–14 days SARS-CoV-2 MUNSTER [153], HARTMAN
mulatta), cynomolgus macaque nAb Respiratory tract: SARS-CoV-1 [154], SPERANZA [155],
(Macaca fascicularis), T-cell immunity upper and lower MERS-CoV ROCKX [156]
African green monkey Inflammatory
(Chlorocebus aethiops) cytokines
Pneumonia
Inflammation
Cat (Felis catus) Therapeutic Seroconversion Asymptomatic to ∼3–7 days SARS-CoV-2 SHI [157]
Transmission Inflammation mild Peak: SARS-CoV-1
∼2 dpi
Dog (Canis lupus familiaris) N/A N/A Asymptomatic Unknown SARS-CoV-2 SHI [157]
Mink (Neovison vison) Therapeutic Laboured Moderate to severe Unknown SARS-CoV-2 MUNNINK [158], SHI [159],
Transmission breathing SARS-CoV-1 NAVEEN [160]
MERS-CoV
Fruit bat (Rousettus aegyptiacus) Therapeutic Seroconversion Asymptomatic 2–12 days SARS-CoV-2 SCHLOTTAU [161]
Transmission Peak: SARS-CoV-1

∼2 dpi
NA: not applicable; nAb: neutralising antibody; dpi: days post-infection. #: mouse ACE2 does not support SARS-CoV-2 infection, so transgenic models
are necessary; ¶: severe disease only in certain transgenic mouse models.
59
Specific protocols can be designed to precisely control the viral strain and inoculum, and
the mode of infection. Similarly, they are valuable tools for optimising the timing
( prophylactic, early or late), dosing and schedule of treatments, and also its mode of
delivery (intranasal, intraperitoneal, i.v.). The impact of antiviral treatment can be evaluated
by measuring viral loads, time to virus clearance, clinical score, time to recovery or death,
in parallel with other key biomarkers of inflammation and coagulation. Importantly,
invasive sampling enables detailed analysis of the progression of SARS-CoV-2 infection and
pathogenesis to multiple anatomic compartments while monitoring differential drug
penetration into various tissue compartments. Finally, certain species can provide clinically
relevant transmission data. Below, we focus on animal models naturally susceptible to
SARS-CoV-2 infection.
Syrian hamster (Mesocricetus auratus) and ferret (Mustela putorius furo) models
Both of these species are naturally susceptible to SARS-CoV-2 infection, are cost-effective
disease models for SARS-CoV-2 infection and are suitable for larger sample sizes [148,
151]. In ferrets, SARS-CoV-2 infection is limited to the URT [46, 148, 149]. Overall, ferrets
react mildly to SARS-CoV-2 infection (lethargy, nasal discharge, wheezing and sneezing),
and most cases result in asymptomatic infection. Ferrets can spread SARS-CoV-2 to naïve
animals, making them useful for transmission studies [148, 151]. Hamsters support high
titres of SARS-CoV-1 and SARS-CoV-2 and exhibit ground-glass opacities after inoculation.
They are one of few animal model organisms to present with laboured breathing and
progressive weight loss upon SARS-CoV-2 inoculation. In hamsters, inflammation of the
URT and LRT occurs quickly after infection [162, 163].
A study testing the antiviral efficacy of HCQ (12.5 mg·kg−1·day−1) and LPV/r
(24 mg·kg−1·day−1) in ferrets challenged with SARS-CoV-2 intranasally and treated 1 day
post-infection via oral gavage for 14 days reported marginally reduced clinical symptoms
and no impact on viral titres in the lungs and nasal turbinate [105]. Similarly, HCQ (6.5
and 50 mg·kg−1·day−1) given prophylactically (−1 day post-infection) or therapeutically
(1 h post-infection) did not have an impact on disease manifestation, progression or viral
load in Syrian hamsters infected with SARS-CoV-2 intranasally [106]. Finally, a third study
showed that HCQ (50 mg·kg−1·day−1) alone and in combination with AZM injected i.p. 1 h
before intranasal infection also failed to demonstrate an impact on virus replication in the
lungs in hamsters infected with SARS-CoV-2. Similar results were obtained for
transmission studies [107]. In the same study, only high doses of FPV given orally
(600 mg·kg−1·day−1) or injected i.p. (1200 mg·kg−1·day−1) significantly reduced
SARS-CoV-2 RNA levels and infectious viral titres in the lungs and markedly improved
lung histopathology but with some observed cytotoxicity. Of note, FPV also reduced
transmission when given as a prophylactic treatment [107]. Accordingly, a high dose of
FPV (700–1400 mg·kg−1·day−1) significantly reduced virus replication in the lungs
accompanied by clinical alleviation of the disease; however, this was associated with signs
of toxicity associated with the treatment [152]. Of note, both studies performed sequencing
analysis of viral genomes in vivo and showed that FPV treatment was associated with
increased variants and could induce a mutagenic effect.
Nonhuman primate models
Nonhuman primate (NHP) models including rhesus macaques (Macaca mulatta),

cynomolgus macaques (Macaca fascicularis) and African green monkeys (Chlorocebus
60 https://doi.org/10.1183/2312508X.10024020
aethiops) are naturally permissive to SARS-CoV-2, SARS-CoV-1 and MERS-CoV infection,

although they exhibit only mild-to-moderate clinical disease associated with SARS-CoV-2
infection [153, 154]. However, they do show innate, humoral and cellular immune
responses to SARS-CoV-2 infection and signs of pneumonia such as ground-glass opacities
and bilateral lung involvement. Viral load in macaques has been shown to peak within
2 days and to become undetectable by day 10 [133, 134, 140, 155]. Although there is
variability in procedure among studies, most NHPs are inoculated intratracheally, orally,
intranasally and ocularly at a total dose of ∼2×106 TCID50 of SARS-CoV-2 [97, 106, 133,
155]. While NHPs are the most relevant COVID-19 animal models, they are expensive to
maintain and their access is limited, resulting in small sample sizes (e.g. approximately five
per group).
Similar to studies in ferrets and hamsters, low (30 mg·kg−1 loading, 15 mg·kg−1
maintenance, n=5) and high (90 mg·kg−1 loading, 45 mg·kg−1 maintenance, n=5) doses of
HCQ in intranasally and intratracheally infected macaques showed no effect on virus
clearance when treated within 1 day of inoculation [133, 134]. Similarly, another study
showed that prophylactic (6.5 mg·kg−1 orally on days −9, −2 and 5 of infection) and
therapeutic (6.5 mg·kg−1 orally 12 h post-infection and roughly every 12 h thereafter) HCQ
treatment of macaques infected with SARS-CoV-2 showed no significant mitigation of
viral load or differences in inflammatory cytokines, despite the detection of HCQ in
plasma (prophylactic: 2–31 nM, n=5; therapeutic: 24–292 nM, n=5) and lung tissues
( prophylactic: 1.5–12.5 nmol·g−1 tissue, n=5; therapeutic: 4.1–34.3 nmol·g−1 tissue, n=5) in
all macaques [106].
So far, RDV is the only repurposed antiviral that shows benefit in NHP models. Rhesus
macaques infected with SARS-CoV-2 and treated early with RDV (12 h post-infection) saw
reduced respiratory disease and pulmonary infiltrates [97]. Viral load in bronchioalveolar
lavages and the lungs were 100-fold lower (n=6) with RDV treatment (10 mg·kg−1 loading
dose, 5 mg·kg−1 maintenance dose for 6 days starting 12 h post-infection); however, RDV
could not reduce viral load in the URT [141]. While pharmacokinetics studies showed
detectable lung and serum levels of the prodrug and downstream metabolites, the authors
did not investigate RDV concentration in the URT. Whether RDV bioavailability was
sufficient for antiviral activity in the URT remains to be evaluated. This study also suggests
that treatment should be initiated as soon as possible to achieve maximal effect, although
such early timing remains difficult to achieve in clinical settings.
Conclusion
The prompt development and worldwide authorisation of multiple COVID-19 vaccines

resulted in dramatic reductions in case numbers and hospitalisations, saving countless lives.
While this is a remarkable achievement, the demand for safe and effective antiviral
therapies for COVID-19 is still crucial to reduce morbidity and mortality in unvaccinated
populations as well as breakthrough infections in the vaccinated population, made more
likely by the emergence of immune-escape variants. Furthermore, identification of
pan-coronavirus antivirals is critical to be prepared for future pathogenic coronaviruses.
Thanks to extraordinary international collaborative efforts, large independent clinical trials

using repurposed antiviral drugs against SARS-CoV-2 were implemented in real time early
in the COVID-19 pandemic. Their outcomes so far have been disappointing, as RDV was
https://doi.org/10.1183/2312508X.10024020 61
the only drug with relatively modest clinical efficacy, although this was not consistent
across independent studies.
A deeper understanding of coronavirus molecular pathogenesis is essential to validate

specific antiviral activities and delineate their mode of action. The administration mode,
timing and pharmacokinetics of antiviral drugs, in particular their bioavailability in the
lungs and URT, are critical parameters for the success of antiviral intervention against
COVID-19. Finally, monitoring the impact of treatment on viral load dynamics in different
anatomical compartments is key to characterising drug efficacy. In this context, preclinical
validation studies with ex vivo human cellular models and highly susceptible animal models
are essential tools to select candidates with strong antiviral potential and safety to be
included in clinical trials.
Importantly, it remains essential, as part of pandemic preparedness, to sustain fundamental

and translational research in pathogenic HCoVs to identify and validate new classes of
antivirals and expand the repertoire of drugs available. In addition to providing multiple
therapeutic options, the key benefit of having different classes of drugs is to block the virus
at different steps of its replication cycle. Such a drug combination approach can lead to
synergistic and more specific antiviral effects and has the added benefit of limiting the
potential emergence of drug-resistant mutants.
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Support statement: This work is supported by Health Research Board (HRB) grant ref no. COV19-2020-088
and Science Foundation Ireland (SFI) grant ref no. 20/COV/8570 as part of the COVID-19 Rapid Response
Research and Innovation Programme established by the Irish government. S. O’Reilly is the recipient of the
Irish Research Council (IRC) Government of Ireland Postgraduate Scholarship, grant ref no. GOIPG/2019/4432.
68 https://doi.org/10.1183/2312508X.10024020
| Chapter 5
Can the immune system be
targeted to treat COVID-19?
Sarah Abdelhafeez1 and Derek Doherty2
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 [https://doi.org/10.1183/2312508X.10024120].
@ERSpublications
Our immune system is vital to fight SARS-CoV-2 infection. However, an overzealous
immune response to SARS-CoV-2 causes morbidity and mortality. This chapter
discusses the immunology of COVID-19 and how it might be targeted by therapeutics
and vaccines. https://bit.ly/3sYBXEZ
S ARS-CoV-2, the causative agent of COVID-19, belongs to the family Coronaviridae,

where “corona” comes from the crown-like resemblance due to the viral spike (S)
proteins projecting from the viral envelope (figure 1) [1]. Currently, the diagnosis of
COVID-19 relies on reverse transcriptase quantitative PCR detection of viral nucleic acids
from nasopharyngeal swabs, yet many individuals who remain asymptomatic or experience
mild disease harbour virus below the levels detected by routine SARS-CoV-2 screening
services [2]. SARS-CoV-2 has been shown to activate innate and adaptive immune
responses; however, uncontrolled or impaired immunity can lead to severe forms of the
disease [3].
Understanding the underlying immunology influencing disease expression and the natural
history of the virus is imperative to develop preventative and therapeutic strategies to tackle
the COVID-19 pandemic. This chapter discusses 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.
1
Trinity College Dublin, Dublin, Ireland. 2Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
Correspondence: Sarah Abdelhafeez (abdelhas@tcd.ie)
https://doi.org/10.1183/2312508X.10024120 69
SARS-CoV-2 RNA Spike protein
Envelope protein Nucleocapsid protein
Lipid envelope Membrane protein
Figure 1. Structure of the SARS-CoV-2 virion. SARS-CoV-2 is an enveloped, positive-sense, single-stranded

RNA betacoronavirus. Its virion is spherical, with four structural proteins. The spike glycoprotein,
membrane protein and envelope protein are located in its lipid bilayer, and the nucleocapsid protein is
complexed with the large viral RNA genome and is associated with the membrane protein.
Innate immunity and therapeutics
The innate immune system acts as a first-line defence against SARS-CoV-2 infection and
comprises physical, cellular and chemical defences. It is essential for the recognition and
restriction of pathogens, and for the consequent activation of the adaptive immune
response [4]. Various innate immune mechanisms and players have been implicated in
immunity against the virus and in COVID-19 pathophysiology, providing potential targets
for therapeutic interventions.
Initiating the innate immune response
The life cycle of SARS-CoV-2 in an infected cell begins with virus entry via the ACE2
receptor (figure 2) [1]. The viral RNA is replicated, and interrupted transcription produces
multiple mRNAs, which are translated into viral proteins. The virions are assembled in the
endoplasmic reticulum and Golgi apparatus before being released from the infected cell [5].
Pathogen recognition receptors (PRRs), which recognise pathogen-associated molecular

patterns (PAMPs) (figure 3), are expressed by SARS-CoV-2-infected cells and innate immune
cells, such as macrophages and dendritic cells. PAMPs include viral single-stranded and
70 https://doi.org/10.1183/2312508X.10024120
IMMUNOLOGY | S. ABDELHAFEEZ AND D. DOHERTY
ACE2 receptor TMPRSS2
SARS-CoV-2 Cytoplasm
1
2
Ribosome
Endosome 3
Viral ssRNA (+sense)
Viral RNA Viral RNA
(–sense) 5 (+sense)
4
9 Viral polymerase
Series of mRNAs 6
ER 8 Viral
proteins
Golgi
SARS-CoV-2 RNA Spike protein 7
Envelope protein Nucleocapsid protein
Lipid envelope Membrane protein
Figure 2. Life cycle of SARS-CoV-2. 1) Virus entry is via the ACE2 receptor, which is highly expressed in
many cells along the respiratory tract, in the oesophagus, and in myocardial cells and kidney cells, among
others. The S protein binds to ACE2, followed by the SARS-CoV-2 virion being proteolytically processed and
activated by transmembrane protease serine 2 (TMPRSS2) on host cells. 2) Once SARS-CoV-2 is
endocytosed, viral positive-sense, single-stranded RNA (ssRNA) is released inside the host cell. 3) The viral
polymerase protein is translated. 4) The viral polymerase protein transcribes negative-sense viral RNA.
5) The viral polymerase uses this negative-sense viral RNA as a template to produce more positive-sense
viral RNA. 6) Interrupted transcription then produces multiple mRNAs. 7) These mRNAs are translated into
structural and nucleocapsid viral proteins. 8) The viral RNA and proteins are assembled into virions in the
endoplasmic reticulum (ER) and Golgi apparatus. 9) The virions undergo vesicle-mediated transport and are
exocytosed from infected cells.
double-stranded RNA produced during replication, which bind to the endosomal Toll-like
receptor (TLR) 3 and TLR7 [6]. PRRs such as membrane-associated TLR2 have been
reported to be activated by SARS-CoV-2 envelope (E) and S proteins [7]. Other studies have
demonstrated that SARS-CoV-2 S protein can also bind and activate TLR1, TLR4 and TLR6
[8]. Other PRRs such as retinoic acid-inducible-gene I receptor (RIG-I) and melanoma
differentiation-associated protein 5 (MDA5) act as RNA sensors [8]. Recognition by PRRs
continues throughout the life cycle of SARS-CoV-2 in the host cell (figure 3) [7]. Upon
recognition, signalling pathways are triggered, resulting in the production and recruitment of
innate immune cells and cytokines. Results from studies of SARS-CoV-1 suggest that
SARS-CoV-2 may modify PRR expression. SARS-CoV-1 can lead to ubiquitination of RIG-I,
MDA5, and TLR3, TLR7 and TLR8, which tags them for degradation [8]. The evasion of
immune recognition of SARS-CoV-2 leads to a dampened innate immune response and
allows diffuse virus replication. This rapidly increasing viral load can trigger an unchecked
immune response, resulting in excessive inflammation and damage to host tissues [9].
https://doi.org/10.1183/2312508X.10024120 71
Recognition T-cell receptor
PRRs CD4+
T-cells
SARS-CoV-2
Innate immune cells
Antiviral
response CD8+
Production of type I T-cells
IFNs
Aberrant Lymphopenia
immune Exhaustion
1. Neutrophilia (increased neutrophils)
response
2. Depleted and functionally impaired
Host tissue
NK cells
damage
3. SARS-CoV-2 infects macrophages and
uses them to evade immunity
4. Increased macrophages e.g. IL-6, Cytokine storm
5. Exhausted dendritic cells IL-1β, TNF-α Hyperinflammation
Increased pro-inflammatory
cytokine production
Figure 3. Immune responses to SARS-CoV-2 infection. Innate immune cells include cytotoxic cells such as
natural killer (NK) cells and phagocytes such as neutrophils, macrophages and dendritic cells. Dendritic
cells also act as professional antigen-presenting cells and bridge the innate and adaptive immune system.
Pathogen recognition receptors (PRRs) can be expressed by innate immune cells and other tissue cells.
PRRs recognise pathogen-associated molecular patterns or PAMPs, including viral single-stranded and
double-stranded RNA produced during replication. Upon recognition, signalling pathways are triggered,
which result in the production and recruitment of innate immune cells and cytokines. Antigens are
presented to cytotoxic CD8+ and helper CD4+ T-cells, which can further differentiate into effector T-cells.
A controlled immune response results in successful virus clearance and optimum antiviral activity.
However, SARS-CoV-2 can modulate the immune response, resulting in extensive tissue damage, mortality
and morbidity in COVID-19 patients.
Cytokines
Cytokines, including IFNs, ILs and chemokines, among others, are effector molecules of
the immune system. They act as signalling molecules that regulate immunity, inflammation,
migration of cells and haematopoiesis [10]. An unbalanced cytokine response is a
significant driver of pathology in COVID-19 patients, and dysregulated innate immunity
has been linked with cytokine storm development [6]. Studies of critically ill COVID-19
patients show an increase in circulating pro-inflammatory cytokines, including IL-6 and
TNF-α, and anti-inflammatory cytokines such as IL-10. Increased granulocyte
colony-stimulating factor, which stimulates granulocyte production in the bone marrow,
and C-C motif chemokine ligand 2 (CCL2), a monocyte chemoattractant, has also been
noted [11]. This has also been documented in SARS and MERS, where an overactive
immune response results in ARDS, multiorgan failure and death [12]. A cytokine storm
refers to the release of an abundance of pro-inflammatory cytokines resulting in an
aggressive immune response, and is implicated in severe forms of COVID-19. Different
factors trigger this aberrant immune response and ultimately result in a positive-feedback
loop of hyperinflammation and tissue damage [8]. Findings from in vitro studies show that
a high SARS-CoV-2 load and disordered cytokine production can lead to a cytokine storm,
accompanied by immunopathological changes in the lungs [13].
72 https://doi.org/10.1183/2312508X.10024120
Once SARS-CoV-2 RNA binds to TLRs, IL-1β and IL-6 are released and are the primary
cytokines associated with fatal outcomes in COVID-19 patients [6]. The highest levels of
IL-6 have been observed in severe COVID-19 patients and nonsurvivors; hence,
monoclonal antibodies (mAbs) directed against IL-6 can alleviate symptoms of COVID-19
[14]. Initially, the SARS-CoV-2 nucleocapsid (N) protein binds to the NF-κB regulatory
elements of the IL-6 promoter, which induces IL-6 expression in the infected airway
epithelium. The mechanism that sustains IL-6 elevation is unclear but is believed to be
driven by SARS-CoV-2-specific PRR activation [6]. TNF-α and IL-6 are both pyrogens
and, with IL-1β, increase vascular permeability, leading to loss of the alveolar–capillary
barrier and culminating in secondary alveolar oedema. TNF-α is also involved in lung
inflammation and fibrosis [8].
IFNs
The binding of PAMPs to PRRs triggers various signalling pathways involved in activating
transcription factors such as NF-κB, IFN-regulatory factor 3 (IRF3) and activator protein 1
(AP-1). These factors synergistically promote the production of type I IFNs, such as IFN-α,
-β and -ω cytokines [6]. Type I IFNs play an essential role in the antiviral response on a
cellular level via the janus kinase ( JAK)/signal transducer and activator of transcription
(STAT) signalling pathway [1]. These cytokines then act in a paracrine manner via IFN-α/β
receptors on neighbouring cells, which leads to the induction of IFN-stimulated gene (ISG)
expression [6]. IFN-α and -β expression determines the magnitude of the innate immune
response, similar to other viral infections. In COVID-19 patients, an impaired type I IFN
response is correlated with critical disease and worse clinical outcomes [3]. IFN-α robustly
inhibits the replication of SARS-CoV-2 in vitro [15]. IFN-β is the leading driver of the
innate immune response in human lungs, and studies show direct suppression of its release
by SARS-CoV-2 [16]. Type I IFNs subsequently stimulate other cytokines and the
expression of antimicrobicidal peptides, and induce expression of ISGs [8]. ISG products
play a vital role in the innate antiviral defence by limiting the entry of virus into host cells
and restricting virus replication after virus entry. ACE2 is an established ISG, and studies
suggest that SARS-CoV-2 may manipulate ACE2 upregulation driven by IFNs to enhance
infection [17].
A subset of critically ill COVID-19 patients have presented with autoantibodies against
type I IFNs, which may be associated with abnormal immune changes and a severe disease
course [17, 18]. Studies have found that the presence of type I IFN-specific autoantibodies
correlated with decreased ISG expression, an overall impaired type I IFN response and a
positive correlation with hospitalisation [19, 20]. Detecting the presence of these anti-type I
IFN autoantibodies could identify patients at risk of developing critical disease, but they
have not been found to be associated with poorer outcomes in already severely ill
COVID-19 patients [18].
Type III IFNs (IFN-λ) work synergistically with type I IFNs to inhibit RNA and DNA virus
replication [3]. Like type I IFNs, IFN-λ is also found to be decreased in COVID-19
infections and is reported to interfere with SARS-CoV-2 replication in human intestinal
cells in vitro [21]. Notably, IFN-λ is present in the lower airways of COVID-19 patients and
has antiproliferative effects on lung epithelial cells by harnessing p53, a tumour suppressor
gene. This slows lung epithelial repair, which may increase the risk of bacterial
superinfection during COVID-19 and result in life-threatening complications [22].
https://doi.org/10.1183/2312508X.10024120 73
SARS-CoV-2 immune evasion strategies and consequences
Studies from SARS-CoV-1 and MERS-CoV show that both structural and nonstructural
proteins play crucial roles in manipulating the host immune response, and some of the
mechanisms that exploit the IFN response are conserved in SARS-CoV-2. These include
avoiding virus detection by PRRs, suppressing IFN transcription and inhibiting IFN-α/β
receptor signalling. It has been shown that 90% of the N protein sequence of SARS-CoV-1
is conserved in SARS-CoV-2, which suggests that SARS-CoV-1 mechanisms of immune
avoidance are probably conserved in SARS-CoV-2 [6]. A study has shown that the
SARS-CoV-2 N protein open reading frame (ORF) 3b protein is a potent inhibitor of IFN
by suppressing its induction more efficiently than its SARS-CoV-1 orthologue [23]. HACHIM
et al. [24] identified ORF3b to be one of the most prevalent antibody-recognised antigens
during early and late SARS-CoV-2 infection, along with the ORF8 protein. SARS-CoV-2
matrix (M) protein inhibits the production of type I and type III IFNs via the RIG-I/
MDA5– mitochondrial antiviral signalling (MAVS) pathways [25].
Another example of the immune evasion strategy of SARS-CoV-1 that may translate to
SARS-CoV-2 is modulating transforming growth factor (TGF)-β receptor signalling by
forming a complex with SMAD family member 3 (SMAD3) proteins. This enhances the
transcription of SMAD3, which is acetylated by the p300 protein, driving lung fibrosis. This
interaction also prevents the complex formation of SMAD3/SMAD4, which enhances
infected cell survival by antagonising TGF-β-sensitised apoptosis [26].
Drugs targeting cytokines
To limit the progression of COVID-19, a balance between pro-inflammatory and

anti-inflammatory immune responses is necessary.
IFN-directed therapy may be useful in COVID-19 infection as SARS-CoV-2 impairs the

type I IFN response. A retrospective analysis of COVID-19 treatment guidelines in China
using aerosolised-recombinant IFN-α, given in combination with ribavirin, an antiviral
used to treat hepatitis C, and the antiretrovirals ritonavir and lopinavir used in HIV
treatment, reported a modest benefit of IFN-α [27]. While assessing the efficacy of IFN-α
alone is difficult, this suggests that induction of the type I IFN pathway is beneficial to
COVID-19 patients. A phase 2 trial showed that a s.c. injection of IFN-β1b combined with
lopinavir, ritonavir and ribavirin in mild-to-moderate COVID-19 patients relieved
symptoms, reduced the length of hospital stay and had no serious adverse effects [28].
Synairgen completed a phase 2 trial of a nebulised solution of IFN-β (SNG001) in 101
COVID-19 patients for 14 days, which showed that this drug was well tolerated and also
revealed an improvement in breathing [16].
However, IFN therapies may not be useful, as it is unclear whether the IFN response
inhibits SARS-CoV-2 replication in vivo. Furthermore, SARS-CoV-2 has been shown to
harness ISGs to boost infectivity [17]. IFN therapies may also cause an excessive
pro-inflammatory response and perpetuate host tissue damage, so more studies into
combination therapies with larger sample sizes should be executed.
Many studies repurposing current biologics to manipulate ILs in COVID-19 have been
carried out. Clinical trials of tocilizumab (TCZ), an antirheumatic mAb against the IL-6
74 https://doi.org/10.1183/2312508X.10024120
receptor, in COVID-19 patients have shown promising results. XU et al. [29] reported
improved symptoms in 15 out of 20 COVID-19 patients treated with TCZ for 5 days.
ROJAS-MARTE et al. [30] studied TCZ in 193 COVID-19 patients and, when intubated
patients were excluded, the results showed a statistically significant decrease in mortality. The
US Food and Drug Administration (FDA) is carrying out phase 3 trials of TCZ in patients
with severe COVID-19 pneumonia [1]. Siltuximab, a mAb against IL-6, and sarilumab, an
anti-IL-6 receptor mAb, are currently being trialled with clinical improvements and reduced
inflammation reported in cases [31, 32]. Another antirheumatic drug, anakinra, has been
studied in COVID-19 patients, and this IL-1 receptor antagonist has been reported to
improve respiratory function and survival [33]. These therapies could be used early in
SARS-CoV-2 infection to prevent a cytokine storm and benefit patients with comorbidities.
Innate immune cells
The recruitment of innate immune cells, another hallmark of inflammation, is strongly

influenced by an individual’s chemokine profile. In COVID-19, cytokine patterns show
decreased serum levels of IFNs but increased levels of pro-inflammatory cytokines and
chemokines, such as CXC motif chemokine ligand 2 (CXCL2) and CXCL8, which recruit
neutrophils, CCL2 and CCL8, which recruit monocytes/macrophages, and CXCL16, which
attracts natural killer cells [8].
Neutrophils
Neutrophils are polymorphonuclear cells that act as “first responders” to infection by

bacteria and fungi. A local burst of inflammatory cytokines such as IL-6 and chemokines
such as CXCL8 and CXCL2 results in neutrophil migration from the bone marrow and
rapid recruitment to lung parenchyma [8]. In contrast to what was previously thought,
neutrophils also play a role in viral infection [34]. Neutrophilia is an early indicator of
COVID-19 and is an indicator of poor outcomes [35]. Neutrophils limit infection by
phagocytosis of pathogens and degranulation of antimicrobial proteins. They are involved
in cytokine production, which restricts virus replication, and neutrophils release high levels
of reactive oxygen species to suppress viral activity [35]. In bronchoalveolar lavage analysis
of COVID-19 patients, reactive oxygen species can lead to oxidative stress and can trigger a
cytokine storm [6]. SARS-CoV-2-activated neutrophils can induce apoptosis, and in
nonsurvivors, extensive neutrophil infiltration in pulmonary capillaries and the alveolar
space in the lower respiratory tract is reported [34].
Neutrophils can produce neutrophil extracellular traps (NETs), which contain DNA fibres,
histones and microbicidal proteins [36]. NETs prevent the spread of pathogens by trapping
and inactivating them using proteins such as neutrophil elastase, cathepsin G and
lysozymes [35]. Research has determined IL-1β, often elevated in COVID-19 patients, to be
the primary inductor in NET production (NETosis). NETs have also been found to
stimulate macrophages to increase IL-1β production, creating a positive-feedback loop [36].
Excessive NETosis damages pulmonary endothelium and causes von Willebrand factor
release, which further activates neutrophils and stimulates platelets to produce clots [36].
Furthermore, NETosis has been implicated in organ damage and mortality in COVID-19
patients [35]. Therapeutics targeting NET formation are being considered in COVID-19
treatment. Dipyridamole, an FDA-approved adenosine uptake inhibitor used to reduce
blood clotting, also inhibits NET formation [37]. Anakinra, mentioned earlier, may also
disrupt the IL-1β–NET feedback loop [36].
https://doi.org/10.1183/2312508X.10024120 75
Natural killer cells
Natural killer (NK) cell numbers are depleted and their functions impaired in patients with
severe COVID-19 [38]. NK cells are cytotoxic cells that mediate the direct killing of
virus-infected cells via Fas cell surface death receptor (FAS) and TNF-related
apoptosis-inducing ligand (TRAIL) receptor binding on target cells and by releasing the
cytotoxic molecules perforin, granzymes and cytokines such as IFN-γ, TNF-α, TNF-β,
IL-10 and granulocyte–macrophage colony stimulating factor [38]. An in vitro model of
SARS-CoV-2 infection showed that antibodies against SARS-CoV-2 S protein can induce
NK cell-mediated antibody-dependent cytotoxicity, illustrating that NK cells contribute to
protective immunity against the virus [6]. NK cells express cluster of differentiation
molecule 16 (CD16), which binds to the Fc portions of antibodies leading to the
antibody-dependent killing of the target cell. In SARS-CoV-2 infection, CD16 expression
on NK cells is significantly downregulated [39]. In mild COVID-19 cases, a reduction in
peripheral blood NK cell concentrations is often observed, and NK levels are lowest in fatal
disease [38]. Low NK levels are correlated with higher IL-6 plasma levels, suggesting
ineffective virus-limiting action by NK cells and increased inflammation [39].
NK cell exhaustion in COVID-19 patients is associated with disease exacerbation.

Peripheral NK cells in COVID-19 patients show decreased production levels of
pro-inflammatory IFN-γ and IL-2, involved in T-helper cell type 1 immune responses and
differentiation of naive T-cells into effector T-cells, respectively [8]. Reduced CD107a, a
marker of degranulation in NK cells and CD8+ T-cells, and increased expression of the
inhibitory NK cell receptor NKG2A, were also reported. IL-6 and IL-10 have been shown
to promote this exhaustion marker [8]. The full implication of this functional impairment
remains unclear, but reversing it may prove a useful therapeutic strategy. Notably, in vitro
studies demonstrate that IL-6 and soluble IL-6 receptors also impair the production of the
cytotoxic effector molecules perforin and granzyme B by healthy donor NK cells, but this
was restored by TCZ treatment [40]. Targeting programmed cell death protein 1 (PD1), an
inhibitory checkpoint expressed by T-cells and NK cells, has been studied in COVID-19
patients to reverse their functional exhaustion and restore their cytotoxicity. Four clinical
trials studying the anti-PD1 mAbs pembrolizumab or nivolumab in SARS-CoV-2-infected
individuals are underway (ClinicalTrials.gov identifiers NCT04335305, NCT04343144,
NCT04413838 and NCT04356508). However, PD1 blockade was reported to cause
excessive inflammation and tissue injury [8]. Therefore, anti-PD1 mAbs, combined with
drugs to prevent treatment-associated inflammation, could be promising in COVID-19
treatment.
Macrophages
Macrophages are antigen-presenting cells involved in phagocytosis and are derived from
circulating monocytes. M1 macrophages produce pro-inflammatory cytokines, phagocytose
pathogens and produce cytotoxic nitric oxide, a vasodilator. Conversely, M2 macrophages
produce anti-inflammatory molecules such as IL-10 and are involved in tissue repair [41].
In early SARS-CoV-2 infection, macrophages can limit virus replication by initiating a type I
IFN response, recruiting other immune cells or inducing CD4+ T-cell differentiation [3].
However, SARS-CoV-2 virions can directly infect macrophages and manipulate them to
evade immunity [3]. Macrophages that expressed ACE2 and engulfed the SARS-CoV-2
N protein were reported to infiltrate the spleen and lymph nodes of COVID-19 patients [8].
76 https://doi.org/10.1183/2312508X.10024120
These macrophages produced copious amounts of IL-6, which stimulates the production of
the inflammatory mediator CRP, typically lacking in viral infections [8]. In severe COVID-19,
there is an increase in macrophages in the lungs, predominantly the M1 phenotype, which
increases short-term mortality, causes delayed recovery of affected tissues and ultimately
results in long-term complications due to chronic inflammation [42].
Pulmonary macrophages have two distinct populations: interstitial macrophages and

alveolar macrophages. A subset of interstitial macrophages, nerve- and airway-associated
macrophages (NAMs), may be significant in the anti-HCoV immune response. Influenza
studies have demonstrated that alveolar macrophages have a pro-inflammatory, antiviral
function, whereas NAMs limit excess virus-induced inflammation by producing IL-10 [43].
Studies have identified distinct macrophage population patterns in COVID-19. In mild
disease, anti-inflammatory monocyte-derived macrophages dominate, whereas in severe
disease, pro-fibrotic and inflammatory alveolar macrophages are enriched. These results
indicate that macrophage polarisation and the relative proportions of macrophage subtypes
play a significant role in COVID-19 severity [6]. More studies to investigate this are
necessary, but theoretically, macrophage activity modulation may be promising in
SARS-CoV-2 infection treatment.
Dendritic cells
Dendritic cells (DCs) are professional antigen-presenting cells that are essential for priming
antigen-specific T-cell responses. A subset of DCs, known as plasmacytoid DCs (pDCs),
play a crucial role in antiviral immunity. They effectively sense intracellular viral RNA via
TLRs and produce large amounts of type I and III IFNs [44]. Any DC that is not a pDC is
referred to as a conventional DC (cDC), and peripheral blood studies show depletion of
cDCs in COVID-19 patients suffering from ARDS [45]. Mature DCs can stimulate helper
CD4+ and cytotoxic CD8+ T-cell memory, and SARS-CoV-2 has been shown to target DCs
directly to limit their maturation, resulting in a delayed immune response [6, 45]. Studies
report a slight increase in mature DCs from bronchoalveolar lavage fluid analysis,
suggesting that they participate in the anti-SARS-CoV-2 immune response in the lungs
[46]. Conversely, other studies have shown reduced numbers and function of DCs in
COVID-19 patients but an increase in the cDC/pDC ratio, with subsequent T-cell
activation impairment [47]. These studies demonstrate that SARS-CoV-2 modulation of
DCs may contribute to the lack of long-lasting adaptive immunity and other defects in
humoral immunity associated with COVID-19 due to interference with T-cell activation.
Aberrant complement and coagulation systems in COVID-19
Along with a cytokine storm, an overactive complement system and aberrant coagulation
contribute to severe COVID-19 and result in a hyperinflammatory, pro-thrombotic state that
causes diffuse tissue damage [48]. Pulmonary micro-thrombosis has been identified in
COVID-19 patients and has been associated with ARDS development. This hypercoagulable
state may trigger disseminated intravascular coagulation, a severe blood-clotting disorder
that culminates in multiorgan dysfunction, in COVID-19 patients [49].
The complement system is an early responder to bacterial and viral infections. It comprises
30 different proteins acting in three pathways, the classical, lectin and alternative pathways,
which converge and lead to activation of the complement components C3 and C5. C3 is
https://doi.org/10.1183/2312508X.10024120 77
proteolytically cleaved into C3a and C3b by C3 convertase. C3b is involved in the
opsonisation of pathogens and contributes to the cleavage of C5 into C5a and C5b. C3a
and C5a promote local inflammation, whereas C5b joins with C6–C9 to form the
membrane attack complex (MAC), resulting in pathogen lysis [50].
Increased serum levels of complement components have been reported in COVID-19

patients. CARVELLI et al. [51] demonstrated a direct correlation between the level of soluble
C5a in COVID-19 patients and the severity of the disease. In post-mortem studies of
SARS-CoV-2-infected lung tissue, GAO et al. [52] reported high expression of
mannose-binding lectin (the initial component of the lectin pathway), C3, C4 and C5b–9
(MAC) in alveoli and pneumocytes.
Virus activation of the coagulation cascade can activate the complement system. Thrombin
and plasmin, coagulation pathway proteins, can cleave C3 and C5, releasing C3a and C5a
anaphylatoxins [53]. Conversely, the complement system amplifies vessel coagulation. C3a
and MAC are implicated in platelet activation, and C5a increases the expression of plasma
and cellular tissue factor, which initiates coagulation [49]. This simultaneous stimulation of
the pro-coagulation mechanisms and dampening of anticoagulation systems results in a
vicious cycle, seen in SARS-CoV-2 pathology [50].
Life-threatening complications, including pulmonary embolism, DVT, myocardial infarction

and ischaemic stroke, can arise from increased disseminated coagulation in COVID-19
patients, despite providing anticoagulant prophylaxis [54]. Studies show that >80% of severe
COVID-19 patients have elevated D-dimer levels, a marker of fibrin-clot formation and
breakdown and of COVID-19 disease severity [55]. Post-mortem lung studies of COVID-19
patients have noted that thrombotic microvascular injury was accompanied by
fibroproliferative changes [56]. Combined, these data show that aberrant complement and
innate immune activation drives clotting cascade activation, vessel oedema and
haemorrhagic consequences, which are complications of COVID-19-associated pneumonia.
Treatment targeting the complement and coagulation systems
Understanding the role of complement in SARS-CoV-2 pathophysiology opens up a realm

of possible therapeutics. Currently, C3 and C5 inhibition are potential targets for
COVID-19 treatment. Eculizumab is an anti-C5 mAb that the FDA has already approved
for use in various autoimmune diseases [57]. DIURNO et al. [58] studied its use in four
critically ill patients with COVID-19 and reported a full recovery in all patients plus a
reduction in their inflammatory markers.
GAO et al. [52] studied BDB-001, another anti-C5a mAb, in COVID-19 patients, and
showed improvement in clinical status within a few days of treatment. AMY-101, a
compstatin-based anti-C3 drug, has been studied in ex vivo whole-blood infection models
and has been reported to interfere with IL-6 release [59]. Narsoplimab, an
anti-mannan-binding lectin serine protease 2 (MASP2) antibody involved in the formation
of C3 convertase in the lectin pathway, has been tested in severe COVID-19 patients.
RAMBALDI et al. [53] reported that this drug caused a rapid and sustained decrease in levels
of the cytokines IL-6 and IL-8 and other markers of endothelial damage such as circulating
endothelial cells, CRP and LDH levels. A decrease in endothelial cell damage and
inflammation is accompanied by a decrease in thrombotic risk [59].
78 https://doi.org/10.1183/2312508X.10024120
Another possible therapeutic opinion is plasmapheresis, the separation of plasma from

other parts of blood, to reduce cytokine levels, complement and coagulation factors. This
already exists as a recommended treatment for many autoimmune diseases such as
thrombotic thrombocytopenic purpura [57].
Adaptive immunity and therapeutics
SARS-CoV-2 antigens are processed into peptides and presented on major histocompatibility
complexes (MHCs) to T-cells. This begins the COVID-19 adaptive immune response, which
involves a cell-mediated response by T-cells and a humoral response by B-cells [8].
T-cell response
T-cell immunity is vital in SARS-CoV-2 infection and may play a role in the progression of
COVID-19 [57]. The major types of T-cells, CD4+ helper and CD8+ cytotoxic T-cells, are
directly involved in the anti-SARS-CoV-2 response by killing infected cells and regulating
other cellular and humoral responses. Cytotoxic T-cells are primed to identify viral
antigens bound to MHC class I and eliminate the virus by releasing granules containing
perforin and granzymes, which induce apoptosis of virus-infected cells [8]. Helper T-cells
identify viral antigens bound to MHC class II and act to stimulate cytotoxic T-cells further
and release cytokines that control macrophage activation, neutrophil recruitment and
immunoglobulin (Ig) class switching in B-cells [60].
Mild cases have shown an elevated CD4+ and CD8+ response and robust antiviral activity associated
with a better prognosis. In contrast, severe cases show T-cell exhaustion and lymphopenia in all
T-cell subsets [61]. Hyperactivated CD8+ T-cells express high levels of NK group 2 member
A (NKG2A), an NK exhaustion marker, and show decreased cytokine production [8].
A study of recovered COVID-19 patients reported that SARS-CoV-2-specific memory

T-cell responses acquired in the early convalescent phase persisted in patients lacking
detectable SARS-CoV-2 antibodies [62]. Previous SARS-CoV-1 studies have reported that
antibody levels diminish over time; however, cellular immunity can last up to 11 years [61].
Identifying viral peptides that elicit a T-cell response (i.e. T-cell epitopes) is imperative for
measuring the cellular response at different stages of disease and T-cell response duration,
which can test vaccine efficacy [63]. However, experimental identification of T-cell epitopes
is challenging. SARS-CoV-2-reactive CD4+ T-cells can be identified in 40–60% of
unexposed individuals, demonstrating cross-reactivity between HCoVs due to their low
genetic variation [61]. Furthermore, human leukocyte antigen (HLA) alleles, which code
for MHC class I and II, are highly polymorphic. An individual has up to 12 unique types
of HLA alleles, but more than 27 000 types are known [63].
In silico methods that utilise various technical approaches and machine learning have been
implemented to overcome these challenges. LEE et al. [61] identified 57 T-cell epitopes from
within the N and S proteins that can bind to various HLA alleles and effectively detect
cellular immune responses in 80–100% of the global population. Of these, 11 were unique
to SARS-CoV-2 and noncross-reactive to seasonal HCoVs. CAN et al. [64] analysed the full
SARS-CoV-2 genome to predict T-cell epitopes and reported that epitopes from the
S protein had the highest antigenicity potential.
https://doi.org/10.1183/2312508X.10024120 79
A coordinated Ig and T-cell response is understood to be protective in COVID-19.

Ongoing B- and T-cell epitope studies could lead to the development of an epitope-based
peptide vaccine to optimise this [64].
B-cell response
Recovered COVID-19 patients have antibodies to SARS-CoV-2, mainly to the S and N

proteins [60]. Seroconversion after SARS-CoV-2 infection follows a similar timeline to that
of SARS-CoV-1 [65]. It usually begins on day 6 post-symptom onset and peaks after
14 days [3]. Numerous studies have investigated the duration of IgG, IgA and IgM
produced by B-cells against various SARS-CoV-2 antigens. Most studies report a rapid but
transient IgA and IgM response against the receptor-binding domain (RBD) of the
S protein and against the N protein. Studies have described how specific IgGs against the
RBD and S and N proteins are produced at a slower rate than its IgA or IgM counterparts,
but they remain at a consistent level and are more durable [3, 8].
Neutralising antibodies (nAbs) block viral infections by targeting virus–receptor

interactions or by binding to the virus itself to prevent uncoating of its genome [66]. Most
of the identified nAbs are specific to the RBD of the SARS-CoV-2 S protein [67]. ROBBIANI
et al. [68] noted that the levels of nAb to SARS-CoV-2 S protein were low in convalescent
COVID-19 patients and correlated positively with age, symptom severity and duration. Five
therapeutic nAbs targeting the RBD and S protein of SARS-CoV-2 are undergoing clinical
trials, aiming to provide short-term, immediate protection against viral infection, unlike
vaccines, which take weeks to produce immunity in individuals [67].
Vaccines
Previously, vaccine development has taken 10–15 years, and an effective and accessible
SARS-CoV-2 vaccine is needed to safely establish herd immunity. Wearing masks, social
distancing, contact tracing and self-isolation have been implemented to limit transmission.
Nonetheless, to minimise morbidity and mortality from COVID-19, vaccines are needed as
well as therapeutics [69]. A successful SARS-CoV-2 vaccine must elicit a sufficient number
of nAbs and a strong T-cell response to ensure effective and long-lasting immunity. Various
vaccine candidates using different vaccine platforms such as RNA, DNA, nonreplicating
viral vectors and inactivated virus have been tested [60]. Phases 1 and 2 of human clinical
trials have been combined to expedite the process, where vaccine safety, immunogenicity
and dose are tested in various group sizes and demographics directly, instead of first in
immunocompetent individuals and then in a wider population. Phase 3 trials are large-scale
trials that evaluate vaccine efficacy and the vaccine’s side-effect profile [60].
As of November 2021, four vaccines have been approved for use in the European Union
(EU) and the UK: the mRNA vaccines by Pfizer/BioNTech and Moderna, and the
recombinant chimpanzee and human adenoviral vector vaccines by Oxford/AstraZeneca
and Johnson & Johnson, respectively. In the EU and UK, Pfizer/BioNTech, Moderna’s
mRNA and Oxford/AstraZeneca’s inactivated chimpanzee-adenoviral vector are the leading
vaccine contenders. The WHO indicated a minimum of 50% efficacy in its target profile to
approve a vaccine for emergency use [70]. The primary end-point of the above vaccines is
preventing COVID-19 and a safety profile. Both Pfizer/BioNTech (BNT162b2) and
Moderna (mRNA-1273) vaccines use a lipid nanoparticle-encapsulated mRNA-based
80 https://doi.org/10.1183/2312508X.10024120
vaccine that encodes a pre-fusion, stabilised, full-length SARS-CoV-2 S protein. The

BNT162b2, mRNA-1273 and Oxford/AstraZeneca AZD1222 vaccines are given in two
doses, 21 days, 28 days and 4–12 weeks apart, respectively [69–71].
BioNTech/Pfizer recruited 43 548 participants over 16 years of age, giving 30 μg per dose
via intramuscular injection into the deltoid. The results show 95% efficacy, and a similar
vaccine efficacy was reported across subgroups defined by sex, age, race and previous health
conditions. The most common adverse effect reported was pain at the injection site; others
included fatigue and headache. The incidence of severe adverse effects was low and was
similar in both the vaccine and placebo groups [71].
Moderna recruited 30 420 volunteers >18 years of age with circumstances or in locations
that put them at risk for SARS-CoV-2 infection. The standard dose was 100 μg per dose of
mRNA-1273, and the trial reported 94.1% efficacy. No safety concerns arose, apart from
self-limiting side-effects similar to the BNT162b2 vaccine. Delayed reactions at the injection
site, including erythema, induration and tenderness, were self-limiting and occurred in
0.8% and 0.2% after the first and second doses, respectively [69].
Oxford/AstraZeneca recruited 11 636 participants. The trial involved geographically and

ethnically diverse participants, 748 from the UK and the remaining from Brazil and South
Africa. Two variations of the vaccine dose were given, the standard dose (SD) contained
5×1010 viral particles, and a low dose (LD) contained 2.5×1010 viral particles. SD/SD
immunisation resulted in 62.1% efficacy, whereas LD/SD immunisation resulted in 90%
efficacy, possibly due to priming the immune response for a more robust response. The
vaccine also had a good safety profile [70].
The notable inactivated vaccines against COVID-19 have been developed by Sinopharm and
Sinovac, both Chinese biopharmaceutical companies, which were both granted emergency
approval by the WHO in mid-2021 [72, 73]. Sinopharm recruited 40 382 participants for their
phase 3 trial to test the efficacy and adverse events of their inactivated vaccines, one containing
the complete genome of the SARS-CoV-2 isolate WIV04 (5 µg per dose) and the other
developed from the SAR-Co-V2 HBO2 strain (4 μg per dose) [74]. Two i.m. injections of either
vaccine were administered 21 days apart. WIV04 and HBO2 vaccines were 72.8% and 78.1%
efficacious in reducing the risk of symptomatic COVID-19, respectively [74]. CoronaVac, the
inactivated whole-virion SARS-CoV-2 vaccine by Sinovac, demonstrated 83.5% efficacy after
two doses 14 days apart via i.m. injection in the 10 218 participants recruited [75].
Concerns have arisen regarding the efficacy of approved COVID-19 vaccines against the
novel SARS-CoV-2 variants. Many strains contain considerable changes to the N-terminal
domain and/or RBD of the SARS-CoV-2 S protein, which may compromise the binding
and neutralising ability of vaccine-induced antibodies [76]. Studies show small decreases in
the neutralisation of post-mRNA vaccination sera against various viral variants of interest
and concern, including alpha, beta (B.1.351), delta and iota (B.1526) [4, 76]. However,
further studies to investigate efficacy against variants are needed. Possible solutions to
overcome mutations include developing replacement vaccines, potentially based on more
conserved proteins with a lower likelihood of mutating, or developing vaccines that may
complement the current vaccines and can be administered in a “vaccine cocktail” [4].
Promising results continue to emerge from ongoing vaccine trials, and while efficacy differs,
the large array of vaccines may aid to ensure vaccine availability and accessibility globally.
https://doi.org/10.1183/2312508X.10024120 81
Conclusion
Substantial research into immune responses has been published since the pandemic’s
announcement, and an understanding of SARS-CoV-2 immunomodulating mechanisms
has provided potential therapeutic targets. Clinical trials investigating already approved
biologics and novel therapeutics in COVID-19 are underway. Immunotherapies
demonstrate promising results in preventing and restricting the excessive activation of
immune cells, hyperinflammation and coagulation seen in SARS-CoV-2 infection.
However, longitudinal studies of humoral and cell-mediated immune responses in
SARS-CoV-2 infection are necessary to provide a concrete timeline of the immune events
at different stages of infection and disease severity. This knowledge will optimise the use of
targeted immunotherapies already in clinical trials. Problems regarding the safety profile of
the immunomodulatory drugs remain, and so clinical trials of combined drug usage to
manage adverse effects are needed. A global effort into expedited vaccine development has
provided funding and support for the immense research into discovering vaccine
candidates and human clinical trials. Despite this, the production cost, storage and shelf-life
of vaccines and the spread of false information online are barriers to successful
SARS-CoV-2 vaccine distribution and uptake that must be addressed.
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use-and-issues-interim-policy-recommendations Date last accessed: 19 November 2021. Date last updated: 1 June
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74. Al Kaabi N, Zhang Y, Xia S, et al. Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19
infection in adults: a randomized clinical trial. JAMA 2021; 326: 35–45.
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75. Tanriover MD, Doğanay, HL et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine
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76. Carreño JM, Alshammary H, Singh G, et al. Reduced neutralizing activity of post-SARS-CoV-2 vaccination serum
against variants B.1.617.2, B.1.351, B.1.1.7+E484K and a sub-variant of C.37. medRxiv 2021; preprint [https://doi.
org/10.1101/2021.07.21.21260961].
https://doi.org/10.1183/2312508X.10024120 85
| Chapter 6
Lung pathology
1
Marie-Christine Copin , Jean-Baptiste Gibier2, Véronique Hofman3 and
Paul Hofman3
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.
1183/2312508X.10024220].
@ERSpublications
Several patterns of acute lung injury in COVID-19 have been described, both isolated
and combined. They correspond with diffuse alveolar damage associated with
interstitial lymphoid infiltrate or, more rarely, acute fibrinous pneumonia. https://bit.ly/
3sYBXEZ
T he management of cell and tissue samples from COVID-19 patients has been a source
of both organisational and sudden diagnostic challenge for clinical and molecular
pathologists around the world. In a study conducted in Europe, HOFMAN et al. [1] evaluated
the consequences of the COVID-19 pandemic on pathology laboratories with significant
activity in thoracic pathology during the period 15 March to 31 May 2020. Analysis of the
survey returned by 53 European pathologists showed heterogeneity of the biosafety
measures used in the first wave of the COVID-19 crisis, as well as a dramatic decrease of
the workload of pathology laboratories. Hence, the COVID-19 pandemic had a major
impact on most of the European pathology laboratories included in the study.
1
Université d’Angers, Université de Nantes, CHU Angers, Inserm, CRCINA, SFR ICAT, Angers, France. 2Université de Lille, CHU Lille,
Institut de Pathologie, Lille, France. 3Laboratory of Clinical and Experimental Pathology, FHU OncoAge, BB-0033–00025, Louis Pasteur
Hospital, Université Côte d’Azur, Nice, France.
Correspondence: Marie-Christine Copin (mariechristine.copin@chu-angers.fr)
86 https://doi.org/10.1183/2312508X.10024220
LUNG PATHOLOGY | M-C. COPIN ET AL.
The COVID-19 breakout has resulted in a high number of deaths of critically ill patients in
ICU. Beyond their routine diagnostic activity, pathologists have been on the front-line of
autopsy management of these patients. The description of autopsy lesions has been
essential for many decades as it provides a better understanding of different diseases,
including notably emerging and re-emerging infectious diseases. Nevertheless, the routine
use of increasingly sophisticated diagnostic methods, such as immunohistochemistry (IHC)
and molecular biology, has gradually limited the practice of autopsy in routine clinical
practice [2]. From the onset of the pandemic, the need for information on lung injury has
gradually increased, initially due to the unusual clinical profile of critically ill patients in
ICU. Post mortem samples were taken first by biopsy of partially and limited autopsies
because of the potential contagion risk [3], and then as part of complete autopsies as soon
as the biosafety rules were clarified, including appropriate personal and environmental
protective equipment [4–7].
In mid-January 2021, the keywords “lung”, “autopsy” and “COVID-19” on Pubmed

retrieved 168 results. Thus, there is growing consensus on the main features of lung
damage in COVID-19. The first clinicaland pathological data collected in the literature
focused on the management of ARDS and the identification of diffuse alveolar damage
(DAD) in post mortem biopsies [3]. It was then suggested that these COVID-19 patients
have a different clinical profile than conventional ARDS, requiring appropriate management
[8–10]. The description of lung lesions then became more refined, highlighting different and
sometimes combined patterns [11].
Early lung lesions in COVID-19 patients
Description of the pathological features of early stage pneumonia caused by SARS-CoV-2 is

essential in order to better understand its pathogenesis and to distinguish the natural
course of infection from the consequences of treatment, different organ failures and
comorbidities or secondary bacterial pneumonia. Early lung lesions, revealed by fortuitous
sampling, were reported in four patients who underwent surgery for a lung tumour before
the onset of clinical symptoms of COVID-19 [12–14]. One patient was diagnosed with
COVID-19 on post-operative day 4 and died on post-operative day 7 [12]. A repeat CT
scan in the second patient revealed bilateral ground-glass opacities in the lower lobes of the
lungs on post-operative day 1; the patient died on postoperative day 17 [12]. The third
patient developed a fever on post-operative day 9. The patient gradually recovered and was
discharged after 20 days of treatment [13]. After surgery, the fourth patient developed
progressive lymphopenia on the first post-operative day and, on discharge, had an episode
of fever in the absence of any respiratory symptoms with clinical remission in the following
weeks [14]. In all four cases, patchy intra-alveolar fibrin was observed and in two of them,
early organisation in the form of fibrous intra-alveolar plugs. Diffuse haemorrhages,
alveolar oedema, neutrophilic margination within septal vessels, type II pneumocyte
hyperplasia and clusters of alveolar macrophages with occasional multinucleated cells were
also noted. The interstitium showed a mild inflammatory infiltrate, mainly composed of
T-lymphocytes. Perivascular inflammatory infiltration and a predominance of macrophage
and lymphocyte infiltrates closer to the visceral pleura were described in the case report by
ZENG et al. [12]. Hyaline membrane formation was not obvious in any case.
These early lesions described as intra-alveolar fibrin balls with early fibrous organisation
were later referred to as an “acute fibrinous and organised pneumonia-like (AFOP-like)
https://doi.org/10.1183/2312508X.10024220 87
pattern” in the literature in post mortem samples from critically ill patients frequently
associated with hyaline membranes [15–21].
Based on the above descriptions of incidentally detected lung injury in asymptomatic

patients, early stage pneumonia caused by SARS-CoV-2 results in lymphocytic pneumonia
associated with AFOP-like lesions [12–14].
More recently, transbronchial lung cryobiopsies were performed at an early stage of the
disease, within 20 days of symptom onset in patients who did not require invasive
ventilation and who recovered completely [22]. The authors noted the absence of hyaline
membranes and typical DAD features. The main finding was atypical type II pneumocyte
hyperplasia associated with vascular changes characterised by alveolar capillary hyperplasia
and postcapillary venule dilatation.
In addition, high expression of pSTAT3 (a protein involved in cytokine production) and

the immune checkpoint molecules PD-L1 and IDO in alveolar epithelial and endothelial
cells, have been shown in early phase pneumonia [22–24].
Post mortem lung lesions
Macroscopic features
The lungs are heavy and oedematous with a diffusely firm consistency. Cut surfaces show
areas of red or tan/grey consolidation and/or patchy haemorrhagic areas [25–29]. BORCZUK
et al. [28] reported detailed analysis of gross findings of the upper and lower airways.
Trachea and large bronchi were widely patent without mucus plugs. Focal white patches
were seen, which histologically showed mucosal ulceration.
Microscopic features: what is known about the natural history of the disease?
Figure 1 shows lung lesions in a SARS-CoV-2-positive asymptomatic male.
The pulmonary pathology findings of COVID-19 have been reported in post mortem lung
samples from severely ill patients with ARDS, many whom had a long hospitalisation duration
and mechanical ventilation. Lung lesions in patients who died early from COVID-19 without
receiving mechanical ventilation have also been described [17, 26, 27, 29–36]. In a prospective
cohort study of autopsied patients, WICHMANN et al. [30] reported five cases with an advanced
directive for best supportive care. Four cases showed no DAD but an extensive neutrophil
infiltration of the alveoli and bronchi, resembling bacterial focal bronchopneumonia. One case
showed DAD, with hyaline membranes, activated pneumocytes, microvascular thrombo-
emboli, capillary congestion and interstitial oedema. In the case of a 94-year-old woman who
was diagnosed with COVID-19 pneumonia and died of acute heart failure, WANG et al. [31]
showed that the alveolar septa were thickened by inflammatory cells, including lymphocytes,
macrophages and a small number of neutrophils. The alveolar spaces were filled with
proteinaceous exudates with varying degrees of hyaline membrane.
The first reportof post mortem pathological features was made using biopsy samples from a
50-year-old Chinese man who died from COVID-19 [32]. The patient was given antiviral
therapy and methylprednisolone. As he refused ventilator support, he received HFNC
88 https://doi.org/10.1183/2312508X.10024220
a) b)
c) d)
Figure 1. Lung lesions in a 58-year-old SARS-CoV-2-positive asymptomatic male. The cause of death was
suicide. a) Focal lesions of diffuse alveolar damage. Haematoxylin and eosin stain (HES) ×100 magnification.
b) In the same area, at a higher magnification, hyaline membranes and pneumocyte II atypical hyperplasia
(arrows). HES ×200 magnification. c) Lymphocytic interstitial and perivascular (arrow) infiltrate. HES ×200
magnification. d) T-cell interstitial and perivascular infiltrate (arrows). Anti-CD3 immunostaining ×200
magnification. Scale bars=200 μm.
oxygen therapy. Lung tissue samples showed the exudative phase of DAD, desquamation of
pneumocytes and hyaline membrane formation. Oedema, interstitial lymphocytic infiltrates
and multinucleated syncytial cells with atypical large pneumocytes in the intra-alveolar
spaces were identified. Based on this pathology report, XU et al. [32] suggested in February
2020 that timely and appropriate use of corticosteroids together with ventilator support
could be considered in severe patients. In our series, one patient was not ventilated and
only benefited from the use of a transnasal humidified oxygen delivery system. Post mortem
biopsy performed at day 9 after the onset of symptoms revealed lymphocytic and acute
fibrinous pneumonia without hyaline membrane formation [15].
Thus, post mortem observations made outside the context of mechanical ventilation have
shown lymphocytic interstitial pneumonia associated with the early exudative phase of
DAD and atypical type II pneumocytes hyperplasia.
DE MICHELE et al. [37] identified a new model characterised by the absence of acute lung injury
(ALI) and the simultaneous presence of vascular congestion and haemangiomatosis-like changes
and intravascular fibrin or platelet aggregates. A shorter hospital stay and the absence of an
identifiable cause at autopsy characterised these patients with a predominantly vascular phenotype.
Microscopic features: patterns
Several patterns have been described in critically ill patients (figure 2). This section will
discuss the different patterns identified.
https://doi.org/10.1183/2312508X.10024220 89
a) b)
c) d)
Figure 2. Lung lesions in critically ill patients hospitalised in the ICU under mechanical ventilation. a) Acute
phase of diffuse alveolar damage (DAD): diffuse hyaline membranes. Haematoxylin and eosin stain (HES)
×200 magnification. b) Organising phase of DAD: fibrosis of alveolar walls. HES ×200 magnification. c) Acute
fibrinous pneumonia (acute fibrinous and organised pneumonia-like pattern): intra-alveolar fibrin balls
(arrows). HES ×100 magnification. d) Organising pneumonia: intra-alveolar fibrous buds (arrows) leading to
an obliterative pattern. HES ×200 magnification.
DAD
Various patterns of lung injury have been proposed as potential consequences of severe
COVID-19 but the predominant pathologic finding in the lungs of severe patients is DAD.
DAD is the histopathological pattern of ALI observed in ARDS whatever the cause. In
settings other than COVID-19, the acute phase of DAD results in both endothelial and
epithelial injuries after an initial insult that leads to an increased alveolar–capillary
permeability. The lesions are characterised by vascular congestion, interstitial and alveolar
oedema, formation of hyaline membranes and accumulation of neutrophils. Reactive/
reparative type II pneumocyte hyperplasia and proliferation of fibroblasts and myofibroblasts
follow an organising phase and reparative attempts. Regeneration of a functioning epithelial
layer allows the clearance of exudative fluid into the interstitium [38, 39]. The two main
phases of DAD, acute and organising, have been described in COVID-19, sometimes
combined, depending on the duration of the disease [8, 26, 28, 33, 34, 36, 37, 41–45].
In addition to DAD, pathologists have also noted T-lymphocytes infiltrating the interstitial
spaces as well as around bronchioles and small vessels, admixed with a variable amount of
plasma cells [44]. The T-cell infiltrate is, according to studies,predominantly CD4+ or
composed of a mixture of CD4+ and CD8+ T-lymphocytes [46, 47]. In the alveolar
lumina, macrophages are numerous and predominant [44, 46, 47].
Large amounts of neutrophils are encountered in secondary bacterial pneumonia or in

aspiration pneumonia [26, 27, 40, 47].
Megakaryocytes are rarely found in the pulmonary microvasculature of normal lung tissues;
however, their number increased in DAD, regardless of the cause. This increase was
90 https://doi.org/10.1183/2312508X.10024220
defined by an average number of more than four CD61-positive cells per 25 high-power
fields [48]. An increased number of pulmonary megakaryocytes located within the alveolar
capillaries of COVID-19 patients has been noted [29, 44, 45]. In a study by
VALDIVIA-MAZEYRA et al. [45], most patients showed advanced DAD and abnormal
coagulation parameters with high levels of fibrinogen, D-dimers and variable
thrombocytopenia. The authors suggested that since the lung is an active site of
megakaryopoiesis, the high number of megakaryocytes in the lung of patients with
COVID-19 could be a compensatory pulmonary response to the prothrombotic state
frequently observed in these patients, leading to platelet consumption.
Atypical type II pneumocyte hyperplasia is described early in the course of COVID-19,

even in asymptomatic patients, and then at any stage of the disease, whereas outside the
context of COVID-19, it is associated with the proliferative phase of DAD [13, 44, 47].
Type II pneumocyte atypia are characterised by cytomegaly, nucleomegaly and prominent
eosinophilic nucleoli. However, these changes are frequently encountered in other
infectious and non-infectious causes of DAD [49, 50].
In a systematic review reported in May 2020, POLAK et al. [20] identified three main
pathologic patterns, as follows. 1) The epithelial pattern. With reactive epithelial changes
and DAD, as described above in deceased patients who did not receive mechanical
ventilation. 2) The vascular pattern. With microvascular damage and thrombi, and AFOP.
3) The fibrotic pattern. With interstitial fibrosis. They noted that the epithelial and vascular
patterns can be present in all stages of symptomatic COVID-19, whereas the fibrotic
pattern usually starts ∼3 weeks after the onset of symptoms. Moreover, the different
patterns can be combined, either simultaneously or consecutively.
Although lung injury in COVID-19 could be considered nonspecific [17, 33], the
combination of DAD with interstitial lymphocytic infiltrates and the clear time-line
progression of the lesions are particular to this disease.
AFOP-like pattern/organising pneumonia

Several patterns of other forms of ALI, including AFOP [15–19, 21, 37, 44] and organising
pneumonia (OP) [19, 44], have also been described.
AFOP is a histological pattern of ALI that does not meet the criteria for DAD. The pattern
of AFOP is characterised by prominent fibrin balls in the alveolar spaces, in a patchy
distribution, constant type II pneumocyte hyperplasia and mild or moderate lymphoplasmacytic
infiltrate, in an interstitial distribution [34, 51, 52]. In COVID-19, type II pneumocyte
hyperplasia is observed early in the course of the disease. The AFOP pattern differs from
DAD in that hyaline membranes are absent; we and others have observed membrane
hyaline formation in COVID-19, justifying the term “AFOP-like” pattern [8, 15, 19, 21, 53].
AFOP-like lesions have been significantly less reported in COVID-19 than DAD and do
not appear to be related to invasive ventilation [20, 54]. In our series, one patient with
AFOP-like lesions had not been ventilated and had only benefited from the use of a
transnasal humidified oxygen delivery system [15]. Fibrin balls and the subsequent
organising fibroblastic tissue in airspaces may be seen in DAD, but do not constitute a
dominant lesion, whereas this is the case in AFOP-like pattern. In addition, this type of
pulmonary lesion is also observed during the early stages of asymptomatic and
symptomatic COVID-19 infection, as mentioned above [13, 15].
https://doi.org/10.1183/2312508X.10024220 91
The entry of SARS-CoV-2 in type II pneumocytes through binding to the ACE2

receptor and membrane fusion dowregulates ACE2. ACE2 downregulates the renin–
angiotensin system (RAS). Thus, the entry of SARS-CoV-2 into alveolar cells leads to the
upregulation of RAS and the alteration of the plasminogen activator inhibitor-1/tissue type
plasminogen activator (PAI-1/tPA) balance and ultimately to the reduction of fibrinolysis
[55–57]. Several studies focus on the impact of RAS pathway deregulation on the high
frequency of thrombosis in COVID-19, but little is known about the impact on fibrin
production in alveolar spaces. Critically ill populations include a high proportion of elderly
people and a high frequency of comorbidities (such as hypertension, diabetes,
cardiovascular disease and obesity) [58–60]. In all these diseases, there is an increased risk
of abnormal regulation of RAS [61]. The factors that determine the occurrence of the
different patterns of lung injury remain to be determined, particularly the influence of
comorbidities, which are known to dysregulate RAS.
The link between deregulated fibrin production in the AFOP-like pattern and obesity
should be explored. In our series (data submitted), six patients were overweight (body mass
index (BMI) of 25–30) and six patients were obese (BMI >30). In all of the patients, post
mortem biopsy showed the AFOP-like pattern at various stages of fibrous organisation [15].
The number of overweight and obese patients in our study could partly explain the high
frequency of the AFOP-like pattern, in comparison with the predominant DAD-type
pattern in the literature [41–45].
Hypofibrinolytic status and increased PAI-1 have already been reported in the context of
the SARS-CoV-1 epidemic in 2002 and 2003 [62]. In an infection model of SARS-CoV,
GRALINSKI et al. [63] showed that fibrin persistence was mediated by overexpression of
PAI-1, which overcomes local urokinase type plasminogen activator and tPA. Moreover,
PAI-1 levels are elevated in both obese insulin-resistant patients and non-insulin-dependent
(type 2) diabetic patients [64]. Thus, PAI-1 could play a central role in the occurrence of
acute fibrinous pneumonia and the AFOP-like pattern by contributing to abnormal
turnover of fibrin in the alveolar space.
VADÁSZ et al. [65] described three patients with COVID-19-associated ARDS requiring
mechanical ventilation, who later developed severe OP confirmed by histological analysis of
transbronchial biopsies. The authors suggested that the corticosteroid sensitivity of OP might
partially explain why some COVID-19 patients benefit from systemic corticosteroids [66, 67]. As
acute fibrinous pneumonia occurs before fibrous organisation, early corticosteroid administration
in severe COVID-19 patients could have a preventive effect on early fibrosis formation due to
the resorption of exudative inflammation. In seven ventilated patients, FLIKWEERT et al. [19]
observed four distinct histopathological patterns: AFOP in one patient, DAD in one patient,
extensive fibrosis in one patient and OP in four patients. The patient characteristics were similar
between these different patterns (age, time from hospital admission to death, duration of
mechanical ventilation, medication) although the authors attempt to explain the high frequency
of OP as a result of a longer duration of hospitalisation and mechanical ventilation.
Other factors beyond viral infection influence lung tissue injury. In a study using a machine
learning-based approach, CALABRESE et al. [68] showed that more severe alveolar injury was
significantly associated with tracheal intubation, prolonged invasive mechanical ventilation,
duration of illness since symptom onset and lower viral quantity. In addition, more severe
alveolar injury was observed in patients treated for neoplasm, aspiration pneumonia or other
infections, even if they were not treated with prolonged invasive mechanical ventilation.
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Using high-parameter imaging mass cytometry, a recent study provided a comprehensive

spatial landscape of the disease by distinguishing the early phase of infection characterised
by inflammatory responses to viral infection, from the late phase driven by virus-
independent mechanisms, thus synthesising previous findings [69].
Airway inflammatory changes

Complete autopsies have shown [28] that airway inflammatory changes (in the trachea,
bronchi and bronchioles) are very frequent, including mucosal ulcerations and acute and/or
chronic inflammation. The inflammatory infiltrate in chronic inflammation is mainly
composed of T-lymphocytes. In a series by BORCZUK et al. [28], large airway inflammation,
acute or chronic, was seen in 92% of patients who have never been intubated. No
significant relationship was seen between overall, acute or chronic large airway
inflammation and intubation or acute bacterial or fungal pneumonia.
Vascular lesions associated with the SARS-CoV-2 infection
Recent observations suggest that macrovascular as well as microvascular thrombotic

processes may play a major role in COVID-19. It is becoming apparent that severe cases of
COVID-19 are characterised by hyperinflammation and a thrombotic phenomenon [70–72].
Vascular lesions, notably those occurring in lung parenchyma, are certainly one of the
main features associated with SARS-CoV-2 infection [70–72]. These lesions are described
more frequently in SARS-CoV-2-positive patients than in patients with other viral
respiratory diseases, such as influenza A (H1N1), for example [73]. Lesions usually
described early in COVID-19 are excessive accumulation of neutrophils in the vascular
lumen. These features are visible in vessels of different types, such as capillaries, venules,
veins and arteries. However, most of the lesions correspond to recent thrombi with
different steps of evolution, from hyalinisation to fibrous organisation (figure 3a and b).
These lesions can be associated with inflammation of the vessel wall and the presence of
endothelialitis (figure 3c). They could be a consequence of a direct attack of the endothelial
cells by the virus itself; the cytokine storm induced by an inappropriate innate immunity
toward the viral infection; and/or the sudden onset of neutrophilic extracellular traps
(NETs) induced by SARS-CoV-2 [74].
Notably, it has been indicated that neutrophil activation and the formation of NETs may
have a prominent role in propagating the major cytokine release observed in severe cases of
COVID-19, representing a previously unrecognised but powerful innate defence response
that may exacerbate lung damage in affected patients [40]. NETs correspond with some
extracellular filaments of chromatin which are associated with some DNA and histones,
and are covered by numerous proteins, mainly from the neutrophils granules [40, 74]. The
role of NETs in the pathophysiology of thrombotic phenomenon has been well known for
several years and has been demonstrated in different animal models showing DVT [75].
The coagulative effect induced by NETs is linked with their filamentous structure of
network organisation, which strongly facilitates platelet adhesion and activation. NETs
therefore act as a major component of thrombi and, in this regard, play a pivotal role in
thrombogenesis, which explains the potential protective role of DNase treatment in
thrombi onset [75]. It is worth noting that NETs can be observed not only in the vascular
lumen but also in the respiratory tree and the interstitial spaces [76]. The vascular features
can be associated with many inflammatory cells of different types, mainly from the
lymphoid lineage, with or without fibrinoid necrosis of the vascular walls.
https://doi.org/10.1183/2312508X.10024220 93
a) b)
c) d)
Figure 3. Vascular lesions. a) Arteriolar microthrombosis (arrow). Diffuse alveolar damage. Haematoxylin
and eosin stain (HES) ×200 magnification. b) Arterial thrombus being organised and recanalised. HES ×200
magnification. c) Diffuse capillaritis. HES ×100 magnification. d) Capillar neoangiogenesis in the alveolar
walls (two arrows on the right side). Normal alveolar capillary bed (arrow on the left side). HES ×100
magnification. Scale bars=200 μm.
Besides the vascular lesions noted in the lung parenchyma, it is also worth noting that many
other organs and tissues observed in patients with COVID-19 show vascular lesions [77].
Some studies have described skin biopsy findings in COVID-19 patients that are
characterised by a perivascular mononuclear and lymphocytic infiltrate with occasional
small-vessel thrombosis [77–80]. Case reports have recently highlighted the presence of
chilblain-like acral manifestations in young COVID-19 patients [81]. Skin lesions are located
on the toes, feet, heals and hands. Biopsies showed vascular degeneration of the basal
epidermal layer, endothelitis and microthrombosis of the papillary dermal capillaries [78].
Kawasaki-like disease, characterised by systemic vasculitis involving small and

medium-sized arteries, has been described in COVID-19 [82].
The development of coronary artery aneurysms was observed in up to one-third of untreated

patients, and both systemic and cerebral artery aneurysms in a few number of patients.
Taken together, endothelial cell inflammation associated with the SARS-CoV-2 infection
occurs whatever the type and the size of the vessels and contributes to tissue
hypoperfusion, thrombosis and vascular dysfunction at any stage of the disease.
The findings described above [22–24] in the early phase of COVID-19 pneumonia
regarding early STAT3 pathway activation, increased PD-L1 expression and endothelial
IDO hyperexpression could explain the diffusion–perfusion mismatch, vasoplegia and silent
hypoxia seen in the early type L pattern [9, 23].
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Differences and similarities with other emerging viral infections
Two fatal cases of influenza A (H1N1) infection have been reported, highlighting the main
pathological abnormality, DAD, which in one case was masked by acute bacterial
bronchopneumonia [50]. ACKERMANN et al. [70] showed that the lungs from seven patients
who died from COVID-19 and those from seven patients who died from influenza A (H1N1)
infection shared a common morphological pattern of DAD and infiltrating perivascular
lymphocytes, but with distinctive vascular features in COVID-19 and a higher frequency of
alveolar capillary thrombosis and neoangiogenesis of the intussusceptive type (figure 3d).
Similarities in clinical presentation have been shown in SARS-CoV-1, MERS-CoV and

SARS-CoV-2 infections from February 2020 [83, 84].
Two autopsy studies, one from Singapore [49] and one from Hong Kong [85], reported the
same post mortem lung changes from 14 patients who died from SARS in 2003. The
predominant pattern of lung injury was DAD, which varied according to the duration of
the illness. Acute-phase DAD, airspace oedema and bronchiolar fibrin were observed in
cases with a duration of ⩽10 days. Later, organising-phase DAD, type II pneumocyte
hyperplasia, squamous metaplasia and acute bronchopneumonia were observed.
In patients with SARS in Toronto, HWANG et al. [86] described surgical biopsies with a
DAD pattern or a predominantly composite AFOP pattern.
Few autopsies of patients who died from MERS-CoV infection have been performed. Lung
injury characterised by exudative DAD, type 2 pneumocyte hyperplasia, rare multinucleated
syncytial cells and infiltration of alveolar septa by lymphocytes, has been described [83, 87].
Virus detection in lung tissue sections
The SARS-CoV-2 viral protein can be detected in tissue sections by virus-specific

antibodies against various spike [28, 34, 43, 54] or nucleocapsid proteins [34, 88–90].
Targeting viral RNA by in situ hybridisation techniques has been also described [25, 28, 43,
77, 78, 88, 90, 91]. SARS-CoV-2 has been detected using IHC in the upper airways [89]. In
the acute phase of DAD, SARS-CoV-2 was detected in the alveolar pneumocytes and
alveolar macrophages using IHC [28, 34, 90] and RNA imaging [47] in the first 2 weeks of
disease [28], and ciliated airway epithelium of the bronchi and trachea. More rarely,
positive cases are seen beyond 2 weeks. BORCZUK et al. [28] confirmed these results using
culture, showing the virus in some patients within the first 2 weeks; the exception was one
case, in whom it was still present 26 days after the onset of symptoms. Occasionally, weak
cytoplasmic staining has been described in the endothelial cells of scattered venules and
alveolar capillaries [34]. At the organising phase of DAD, no virus has been detected in
lungs or airways. The loss of type II pneumocyte expression at this stage relates to what is
known about viral clearance [34, 90].
SAUTER et al. [34] noted peculiar staining of hyaline membranes with SARS-CoV-2
antibodies in all the IHC-positive cases tested in their series. The possibility of nonspecific
staining was taken into account, but the absence of staining in the hyaline membranes of
the control cases of non-COVID-19 DAD seemed to confirm its specificity and could
reflect remnants of lytic infections. IHC and immunofluorescence for SARS-CoV-2
https://doi.org/10.1183/2312508X.10024220 95
nucleoprotein and spike protein may have a relatively low sensitivity and limited specificity,
but can be useful in localising infection, especially in cases where RT-PCR cannot be
performed when RNA quality is degraded and/or in low quantities.
Over the years, electron microscopy has emerged as a powerful tool for the diagnosis and
characterisation of viral infections. Thus, during the early pandemic phase of SARS-CoV-2,
many publications reported ultrastructural images of viral particles within tissues and cells
as evidence of infection [92]. However, it quickly appeared that, even in high-quality
journals, several images tagged as SARS-CoV-2 viral particles were questionable or
represented other cellular substructures, such as rough endoplasmic reticulum,
multivesicular bodies and clathrin-coated vesicles [43, 93–95]. These discrepancies
highlighted the difficulty in making a positive diagnosis of SARS-CoV-2 via electron
microscopy alone, as it requires both expertise in viral particle identification, as well as
knowledge of the common presentation of cellular organites and substructures within
autopsy tissues that have been processed for routine electron microscopy. Therefore, in
order to provide valuable information about the localisation of coronavirus in tissues,
ultrastructure analysis should ideally be associated with immunolabelling techniques such
as immuno-gold or ultrastructural in situ hybridisation. When these techniques are not
available, extra care should be taken to avoid misinterpreting the results, and published
guidelines for identifying coronavirus by transmission electron microscopy should be used
[96]. In the lung, direct visualisation of coronaviruses has been reported by expert
ultrastructural virologists in the endothelial cells and in type II pneumocytes [44, 89, 93].
Conclusion
COVID-19 lung lesions are now well described, with an increasing number of autopsy
series reported in the literature. However, there is still much progress to be made in
understanding the factors that influence the occurrence of the different patterns of lung
injury. In the first wave, the very early description of thrombosis and microvascular lesions
in post mortem lung samples contributed greatly to defining the rules of prophylaxis and
antithrombotic treatment. The scale of the pandemic reminds us of the importance of
describing pathological lesions to understand the natural history of the disease but also to
help explain the response to treatment, such as corticosteroid therapy, or better adapt
mechanical ventilation modalities.
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100 https://doi.org/10.1183/2312508X.10024220
| Chapter 7
Clinical features and acute
management in adults
Nuzhath Khan1, Lucy Lamb1,2 and Rachel Moores1
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
[https://doi.org/10.1183/2312508X.10025520].
@ERSpublications
COVID-19 management includes respiratory support, management of fluids, electrolytes,
nutrition and diabetes, VTE prevention, early escalation decisions and evidence-based
use of antibiotics, steroids, remdesivir and immunomodulation https://bit.ly/3sYBXEZ
C linical experience of the management of COVID-19 and the evidence base to guide
this have increased exponentially since the global pandemic began. This multisystem
disease requires a holistic and evidence-based management approach. This chapter outlines
the clinical and diagnostic features of the disease and ward-based management strategies. A
holistic clinical management framework is provided, which includes respiratory management,
assessment of fluids, electrolytes and nutrition, thromboembolic management, diabetes
management, recommendations for the use of available treatments, appropriate use of
antibiotics, escalation decisions and long-term follow-up.
1
Royal Free Hospital, Infectious Diseases, London, UK. 2Academic Dept of Military Medicine, Royal Centre of Defence Medicine,
Birmingham, UK.
Correspondence: Rachel Moores (rachel.moores@nhs.net)
https://doi.org/10.1183/2312508X.10025520 101
Clinical features
COVID-19 is a multisystem disease demonstrating both pulmonary and extrapulmonary
manifestations. Common presentations are fever (83–98%), cough (67–82%), shortness of
breath (31–55%) and generalised symptoms including fatigue, myalgia, headache, nasal
discharge and sore throat [1–6]. Anosmia and ageusia are particularly characteristic of the
disease [7–9]. The incubation period is between 3 and 9 days [10].
Pulmonary manifestations may range from cough and dyspnoea to hypoxaemic respiratory
failure and ARDS requiring mechanical ventilation. The WHO categorises COVID-19 as
mild, moderate, severe and critical disease. Mild disease describes symptoms of COVID-19
without evidence of viral pneumonia or hypoxia. Moderate disease describes cases with
SpO2 >90% on room air and without features of severe pneumonia. Severe disease describes
clinical signs of pneumonia plus one of the following: SpO2 <90% on room air, respiratory
rate >30 breaths·min−1 and/or signs of respiratory distress. Critical disease describes ARDS,
sepsis or other conditions requiring life-sustaining therapies such as invasive ventilation,
NIV or vasopressor support [11].
A large study of 72 314 cases from the first wave of the pandemic in China found that 81%
of cases had mild disease without features of pneumonia, 14% of cases showed features of
severe disease (dyspnoea, tachypnoea, SpO2 <93% and arterial oxygen tension (PaO2)/FIO2
ratio <300) and 5% of cases showed features of critical disease (respiratory failure, septic
shock and multiorgan dysfunction) [12]. Respiratory symptoms may develop or worsen
9–12 days after initial symptom onset [5, 13]. Risk factors for severe disease include older
age, male sex, hypertension, diabetes, chronic cardiac, renal and pulmonary conditions,
smoking, obesity, malignancy and immunodeficiency. Black, Asian and minority ethnic
populations are also at increased risk of severe disease [2, 10, 14–18].
Many extrapulmonary manifestations have been noted in COVID-19 including

gastrointestinal, thromboembolic, neurological, cardiac, renal, endocrine and dermatological
manifestations (figure 1).
There are various proposed pathophysiological mechanisms for multisystem involvement.

One mechanism is direct virus-mediated cell damage. ACE2 is the major receptor for cell
entry of SARS-CoV-2. ACE2 expression has been demonstrated in the respiratory tract,
vascular endothelium, and gastrointestinal, renal, myocardial, neural and endocrine tissues.
Other proposed mechanisms include endothelial cell damage and thromboinflammation, as
well as cytokine release and hyperinflammation. Dysregulation of the renin–angiotensin–
aldosterone (RAAS) system is also important. There is downregulation of lung-protective
ACE2 surface expression related to viral entry [19].
Extrapulmonary symptoms can present with or without respiratory symptoms (figure 1).
Gastrointestinal symptoms (15%) include loss of appetite, diarrhoea, vomiting and
abdominal pain [20]. Thromboembolic complications are frequently seen and are
associated with increased mortality in COVID-19. These involve both the venous and
arterial systems, with pulmonary embolism (PE; 13% in hospitalised cases), DVT,
ischaemic stroke and myocardial ischaemia all observed [21–23]. Higher rates are seen in
critically ill and ICU patients, and high rates of clotting in haemofiltration and
extracorporeal membranous oxygenation (ECMO) circuits are reported [24, 25]. Post
mortem reports describe thrombotic and microangiopathic pathology [26–28].
102 https://doi.org/10.1183/2312508X.10025520
FEATURES AND MANAGEMENT IN ADULTS | N. KHAN ET AL.
Upper respiratory tract Central nervous system

Anosmia Fever
Ageusia Headache
Sore throat Fatigue
Nasal congestion Myalgia
Ischaemic stroke
Respiratory Encephalopathy
Cough Delirium
Dyspnoea Low mood
Memory impairment
Cardiac
Myocardial ischaemia Gastrointestinal
Myocarditis Diarrhoea
Arrhythmia Vomiting
Abdominal pain
Renal Reduced appetite
Acute kidney injury
Endocrine
Diabetes
Vascular
Hyperglycaemia
Pulmonary embolus
Diabetic emergencies
DVT
Catheter-associated Skin
thrombus Macular, petechial,
Kawasaki-like rashes
Figure 1. Pulmonary and extrapulmonary manifestations of COVID-19. Figure created using BioRender.com.
Neurological manifestations include headache, anosmia, ageusia, impairment of consciousness,

encephalopathy and ischaemic stroke [29, 30]. Neuropsychiatric presentations include acute
confusional state, low mood, memory impairment and fatigue [31]. Cardiac manifestations
such as myocardial ischaemia, myocarditis and arrhythmias are also described (19.7%).
Myocardial injury is associated with increased mortality [32–34]. Acute kidney injury
(AKI) is the most common renal manifestation (36.6%), with higher prevalence in
ventilated patients [35]. AKI is associated with poor prognosis [36].
Hyperglycaemia and acute diabetic complications, such as diabetic ketoacidosis (DKA) and
hyperosmolar hyperglycaemic state (HHS), can be seen in COVID-19 patients with or
without pre-existing diabetes. One literature review of 110 COVID-19 patients with DKA
and/or HHS found that 77% of these patients had pre-existing type 2 diabetes mellitus,
while 10% had newly diagnosed diabetes mellitus [37]. These findings may be due to the
direct effect of the infection, as well as occurring as complications of treatments for
COVID-19, including dexamethasone and other medications [38–40]. This is discussed
further in the Diabetes management section.
Finally, viral exanthems have been noted including macular and petechial rashes and
Kawasaki-like illness in children [41, 42]. In children and adolescents, the term
“multisystem inflammatory syndrome” has been used to describe a syndrome of fever and a
systemic inflammatory response that may be present with a rash [43].
https://doi.org/10.1183/2312508X.10025520 103
Laboratory and radiology findings and recommendations
Laboratory and radiology investigations are useful in providing diagnostic and prognostic
information in COVID-19 patients admitted to hospital (table 1).
Laboratory findings and recommendations
A complete blood count often shows lymphopenia (68%) and mild thrombocytopenia
(36.2%). Thrombocytopenia is a poor prognostic indicator [10, 44]. Abnormalities in the
Table 1. A suggested “order set” of baseline investigations for patients hospitalised with
COVID-19
Investigation Rationale
Upper respiratory tract swab Reverse transcriptase PCR is used for diagnosis
Full blood count Lymphopenia and mild thrombocytopenia may be seen;
thrombocytopenia is a poor prognostic indicator [10, 44]
Renal profile and electrolytes For early identification of acute kidney injury and electrolyte
imbalance
Liver function tests Mild transaminitis can be seen (AST>ALT) [20]
Inflammatory markers This may include CRP, erythrocyte sedimentation rate,
procalcitonin and ferritin; these track with disease severity
[45]
Clotting profile D-dimer, prothrombin time and fibrinogen may be raised; raised
D-dimer is a marker of poor prognosis; disseminated
intravascular coagulation is seen less frequently and indicates
severe disease [46]
Cardiac markers These may include troponin, creatinine kinase, LDH and
N-terminal pro-brain natriuretic peptide; myocarditis and
myocardial ischaemia may be seen [32]
ECG Baseline assessment for conduction abnormalities and evidence
of left ventricular hypertrophy or electrolyte disturbance
Urine dip Proteinuria and haematuria may be seen [47]
Capillary blood glucose Hyperglycaemia and acute diabetic complications may be
±blood ketones seen [48]
HbA1c Useful in a setting of hyperglycaemia; diabetes is an
independent risk factor for severe disease [48]
Venous blood gas Rapid assessment of electrolytes and acid–base status
Blood culture Useful to rule out other infections in a setting of fever; bacterial
coinfection is uncommon [49]
Sputum culture Bacterial coinfection is uncommon but useful if an alternative
diagnosis is considered
HIV test Immunocompromised patients, including patients with HIV, are
at increased risk of severe COVID-19 disease [50]; routine HIV
testing is recommended in settings of high prevalence and
where local guidelines support universal testing
Hepatitis “screen” This may include hepatitis B surface antigen and hepatitis C
antibody; screening for blood-borne viruses is good practice,
especially in areas of high prevalence
Chest radiograph A baseline chest radiograph is recommended
HbA1c: glycated haemoglobin A1c; AST: aspartate aminotransferase; ALT: alanine amino-
transferase.
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coagulation profile include raised D-dimer (46.4%), raised fibrinogen and mildly prolonged
prothrombin time (58%). These reflect the pro-inflammatory and pro-coagulant states in
COVID-19. Disseminated intravascular coagulation with severe thrombocytopenia and low
fibrinogen is seen less frequently and is associated with severe disease. D-dimer levels
correlate with disease severity and raised D-dimer indicates poor prognosis [23, 24, 46, 51].
Raised levels of inflammatory markers such as CRP, erythrocyte sedimentation rate,
procalcitonin and ferritin also reflect disease severity [45]. Elevated baseline serum
creatinine (15.5%) and blood urea nitrogen (14.1%) may be seen in the setting of AKI [36,
52]. Elevated liver enzymes such as aspartate aminotransferase (64.2%) and alanine
aminotransferase (ALT; 21.2%) are also commonly noted [10, 20]. Markers of myocardial
injury such as high-sensitivity troponin (12.2%), creatinine kinase, N-terminal pro-brain
natriuretic peptide and LDH may be raised and associated with clinical features of
myocardial injury. Raised high-sensitivity troponin is a marker of poor prognosis [32, 53–55].
Table 1 summarises the recommendations for laboratory investigations in COVID-19

patients admitted to hospital. These include a full blood count, renal, liver and clotting
profiles, and inflammatory and cardiac markers, as mentioned. Regular blood glucose
monitoring is recommended, as well as measuring baseline glycated haemoglobin A1c
(HbA1c) in patients with hyperglycaemia, testing for blood-borne viruses including HIV,
and other investigations such as venous blood gas, blood culture, sputum culture and
urinalysis.
Radiological findings and recommendations
Radiological findings can support the diagnosis of COVID-19. Chest radiograph

abnormalities are present in up to 75% of symptomatic patients. Typical findings are of
bilateral patchy ground-glass change or consolidation, usually at the peripheries and with a
basal predominance. Linear atelectasis is also commonly seen. Chest CT has high sensitivity
(70–80%) and specificity (90%) in the diagnosis of COVID-19. Chest CT commonly shows
bilateral ground-glass opacification at the bases and/or peripheries [10, 56]. Chest CT may
be performed in cases of diagnostic uncertainty or to assess complications later in the
disease course. For example, superadded bacterial infection, empyema, lung cavitation,
pneumothorax and pneumomediastinum are seen infrequently but may present in severe
disease and in the ICU setting [57].
Thromboembolic events occur frequently in hospitalised COVID-19 patients (21%) [23].

Raised D-dimer may warrant early CT pulmonary angiography (CTPA) or empirical
treatment-dose anticoagulation if imaging is not immediately available, especially in the
presence of compatible clinical features. For example, a D-dimer level between 1000 and
7500 ng·mL−1 may suggest an intermediate probability and >7500 ng·mL−1 may suggest a
high probability of venous thromboembolism [58].
Magnetic resonance imaging of the brain may be performed when neurological

manifestations are present. In COVID-19 patients, when indicated, this may show acute
and subacute infarcts, microhaemorrhages, leukoencephalopathy, leptomeningeal enhancement
and cortical FLAIR (fluid attenuated inversion recovery) signal abnormality [59].
Some radiological investigations that require close patient contact may pose an increased
risk of nosocomial transmission to healthcare workers. These might include ultrasound of
https://doi.org/10.1183/2312508X.10025520 105
the liver and kidneys. Although AKI and raised liver enzymes may be seen in COVID-19,
obstructive renal and hepatobiliary pathology is not a common feature [20]. Therefore,
routine liver and renal ultrasound is not required unless specific indications are present. A
transthoracic echocardiogram should ideally be performed at the bedside if required [60].
Acute clinical management of COVID-19
The following sections describe systemic management of COVID-19 in the ward setting.
Figure 2 summarises these management strategies.
Respiratory management
Respiratory presentations range from cough and dyspnoea to acute severe hypoxaemic
respiratory failure (14%) and ARDS with multiorgan failure (5%) [12]. Management in the
ward setting involves supplemental oxygen, NIV and prone positioning.
Supplemental oxygen should be given to patients with hypoxaemia to maintain target

SpO2 [61]. The WHO COVID-19 “living guidelines” suggest administering supplemental
oxygen therapy to stable hypoxaemic patients to target SpO2 >90% [11]. The authors
comment that SpO2 of 90% as a cut-off is arbitrary and clinicians must use their
Supplemental oxygen to maintain target oxygen SpO2.

Pulmonary Consider NIV if target saturation not maintained with 40% FIO2.
Assess fluid/feeding Assess fluid, electrolytes and nutrition. Monitor for AKI.
Prophylactic LMWH in hospital unless high bleed risk.

Anticoagulation
Monitor for PE/DVT, ischaemic stroke, myocardial ischaemia.
Routine antibiotic use is not recommended.
Antibiotics Review/stop antibiotics if no indication.
Dexamethasone and remdesivir in hospitalised patients requiring oxygen.

Novel treatments Monitor hyperglycaemia. Tocilizumab in selected patients.
Diabetes/drug chart Monitor and treat hyperglycaemia, DKA and HHS.

Review oral antidiabetic and antihypertensive medication.
Early CPR decision. Palliative care if appropriate.
Escalation Minimise barriers to communication.
Monitor Monitor progress. Repeat/review investigations as needed (e.g. CXR,

inflammatory markers, D-dimer).
CTPA if raised D-dimer and clinical suspicion of DVT/PE.
Investigations Reduce close-contact tests (e.g. US) unless indicated.
Follow-up and monitor for ongoing fatigue, dyspnoea and other prolonged
Chronic management symptoms. Psychosocial support.
Figure 2. A systemic strategy for management of COVID-19. AKI: acute kidney injury; PE: pulmonary
embolism; DKA; diabetic ketoacidosis; HHS: hyperosmolar hyperglycaemic state; CPR: cardiopulmonary
resuscitation; CXR: chest radiograph; CTPA: CT pulmonary angiography; US: ultrasound. Figure created
using BioRender.com.
106 https://doi.org/10.1183/2312508X.10025520
judgement as to whether low SpO2 is a sign of severe disease or within an acceptable

range for a given patient, for example, with chronic lung disease. The Surviving Sepsis
Campaign guidelines recommend starting supplemental oxygen therapy when peripheral
SpO2 is <92%, and maintaining SpO2 no higher than 96% in those with acute hypoxaemic
respiratory failure [62]. SpO2 targets vary between guidelines, and individual patient
factors should be considered.
Escalation from supplemental oxygen, in some cases, may involve the use of NIV. This may
include CPAP, HFNC and noninvasive positive-pressure ventilation (NIPPV).
Early pandemic observational data suggested that NIV could be applied as a holding
measure to delay the need for mechanical ventilation when ICU resources were severely
limited [63]. However, there have been concerns that use of these devices delays the
decision for invasive ventilation, and in the interim may exacerbate lung injury via “patient
self-induced lung injury” ( p-SILI) [64]. In these cases, p-SILI may be induced by exposure
to high tidal volumes and intense respiratory effort in patients with relatively compliant
lungs, coupled with raised transvascular pulmonary pressure and fluid leak [64, 65]. There
have also been concerns regarding increased risk of nosocomial infection for healthcare
workers from aerosol generation from the use of NIV devices [64].
A preliminary report from an adaptive multicentre RCT has shown a decrease in the
primary composite outcome of tracheal intubation or mortality within 30 days in patients
who received CPAP (36.3%) compared with conventional oxygen therapy (44.4%) [66].
There was no difference in the primary composite outcome between HFNC and
conventional oxygen therapy. The decrease in the primary composite outcome in the CPAP
group was driven by the decrease in incidence of tracheal intubation, with no significant
difference in the rate of 30-day mortality in either the CPAP or HFNC group compared
with conventional oxygen therapy. The authors comment that the lower rates of tracheal
intubation in the CPAP group may have reflected a greater willingness in clinicians and
patients to delay intubation [66].
Recommendations vary widely regarding the type of NIV device to be used and when to
instigate such measures. For example, the National Institute for Health and Care Excellence
(NICE) guidelines currently recommend a trial of CPAP (but not HFNC) if supplemental
oxygen at 40% FIO2 is insufficient to maintain target SpO2 [61]. The Surviving Sepsis
Campaign guidelines currently recommend HFNC over NIPPV in COVID-19 acute
hypoxaemic respiratory failure despite conventional oxygen therapy [62]. The WHO
currently recommend a trial of HFNC, CPAP or NIPPV in patients with “mild ARDS” [11].
NIV should be considered on an individual basis, taking into account the patient’s clinical
status, comorbidities and treatment escalation decisions. For example, the WHO recommends
that patients with hypoxaemic respiratory failure with haemodynamic instability, multiorgan
failure or abnormal mental status should not receive NIV in place of invasive ventilation, if
this is deemed appropriate [11]. NICE recommends NIV should be considered when invasive
mechanical ventilation (IMV) would be a suitable option but not immediately required, or
when respiratory support would not be escalated beyond a trial of NIV measures [61]. These
treatment escalation decisions should be documented as early as possible.
Finally, another intervention that has been used in COVID-19 hypoxaemic patients is
prone positioning. Prior to the COVID-19 pandemic, the prone position was shown to
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improve oxygenation in patients with ARDS [67]. The mechanism is thought to involve a
reduction in shunt and ventilation/perfusion heterogeneity by recruitment of pulmonary
units open to ventilation in the dorsal lung, along with more homogeneous distribution of
lung stress and strain [67]. Electrical impedance tomography studies visually demonstrate
improvements in ventilation and perfusion matching with prone positioning in
mechanically ventilated COVID-19 patients [68].
Prone positioning has also been applied to spontaneously breathing COVID-19 patients,
including those receiving NIV, described as “awake prone positioning” [69, 70]. One
meta-analysis showed that prone positioning improved the PaO2/FIO2 ratio with improved
SpO2 compared with the supine position in COVID-19 patients [71]. Most studies included
in the meta-analysis were observational, and there was no significant difference in the
incidence of intubation or number of patients discharged alive with prone versus supine
positioning. A single-centre observational study demonstrated that prone positioning, in
selected patients, showed clinical benefit and survival without the need for escalation of
therapy, including mechanical ventilation [72]. However, RCTs are required to ascertain
whether prone positioning shows any improvements in mortality or reduces the need for
mechanical ventilation in COVID-19 patients.
Prone positioning and NIV should be part of the treatment escalation plan and offered to
selected patients who are likely to benefit from these procedures. If a trial of these
treatments is not successful, they should be either stopped in favour of comfort care or
escalated to higher-level care as appropriate.
Specialist advice should be sought in initiating, monitoring and weaning off NIV.
Key messages
• Provide supplementation oxygen to patients with hypoxaemia to maintain individualised
target SpO2.
• Consider a trial of NIV if supplemental oxygen at 40% FIO2is insufficient to maintain
target SpO2 [61] in cases where invasive ventilation would be appropriate but not required
immediately.
• Consider use of awake prone positioning.
• Review the response to NIV and prone positioning, and seek critical care review and
preparation for intubation if no response.
• The use of prone positioning and NIV should form part of the treatment escalation plan.
• Seek specialist advice in initiating, monitoring and weaning off NIV.
Fluid, electrolyte and feeding management
Appropriate fluid and feeding management is essential in treating patients with COVID-19.
Early pandemic guidelines suggested a conservative fluid management approach, especially
in ARDS [73]. However, guidelines now recommend maintaining euvolaemic fluid status in
COVID-19 [61]. Fever, tachypnoea, gastrointestinal losses, and interruption of food and
fluid intake due to oxygen delivery devices and prone positioning are all factors that increase
the risk of developing AKI. Risk factors for developing AKI include chronic kidney disease,
heart failure, liver failure, diabetes, a previous history of AKI and age >65 years [61]. Many of
these risk factors overlap those predicting the development of severe COVID-19 disease.
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Fluid balance can be assessed clinically, using fluid balance records and monitoring of
laboratory parameters [61]. Fluid management strategies should be individualised to each
patient in resuscitation, maintenance, replacement and redistribution. In resuscitation
scenarios, a fluid “challenge” can be given and the response monitored at regular intervals
using an ABCDE (airway, breathing, circulation, disability, exposure) approach (e.g. target
blood pressure, heart rate, capillary refill, respiratory rate, skin temperature) [74].
Maintenance fluid administration should aim to achieve euvolaemic status [61].
Electrolyte imbalances have been noted in COVID-19, which include hypokalaemia,

hyponatraemia and hypophosphataemia. Several pathophysiological mechanisms have been
proposed. These include effects of SARS-CoV-2 infection on RAAS, the syndrome of
inappropriate antidiuretic hormone (SIADH), Fanconi syndrome, tubulopathy and
gastrointestinal losses [75]. One explanation for hypokalaemia is hyperaldosteronism
caused by increased angiotensin II activity as a result of downregulation of ACE2 by
SARS-CoV-2 infection. SIADH may be an important mechanism for hyponatraemia,
especially in patients with pneumonia [76]. Increased gastrointestinal losses are another
important cause of electrolyte imbalance, as gastrointestinal symptoms are relatively
common in COVID-19 [20]. Some studies have described injury to the renal proximal
tubule cells resulting in an “incomplete Fanconi syndrome” causing hypophosphataemia as
well as proteinuria, glycosuria and hyperuricosuria [77]. Hypocalcaemia has also been
noted, but the mechanism is unclear [78].
Fluid and electrolyte management in COVID-19 is similar to management in those without

the infection, and local guidelines should be followed. All potential underlying causes
should be considered. For example, hyponatraemia in community-acquired pneumonia
may be due to SIADH, as well as hypovolaemia, with some cases of hypervolaemic
hyponatraemia [79]. Therefore, considering all possible causes and mechanisms is
important, rather than focusing exclusively on COVID-19-related pathophysiology.
Nutrition is another important consideration in recovering from COVID-19 illness. Acute

illness, use of respiratory devices and gastrointestinal symptoms impede adequate nutrition.
Early nutritional assessment should be made with specialist dietetic involvement [80].
Enteral (including nasogastric feeding) and parenteral nutrition should be considered on a
case-by-case basis. The role of vitamins such as B vitamins and vitamins C and D has been
proposed to be important in COVID-19; however, the evidence so far is not conclusive
[81]. One small RCT found that administering a high dose of vitamin D, or a metabolite of
vitamin D, reduced the need for ICU treatment for hospitalised COVID-19 patients [82].
However, another RCT did not show a significant difference in requiring ICU or
in-hospital mortality between patients receiving high-dose vitamin D and placebo. The data
have been too conflicting and inconclusive to recommend vitamin D as a preventative or
treatment for COVID-19.
Key messages
• Fever, tachypnoea, gastrointestinal losses and interruption to feeding increase the risk of
developing AKI.
• The response to a fluid “challenge” should be assessed using the ABCDE approach in
fluid resuscitation.
• Aim for euvolaemic status in patients with COVID-19 in fluid maintenance.
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• Monitor and replace electrolytes p.r.n. Fluid and electrolyte replacement must be
individualised to the patient.
• Ensure early nutrition and dietetic assessment.
Thromboembolic management
Thrombotic events are common in COVID-19. This is due to systemic inflammation and
endothelial injury induced by the virus, coupled with illness and immobilisation [23]. One
large meta-analysis of hospitalised COVID-19 patients demonstrated a venous thrombo-
embolism rate of 21%, a PE rate of 13% and an arterial thromboembolism (ATE) rate of
2% [23]. These rates were higher in patients in ICUs. Central venous catheters, ECMO and
renal replacement therapy circuits are frequently occluded [24, 25]. Raised D-dimer,
fibrinogen and prolonged prothrombin time are noted [51]. D-dimer levels correlate with
disease severity and are associated with increased mortality [51]. Thromboembolism is
associated with increased mortality in COVID-19 [23].
CTPA and other appropriate imaging should be considered in patients with raised D-dimer
and clinical suspicion of PE and/or DVT. There is no exact cut-off value for D-dimer in the
context of COVID-19, but levels >1000 ng·mL−1 at admission may indicate an intermediate
probability of PE [58]. ATE such as ischaemic stroke and myocardial ischaemia is also seen
in COVID-19, and therefore monitoring for features of ATE is important [23].
The use of therapeutic anticoagulation with heparin in moderately and critically ill
COVID-19 patients was investigated in a large, multiplatform, adaptive RCT [83, 84].
Administering therapeutic anticoagulation with heparin in moderately ill patients (those
not requiring respiratory or cardiovascular organ support) increased the probability of
survival to hospital discharge and reduced the need for ICU-level organ support compared
with usual-care thromboprophylaxis [83]. Overall, 1.9% of moderately ill patients assigned
to receive therapeutic-dose heparin suffered a major bleed event compared with 0.9% of
moderately ill patients assigned to usual-care thromboprophylaxis [83].
In comparison, administering therapeutic-dose heparin did not increase the probability of

the number of “organ support-free days” or survival to hospital discharge compared with
usual-care thromboprophylaxis in critically ill patients with COVID-19 (those requiring
ICU-level care with organ support) [84]. Overall, 3.8% of critically ill patients assigned to
receive therapeutic-dose heparin suffered a major bleed compared with 2.3% of critically ill
patients assigned to usual-care thromboprophylaxis [84].
The difference in outcome in these two groups may be explained by differences in the
pathophysiology of thrombosis and the effect of heparin in mild versus severe COVID-19
infection. It is postulated that thrombus formation may be driven by a combination of vascular
endothelial damage and microvascular injury, along with activation of cytokines, complement,
platelets and inflammatory cells [85]. These surface-bound complexes and fibrin-bound thrombin
are more resistant to inhibition by antithrombin, which is activated by heparin. Therefore, patients
with more severe disease may have a degree of resistance to anticoagulation with heparin [85].
Earlier guidelines recommended prophylactic LMWH for all COVID-19 hospitalised patients,
unless they are at very high risk of bleeding [86]. However, following more recent findings,
the exact dose of heparin for hospitalised patients with COVID-19 may vary in local
110 https://doi.org/10.1183/2312508X.10025520
guidelines. Some guidelines may recommend administering “double-dose” prophylaxis or

higher-than-usual-dose thromboprophylaxis. Indeed, in the study of therapeutic-dose heparin
in moderately ill COVID-19 patients, the “usual-care thromboprophylaxis” group received a
mixture of “low-dose” (71.7%) and “intermediate-dose” (26.5%) thromboprophylaxis [83].
There was greater heterogeneity in the thromboprophylaxis dose in the study looking at
critically ill patients: 41% of patients received “low-dose” thromboprophylaxis, while 51% of
patients received “intermediate-dose” thromboprophylaxis [84].
Despite variations in practice, assessing individual patient risk factors can help with
decisions about anticoagulation. Measurement of D-dimer is useful in ascertaining clotting
risk in COVID-19 patients. For example, the benefits of treatment-dose heparin compared
with usual-dose thromboprophylaxis were greater in moderately ill patients with a D-dimer
level higher than twice the upper limit of normal [83]. However, the risk of a major bleed
was higher in the treatment-dose group (1.9%) compared with usual-dose thrombo-
prophylaxis (0.9%) in moderately ill COVID-19 patients. Therefore, close attention must be
paid to the individual bleed versus clotting risk.
Key messages
• Monitor platelet count and coagulation profile, including D-dimer level, in all patients
with COVID-19.
• Prescribe thromboprophylaxis in all patients with COVID-19 who require hospital
admission, taking into account the individual patient’s bleed versus clotting risk (dosing
may vary according to local guidelines).
• Consider CTPA in patients with a raised D-dimer level and clinical suspicion of PE and/
or DVT.
• Monitor for features of ATE such as ischaemic stroke and myocardial ischaemia.
Diabetes management
Diabetes is an independent risk factor for developing severe infection with COVID-19.
Patients with diabetes are twice as likely to have a fatal outcome from COVID-19 [48]. This
is partly due to the increased incidence of diabetes in older age and the association with
cardiovascular disease. Patients with diabetes are recognised to be at increased risk of
developing infections due to defects in cellular immunity. In addition to this, several
mechanisms directly related to SARS-CoV-2 infection may increase the risk of diabetic
complications. Downregulation of ACE2 expression related to viral entry increases
hyperinflammation. Chronic hyperglycaemia has also been shown to downregulate ACE2
expression. ACE2 is expressed on pancreatic β-cells, and therefore virus-mediated damage
to pancreatic β-cells could induce new-onset diabetes [48].
Diabetic complications such as DKA have been observed in COVID-19 patients without
previous diabetes [39, 87], as well as in those with pre-existing diabetes (including type 2
diabetes) [37]. Close monitoring of blood glucose, usually in the form of capillary blood
glucose, is recommended in COVID-19, especially in patients receiving glucocorticoids.
Venous blood gas analysis on admission provides useful information about blood glucose
level and acid–base status. Blood ketones should also be measured in hyperglycaemia.
Many diabetic and nondiabetic patients require insulin therapy during COVID-19 illness.
This is due to factors such as sepsis, dehydration, corticosteroid therapy for COVID-19
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(discussed in the Corticosteroids section), defects in insulin production [88] and increased
insulin resistance [48]. Guidelines exist to aid clinicians with initiating and modifying
insulin therapy when required [89]. Close monitoring and replacement of electrolytes such
as potassium should be undertaken with insulin therapy. Special attention should be paid
to insulin dose adjustment for patients recovering from COVID-19, especially after
stopping corticosteroid treatment.
Certain classes of diabetic medications should be withheld during acute COVID-19 illness
according to current guidelines [48]. Metformin is withheld due to increased risk of lactic
acidosis, with close monitoring of fluid balance and renal function. Sodium–glucose
cotransporter 2 (SGLT-2) inhibitors are withheld due to the risk of DKA, including
euglycaemic or moderate hyperglycaemic ketoacidosis. Glucagon-like peptide-1 (GLP-1)
receptor agonists can be continued with close monitoring and avoiding dehydration.
Dipeptidyl peptidase-4 (DPP4) inhibitors are generally well tolerated and can be continued.
Insulin therapy should always be continued, and increased doses may be needed [48].
Other medications may be reviewed on a case-by-case basis. Angiotensin-converting enzyme

(ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be continued in
COVID-19 in the absence of AKI or hypotension [60]. There were initial concerns with a
theoretical risk of increased ACE2 expression aiding virus entry with the use of ACE inhibitors
and ARBs. However, these medications are helpful in reducing the deleterious effects of
unopposed angiotensin II activity. ACE inhibitors and ARBs may reduce lung inflammation
via the protective ACE2-mediated pathway [60, 90]. Statins should be continued for their
long-term benefits unless the patient is at risk of rhabdomyolysis or has transaminitis [48, 60].
Key messages
• Monitor blood glucose level in all patients with COVID-19. Baseline venous blood gas
analysis provides useful information about blood glucose level and acid–base status.
• Review medications including oral antidiabetic medications and antihypertensive
medications on a case-by-case basis.
• Treat hyperglycaemia with insulin according to local protocols. Treat DKA and HHS
according to local protocols.
• Monitor and replace electrolytes such as potassium with insulin therapy.
• Seek specialist advice on initiating and adjusting insulin therapy.
Antibiotic management
Excluding bacterial coinfection in COVID-19 can be challenging. Inflammatory markers such

as CRP and ferritin are frequently elevated. These markers also correlate with disease severity,
making it difficult to exclude secondary bacterial infection later in the disease process.
However, evidence has shown that bacterial coinfection is uncommon in COVID-19

outside the ICU. Two large meta-analyses found an overall incidence of 3.5% and 7% of
bacterial coinfection in COVID-19 patients [49, 91]. Despite this, a high proportion of
patients with COVID-19 were administered antibiotics (71.9%) [49]. Patients who required
admission to the ICU had higher rates of coinfection (14%). This raises concerns regarding
antibiotic stewardship and adverse effects from antibiotic use when they are not required.
The lack of an elevated total white cell count at presentation and a lack of response of CRP
to antibiotics may be useful to exclude bacterial coinfection [92].
112 https://doi.org/10.1183/2312508X.10025520
Key messages
• Bacterial coinfection is not common in COVID-19 in the ward-based setting.
• Routine or empirical use of antibiotics is not recommended.
Escalation decisions, end-of-life management and communication
Early decisions on treatment escalation are crucial in the management of patients with
COVID-19. This ensures appropriate use of ICU resources, as well as avoiding
interventions that are unlikely to be successful and may cause harm to individual patients.
Patient frailty is a good indicator of disease outcome. The Clinical Frailty Scale can be used
to inform decisions about suitability for cardiopulmonary resuscitation (CPR) [93]. Patients
and relatives should be encouraged to consider and document care preferences as soon as
possible after admission [94]. Timely palliative care interventions have been shown to be
beneficial in avoiding inappropriate CPR and directing “comfort care” where appropriate [95].
COVID-19 poses several challenges in communication with patients and relatives.

Restrictions in hospital visiting due to infection control considerations and use of PPE such
as visors and masks make communication extremely difficult. Clinicians must take these
factors into consideration when aiming to provide holistic care for patients with
COVID-19. Use of technology such as remote communication via web-based platforms can
be utilised to facilitate contact with those close to the patient [96].
Key messages
• Make early decisions on escalation status and suitability for CPR. Use of the Clinical
Frailty Score is helpful.
• Consider and minimise barriers to communication with patients and relatives.
Technology can be used for remote communication.
Therapeutic treatments for COVID-19
The emergence of COVID-19 has led to an unprecedented effort to find potential treatments.
Large, adaptive platform trials have been developed to explore therapeutic options. Over 100
therapeutic agents are being investigated in clinical trials at the time of writing (available
from https://clinicaltrials.gov). These include both novel and repurposed treatments. A
detailed discussion of these treatments is outside the scope of this chapter. The following is a
brief outline of specific treatments for which current evidence and guidelines exist. These can
be broadly divided into antiviral and “immunomodulating” treatments.
Antiviral treatments
Many adverse effects of COVID-19 may result from local or systemic viral replication.
Broadly speaking, the use of antiviral treatments may be most beneficial during a phase of
increased virus replication earlier in the disease process [97]. However, the temporospatial
dynamics of virus replication, especially in immunocompromised patients, is not fully
understood.
Remdesivir is currently the only antiviral drug approved by the US Food and Drug
Administration (FDA) for the treatment of COVID-19. Remdesivir is a nucleotide analogue
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pro-drug whose intracellular phosphorylated product is a substrate for viral

RNA-dependent RNA polymerase. This inhibits virus replication by causing premature
chain termination [98]. Other repurposed drugs targeted towards inhibiting virus cell entry
(chloroquine and hydroxychloroquine) and viral protease inhibitors such as ritonavir/
lopinavir have not shown efficacy in RCTs [99].
Remdesivir
Remdesivir has been evaluated in several clinical trials.
The ACTT-1 (Adaptive COVID-19 treatment trial) was a large, double-blind,

placebo-controlled, randomised trial involving 1063 hospitalised patients with COVID-19
[100]. The primary outcome of this trial was time to recovery, defined by either discharge
from hospital or hospitalisation for nonmedical reasons. The ACTT-1 found that
remdesivir reduced median time to recovery compared with placebo (10 versus 15 days).
The benefit was most apparent in patients receiving supplemental oxygen. There was no
significant difference in median time to recovery in patients receiving IMV or ECMO.
Although the mortality rate was numerically lower in the remdesivir arm compared with
the placebo arm, the difference was not statistically significant.
The WHO SOLIDARITY trial was a large, nonblinded, adaptive platform trial. Interim
findings from this trial evaluated 11 266 patients with COVID-19 treated with repurposed
antiviral agents, including remdesivir, hydroxychloroquine, lopinavir and IFN regimens
[99]. The SOLIDARITY trial found that none of these drugs reduced in-hospital mortality,
initiation of ventilation or hospital stay in hospitalised patients with COVID-19. The
antiviral arms of the trial, except remdesivir, were discontinued due to futility. There was a
trend towards reduced mortality with remdesivir in patients receiving “low-flow or
high-flow oxygen” at baseline; however, statistical significance was not reached.
The DisCoVeRy trial (Trial of treatments for COVID-19 in hospitalized adults) was a large,
adaptive, multicentre, randomised trial analysing 857 hospitalised COVID-19 patients [101].
The study found that there was no significant difference in the odds of better clinical status at
day 15 between “remdesivir plus standard of care” versus “standard of care only”. The findings
were consistent across all pre-specified subgroup analysis including duration of symptoms and
disease severity before random assignment. There was also no significant difference in 28-day
mortality between the two arms. However, the trial did find that progression to IMV or
ECMO was reduced in patients who were not requiring these treatments at baseline. This
finding was also supported in the ACTT-1 [100].
The differences in the outcomes of these trials may be explained by differences in trial
design. The primary end-point of the ACTT-1 was “time to recovery” and the study was
not powered to evaluate mortality [100]. A retrospective post-hoc analysis of the trial data
categorised patients according to risk quartiles based on characteristics in addition to
oxygen status, such as platelet count, absolute lymphocyte and neutrophil count [102]. The
post-hoc analysis found that treatment with remdesivir was associated with lower
progression to IMV or death across the cohort [102]. However, the risk profile used in the
study has not been validated in prospective controlled trials.
In contrast, the SOLIDARITY trial was powered to evaluate mortality but lacked
granularity in subgroup analysis [99]. The number of deaths reported was lower in patients
receiving supplemental oxygen (but not ventilated) with remdesivir versus control; however,
114 https://doi.org/10.1183/2312508X.10025520
this did not differentiate between “low-flow” and “high-flow” oxygen. Overall, the stratified
rate ratios for death in both the SOLIDARITY trial and the ACTT-1 suggest little or no
mortality benefit from remdesivir in the hospitalised setting [99].
The DisCoVeRy trial also failed to show clinical or mortality benefit with remdesivir in
hospitalised patients [101]. However, there is a suggestion that the time of initiation of
remdesivir in hospitalised patients in these studies was beyond the time of peak viraemia in
most patients [103]. The median time from symptom onset to treatment initiation was
9 days in the DisCoVeRy trial. This may be long after the peak viral load in most patients
[103]. The ACTT-1 found that the median time to recovery was shorter in patients who
received remdesivir with duration of symptoms <10 days [100].
At the time of writing, remdesivir is approved by the FDA for hospitalised patients requiring
supplemental oxygen [104]. However, the WHO has made a conditional recommendation
against remdesivir in hospitalised patients with COVID-19. The recommendation was based
on the WHO SOLIDARITY meta-analysis of trials of remdesivir, which found the credibility
of subgroup analysis was insufficient to make a positive recommendation for the use of
remdesivir based on lack of a prior hypothesis, little previous supportive evidence and
arbitrary cut-off points when examining subgroups [105]. There was also consideration of
resources and impact on health equity in the recommendation.
Remdesivir is an intravenous drug. It is administered at a loading dose of 200 mg, followed by a

maintenance dose of 100 mg once a day [106]. It may be most efficacious when commenced
early, for example, within 10 days of symptom onset [100]. A 5-day course of remdesivir appears
to have similar outcome to a 10-day course [107]. Guidelines recommend starting remdesivir in
adults aged ⩾12 years who weigh >40 kg and are hospitalised requiring supplemental oxygen
[104]. Remdesivir is not recommended for use in patients with an estimated glomerular filtration
rate (eGFR) of <30 mL·min−1 [104]. Patients with end-stage renal failure on haemodialysis are
exempt from the eGFR cut-off in some guidelines [108]. Remdesivir should be discontinued if
ALT levels increase to more than five times the upper limit of normal. More data are required on
the efficacy and safety of remdesivir in children and pregnant women, but remdesivir should not
be withheld from pregnant patients if otherwise indicated [104].
Key messages
• Remdesivir is an i.v. antiviral medication.
• It has been shown to reduce time to recovery in patients with COVID-19 compared with
placebo.
• Remdesivir may be used in adults ⩾12 years with weight >40 kg and eGFR
>30 mL·min−1 who are requiring supplemental oxygen.
• Remdesivir should be discontinued if the ALT is more than five times the upper limit of
normal.
• Remdesivir may be most effective if commenced within 10 days of symptom onset.
• Remdesivir can be given for 5–10 days; 5- and 10-day courses may have similar outcomes.
• More data are required for use in children and pregnant women.
Immunomodulating therapies
The term “immunomodulating” therapy is used broadly to describe treatments that alter
the host immune response to SARS-CoV-2 infection.
https://doi.org/10.1183/2312508X.10025520 115
Corticosteroids are included in this group and have broad immunomodulating and
anti-inflammatory properties. Other agents include treatments that aim to provide passive
immunity such as convalescent plasma, hyperimmune globulin and synthetic neutralising
antibody cocktails [104, 109]. Targeted anti-inflammatory treatments that modulate the
immune response via cytokine release pathways include IL inhibitors (e.g. the IL-1
inhibitors anakinra and canakinumab, and the IL-6 inhibitors tocilizumab and sarilumab),
kinase inhibitors (e.g. janus kinase inhibitor baricitinib) and IFNs [104]. This is not an
exhaustive list, and many treatments are still being investigated at the time of writing.
Corticosteroids
Corticosteroids have been shown to be effective in the treatment of severe COVID-19. A
report by the RECOVERY (Randomised evaluation of COVID-19 therapy) trial group
included 6425 participants in a randomised, open-label trial of low-dose dexamethasone in
hospitalised patients with COVID-19 [110]. There was a significant reduction in 28-day
mortality with dexamethasone compared with placebo in hospitalised patients requiring
supplemental oxygen (23.3% versus 26.2%) or mechanical ventilation (29.3% versus 41.4%).
No mortality benefit was seen in patients not requiring supplemental oxygen. The dose of
dexamethasone was 6 mg i.v. or orally for up to 10 days, with a median duration of 7 days.
The FDA recommends low-dose dexamethasone for patients with COVID-19 who are
hospitalised requiring supplemental oxygen, NIV and invasive ventilation [104]. The WHO
has made a strong recommendation for systemic corticosteroids in treating severe and
critical COVID-19 [111]. Corticosteroids are also recommended in pregnant women with
COVID-19 [104], but alternatives to dexamethasone can be used. Other corticosteroids that
are equivalent to 6 mg of dexamethasone include prednisolone 40 mg, methylprednisolone
32 mg and hydrocortisone 160 mg.
The side-effects of corticosteroids should be monitored carefully, including blood glucose

levels. Clinicians should monitor for hyperglycaemia and other adverse effects of
short-term corticosteroid use including gastrointestinal bleeding ( proton pump inhibitors
or histamine H2 receptor antagonists may be co-prescribed), fractures and avascular
necrosis, confusion and psychosis [88, 111, 112]. In the RECOVERY trial, patients received
dexamethasone for up to 10 days with a median duration of 7 days, and dexamethasone
was discontinued on discharge. Current guidelines recommend stopping corticosteroids on
hospital discharge [104, 105]. Some studies have described cryptogenic and secondary
organising pneumonia in COVID-19, and a longer or tapering duration of steroids has
been used in these cases [113, 114]. However, most cases of COVID-19 organising
pneumonia appear to have a good prognosis [115]. It is therefore important to consider
stopping corticosteroids in patients in whom risks outweigh benefits. These groups may
include discharged patients, patients who are not on oxygen therapy and those who
experience severe side-effects.
Key messages
• Low-dose corticosteroids have been shown to reduce mortality in COVID-19.
• Start low-dose corticosteroids (usually dexamethasone 6 mg) in patients with COVID-19
who are hospitalised requiring supplemental oxygen, NIV or invasive ventilation.
• The recommended duration is 7–10 days.
• Monitor for adverse effects of corticosteroids such as hyperglycaemia. Monitor blood
glucose levels. Stop steroids early if the patient no longer requires oxygen and stop
116 https://doi.org/10.1183/2312508X.10025520
steroids on hospital discharge.

• Administer proton pump inhibitors or histamine H2 receptor antagonist therapy with
steroids.
Tocilizumab
The IL-6 inhibitor tocilizumab has been shown to be effective in the treatment of
COVID-19 [116]. A large RCT of 4116 patients by the RECOVERY trial group found that
tocilizumab was associated with a significant reduction in 28-day mortality (31%) versus
standard of care alone (35%) in hospitalised COVID-19 patients with hypoxia and with
CRP ⩾75 mg·L−1 (rate ratio 0.85, 95% CI 0.76–0.94; p=0.0028) [116]. To date, the
RECOVERY trial has been the largest trial investigating tocilizumab in COVID-19 patients,
and when the results are considered with previous trials, a significant 14% proportional
reduction in 28-day mortality was seen with use of tocilizumab [116].
NICE guidelines recommend starting tocilizumab in hospitalised patients with COVID-19

who require supplemental oxygen with CRP ⩾75 mg·L−1 or who are within 48 h of starting
invasive ventilation or NIV [61]. The National Institutes of Health (NIH) guidelines
recommended starting tocilizumab in hospitalised patients with COVID-19 (i.e. within the
first 3 days of admission) who are admitted to the ICU in the prior 24 h and who require
invasive ventilation or NIV, or in patients not requiring the ICU but who have rapidly
increasing oxygen demands requiring NIV [104]. The NIH also recommends a cut-off for
CRP of ⩾75 mg·L−1 for starting tocilizumab.
Tocilizumab is contraindicated in uncontrolled serious bacterial, fungal or non-SARS-CoV-2

viral infection, in patients who are significantly immunosuppressed (although this is not clearly
defined), if there has been recent use of other biological drugs or for known hypersensitivity to
tocilizumab. The NIH also suggests caution in patients who have ALT levels more than five
times the upper limit of normal and a high risk of gastrointestinal perforation [104].
Tocilizumab should be given to patients who are having or have completed a course of
corticosteroids. The dose of tocilizumab is 8 mg·kg−1 actual body weight up to 800 mg. The
NIH does not recommend a second dose of tocilizumab. Sarilumab is another IL-6
inhibitor that may have a similar mode of action to tocilizumab, but only small numbers of
cases were studied in trials [104].
Key messages
• Consider starting tocilizumab in hospitalised COVID-19 patients who are requiring
invasive ventilation or NIV within 48–72 h of hospital admission.
• In suitable cases, administer tocilizumab at a dose of 8 mg·kg−1 actual body weight up to
800 mg as a single dose.
• Consider contraindications such as uncontrolled serious bacterial, fungal or
non-SARS-CoV-2 viral infection, significant immunosuppression, recent use of other
biological drugs or known hypersensitivity to tocilizumab.
• Use caution in patients who have ALT levels more than five times the upper limit of
normal and a high risk of gastrointestinal perforation.
Long-term follow-up
There is increasing recognition of the long-term effects of SARS-COV-2 infection, with
some patients experiencing ongoing symptoms after recovering from the acute phase of the
https://doi.org/10.1183/2312508X.10025520 117
illness or experiencing typical symptoms for longer than would be expected [117]. A study
based in Italy of 143 patients showed that 87.1% had at least one symptom 60 days after
symptom onset, particularly fatigue and dyspnoea [118]. Symptoms may include fatigue,
dyspnoea, joint pain, chest pain, cough, anosmia, lack of appetite, vertigo, myalgia and
diarrhoea. Mental health and psychosocial issues are also important. Long-term follow-up
of physical and psychological symptoms and rehabilitation is an important consideration. A
full description of these management strategies is outside the scope of this article and
guidelines are available from sources such as the Infectious Diseases Society of America
(IDSA) [119] and NICE [120].
Conclusion
COVID-19 is a multisystem disease. Holistic and optimal care of COVID-19 patients

requires a systemic approach including review of oxygenation, fluids, electrolytes, feeding,
clotting, diabetes and antibiotics. Early decisions about resuscitation status are crucial, as
well as recognising challenges to communication with patients and relatives. There is
increasing recognition for the management of long-term effects from COVID-19 including
psychosocial considerations. Therapeutic options currently include corticosteroids and
antiviral and immunomodulating treatments. This remains an evolving field, and
treatments should be used with an evidence-based approach.
Diagnosis of COVID-19 is usually based on an upper respiratory tract swab reverse

transcriptase PCR, supported by radiology and biochemical/haematological parameters.
Laboratory investigations include a complete blood count, a renal and liver profile, and
inflammatory markers, a clotting profile and cardiac markers. Repeated measures of
parameters that track with disease severity may be helpful in monitoring progress. Baseline
HbA1c is recommended in patients with hyperglycaemia at presentation or during
treatment. All patients benefit from capillary blood glucose monitoring to exclude
hyperglycaemia. Bacterial coinfection is infrequent with COVID-19 [49, 91]; however, a set
of blood cultures and a sputum specimen for microscopy and culture at baseline is useful
in case of an alternative diagnosis. Routine testing for HIV is recommended as part of the
COVID-19 “order set” in areas of high prevalence and where local guidelines support
universal testing [121]. Testing for other blood-borne viruses such as hepatitis B and C is
good practice, especially in areas of high prevalence. There is an increased mortality rate in
COVID-19 with HIV infection and other conditions causing immunosuppression [50].
Venous blood gas analysis at baseline provides useful information about acid–base status
and lactate levels. COVID-19 generally causes hypoxaemic respiratory failure. Arterial
blood gas analysis may be reserved for severe or critical disease and/or those at risk of
developing hypercapnic respiratory failure. Other “bedside” investigations include urine
dipstick and ECG. Urinalysis is recommended, as proteinuria and haematuria as well as
AKI have been noted in COVID-19 [36, 47, 48].
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| Chapter 8
Management in the ICU
Sachin Ananth1, Avinash Aujayeb 2, Shari B. Brosnahan 3,
Lieuwe D. Bos 4, Rebecca F. D’Cruz5, Daniel López-Padilla 6,
Anthony Lubinsky3, Hrishikesh S. Kulkarni7, Toni Marín 8 and
Ema Swingwood 9,10
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 [https://doi.
org/10.1183/2312508X.10025920].
@ERSpublications
Patients with COVID-19-related ARDS are generally managed like patients with ARDS due
to other causes. But there are specific considerations with respect to infection control,
complications and long-term follow-up, as discussed in this chapter. https://bit.ly/3sYBXEZ
P atients 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 [1–3]. This chapter will review current
evidence-based management of this patient population.
Oxygen support
Early intubation and mechanical ventilation used to be advocated in all patients requiring
>5 L of oxygen. Recent emerging data, however, support the application of noninvasive
1
West Hertfordshire Hospitals NHS Trust, Watford, UK. 2Northumbria HealthCare NHS Foundation Trust, Newcastle upon Tyne, UK.
3
Division of Pulmonary, Critical Care and Sleep Medicine, New York University Langone Health, New York, NY, USA. 4Intensive Care,
Amsterdam UMC, Amsterdam, Netherlands. 5Guy’s and St Thomas’ NHS Foundation Trust, London, UK. 6Hospital General
Universitario Gregorio Marañón, Madrid, Spain. 7Division of Pulmonary and Critical Care Medicine, Washington University School of
Medicine, Washington, DC, USA. 8Respiratory Intermediate Care Unit and Ventilation Dept, Thorax Institute, Germans Trias i Pujol
University Hospital, Barcelona, Spain. 9Adult Therapy Services, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol,
UK. 10The University of the West of England, Bristol, UK.
Correspondence: Lieuwe D. Bos (l.d.bos@amc.uva.nl)
124 https://doi.org/10.1183/2312508X.10025920
MANAGEMENT IN THE ICU | S. ANANTH ET AL.
respiratory therapies (NRTs) including HFNC, CPAP and NIV. Systematic reviews and
meta-analyses of non-COVID-19-related ARDS have demonstrated improved clinical
outcomes in those receiving NRTs over standard oxygen therapy with regard to mortality
and the requirement for endotracheal intubation [4], with demonstrable benefits of HFNC
specifically [5, 6]. However, these analyses did not include patients with ARDS secondary
to COVID-19. At the start of the pandemic, there was a lack of evidence regarding the
most effective respiratory management for this patient cohort. Additionally, there was
concern regarding the safety of both patients and healthcare workers due to increased risk
of virus transmission through aerosol generation from management strategies [7, 8].
Currently, almost 19% of COVID-19 patients are treated with NRTs [9].
HFNC or CPAP
There is just one RCT to date that has compared HFNC and CPAP with standard oxygen
therapy in COVID-19 patients. The RECOVERY-RS (Randomised evaluation of COVID-19
therapy – respiratory support) trial showed no difference in the need for intubation or
mortality between patients treated with HFNC or standard oxygen therapy [10]. There was,
however, a significant reduction in the need for intubation (estimated effect 0.72, 95% CI
0.53–0.96) in those patients randomised to CPAP, although this did not result in a lower
mortality. Given the pragmatic nature of this study, it is unclear whether the lack of
effectiveness of HFNC was due to the application of the intervention by the treating
physician or to a given lack of effect in patients with COVID-19, which would contrast
with findings in patients with acute hypoxaemic respiratory failure due to other causes.
Taken together, CPAP should be favoured as a first-line NRT in patients with acute
hypoxaemic respiratory failure due to COVID-19. When not tolerated, it could be
substituted by HFNC or conventional oxygen therapy.
Safety measures
Data regarding nosocomial transmission of COVID-19 during HFNC and CPAP
application are inconclusive [7, 8, 11]. HFNC and CPAP are widely considered to be an
AGP, and current recommendations advocate HFNC delivery in negative-pressure rooms,
with appropriate PPE and reverse isolation protection [12, 13]. Empirical evidence suggests,
however, that there is no increase in, and possibly even less, aerosol formation during
HFNC or CPAP compared with the use of a conventional oxygen mask or nasal prongs [14].
Monitoring
Continuous monitoring of respiratory rate (RR), heart rate, and pulse oximetry and serial blood
gas analysis should be implemented to facilitate early detection of treatment failure [15–23]. The
ROX index (calculated as (SpO2/FIO2)/RR) has been validated in patients with ARDS receiving
HFNC and NIV, with a higher index consistently associated with a lower risk for intubation,
although no cut-off value has sufficient predictive accuracy to be used in isolation [24].
However, some authors state that this index does not add value to RR alone in COVID-19
patients, highlighting the need for continuous monitoring and reinforcing the surveillance of
patients with RR ⩾26 breaths·min−1 measured half an hour after HFNC or NIV onset [21].
Awake prone positioning
Prone positioning (PP) is well established in the management of patients receiving invasive
mechanical ventilation (IMV) (see Adjunctive treatments section), with documented
benefits such as a reduction in mortality [25–27]. The physiological benefits of PP occur
https://doi.org/10.1183/2312508X.10025920 125
through recruitment of dorsal, often poorly ventilated lung units, leading to amelioration of
the ventral–dorsal transpulmonary pressure gradient. This improves ventilation–perfusion
mismatch and gas exchange. Prior to COVID-19, it had been questioned whether these
physiological benefits could be applied to the conscious population as there were few
studies that evaluated the physiological effects of awake PP before 2020 [28–30].
Since the onset of the COVID-19 pandemic, prudent critical care resource allocation and hospital
flow have been paramount, and interest in conscious PP re-emerged. Awake PP has been
associated with a decreased risk of intubation (hazard ratio 0.75, 95% CI 0.62–0.91), without a
signal of harm in terms of 28-day mortality (hazard ratio 0.87, 95% CI 0.68–1.11) in a meta-trial
[31]. The increased clinical and scientific interest in PP has resulted in guideline publications to
aid safe and effective implementation of this treatment approach (figure 1) [32, 33].
Endotracheal intubation
Indications
There are no evidence-based guidelines describing the optimal time point for endotracheal
intubation, either in all-cause acute respiratory failure or in COVID-19 specifically [34].
Indications:
FIO2 >28% to achieve SaO2 92–96% (88–92% if
risk of hypercapnic respiratory failure) AND
suspected/confirmed COVID-19
Consider prone position if:

• Able to communicate and co-operate with procedure
• Able to rotate to front and adjust position independently
• There are no anticipated airway issues
Absolute contraindications:
• Respiratory distress
• Immediate need for intubation
• Haemodynamic instability or arrhythmia
• Agitation or altered mental status
• Unstable spinal/thoracic injury/recent abdominal surgery
Assist patient into prone position
Monitor oxygen saturations for 15 min:

SaO2 92–96% (88–92% if risk of hypercapnic respiratory
failure) and no obvious distress
Continue proning process If deteriorating oxygen saturation, modifications can

be made. Escalate to critical care if appropriate.
Discontinue if:
• No improvement with change of position
• Patient unable to tolerate position
• RR >35, looks tired, using accessory muscles
Figure 1. Flowchart for awake prone positioning. RR: respiratory rate. Reproduced and modified from [32]
with permission.
126 https://doi.org/10.1183/2312508X.10025920
However, it is considered judicious that intubation should not be delayed in cases of severe
ARDS or hypoxaemia refractory to oxygen escalation therapy, including NRTs. The “silent
hypoxaemia” phenomenon has been described in patients with COVID-19 who have
minimal signs of respiratory distress [35]. Given the variation in acute presentations, a
reasonable approach includes consideration of a range of symptoms and signs, listed in
table 1 [24, 34–37], which must be balanced with potential resource limitations (e.g.
availability of ventilators or staff, ICU capability), the clinical trajectory and individual
patient wishes [34].
Safety measures
Endotracheal intubation is classified as an AGP by the WHO [38]. Data following the
SARS-CoV-1 pandemic in 2003 indicated that healthcare workers are at increased risk of
infection, especially when involved in airway-related procedures [39]. A systematic literature
review and meta-analysis found a significant increased OR of 5.5 for infection in healthcare
workers exposed to AGPs in SARS-CoV-1 patients. Additionally, the intubation procedure
carried an absolute risk of 10–15% [40]. It is consequently presumed that COVID-19 poses
similar risks to clinicians [41], and intubation procedure recommendations have been
updated accordingly for patients who are suspected of having or have confirmed
COVID-19 diagnoses [42].
A recent study undertook air sampling around a patient during controlled intubation and
concluded that intubation does not generate any more aerosol than coughing [43];
however, the findings of this small study must be translated into other intubation scenarios
with caution. Emergency intubation may put both patients and healthcare workers at
increased risk of virus transmission, and early, planned intubation, with appropriate
utilisation of PPE, clamping of endotracheal tubes, use of video-laryngoscopy, specified
roles and minimisation of the number of experienced clinicians involved, may reduce this
risk [32, 42, 44].
Lung-protective ventilation
Clinical presentation and histopathology suggest that severe COVID-19-related acute

hypoxaemic respiratory failure is similar to ARDS due to other causes [1–3]. Additionally,
pulmonary endothelial vasculopathy has been described as a prominent feature of severe
COVID-19 pneumonia based on post-mortem examination showing evidence of pulmonary
capillary endothelial injury, thrombosis and CT findings suggesting pulmonary arteriolar
abnormality [45, 46]. Compared with large samples of patients with non-COVID-19-related
Table 1. Factors associated with endotracheal intubation indication in COVID-19 patients
Progressively increasing oxygenation requirements, despite oxygen escalation therapy

Increasing vasopressor support
Persistent thoracoabdominal asynchrony
Increasing work of breathing
Increasing respiratory distress
Low ROX index
Hypercapnia
Altered state of mind
https://doi.org/10.1183/2312508X.10025920 127
ARDS, patients with COVID-19 have been shown to have, on average, slightly higher
respiratory system compliance and a higher dead-space fraction [47, 48]. In a subset of
patients with COVID-19 with relatively higher compliance of the respiratory system than
was observed in other studies, recruitment resulted in less improvement in respiratory
mechanics than in a historical control group [49]. There is a need for better phenotyping of
COVID-19 patients, and premature efforts might result in erroneous classifications [50].
A lung-protective ventilation strategy during IMV targeting tidal volumes of 6–8 mL·kg−1
of predicted body weight, a plateau pressure of <30 cmH2O and a driving pressure of
<15 cmH2O is generally recommended [51–53]. Positive end-expiratory pressure (PEEP) is
required to prevent atelectasis and maintain adequate oxygenation, but excessive PEEP can
lead to barotrauma and haemodynamic compromise. The optimal PEEP for individual
patients with COVID-19 balances the benefits in terms of recruitment with the
disadvantages of increased pulmonary pressures such as overdistention and haemodynamic
compromise. Anatomical recruitment can be assessed by chest CT, lung ultrasound or
electrical impedance tomography, while gas recruitment can be assessed by the compliance
of the respiratory system, the recruitment index and quantification of gas exchange. Most
cohorts describing large numbers of mechanically ventilated patients with COVID-19 have
reported a median PEEP of 10–15 cmH2O [48, 54, 55].
Minute ventilation should be adjusted to maintain a pH >7.2 while maintaining a low tidal
volume and driving pressure. The optimal oxygenation target in patients with COVID-19
who require mechanical ventilation has not been well studied. Considerations include
minimisation of FIO2 to minimise oxygen toxicity and resorption atelectasis. One study of
liberal versus conservative oxygenation targets (PaO2 90–105 versus 55–70 mmHg) in
patients with ARDS was stopped early with increased 90-day mortality and reports of
mesenteric ischaemia in the conservative oxygen target arm [56].
Adjunctive treatments
Prone positioning
A prone body position improves ventilation–perfusion matching and distribution of

ventilation, and has been shown to improve survival in patients with persistent ARDS and
a PaO2/FIO2 ratio <150 mmHg [25]. Complications due to PP can include pressure injuries
on the anterior surface of the body, especially the face, and rarely displacement of lines,
tubes and other life-support devices. Multidisciplinary “proning teams” have been
organised to provide PP treatment to large numbers of patients in COVID-19 pandemic
circumstances with a low rate of complication [57]. PP should be offered to patients with
severe hypoxaemic respiratory failure due to COVID-19 in the absence of
contraindications. While data from RCTs in COVID-19 are pending, we would suggest PP
for ⩾16 h following previously published RCTs in ARDS [25].
Recruitment manoeuvres
Recruitment manoeuvres involve a brief, controlled application of increased airway pressure

to reduce open atelectatic lung units, followed by subsequent stabilisation of these units
using PEEP. A variety of recruitment manoeuvre types have been used in patients with
ARDS with variable results [58]. One trial that applied a routine recruitment manoeuvre
128 https://doi.org/10.1183/2312508X.10025920
strategy with a high PEEP strategy in patients with severe ARDS was associated with worse
outcomes [59]. Based on the evidence in non-COVID-19-related ARDS, it is unlikely that
routine recruitment manoeuvres are beneficial, and they should only be tried if there is
indeed a potential for recruitment at moderate airway pressures.
Venovenous extracorporeal membrane oxygenation
Trials of venovenous extracorporeal membrane oxygenation (VV-ECMO) support in ARDS

have shown improved outcomes in patients treated at an ECMO centre compared with
referral hospitals, and a trend towards improved 60-day mortality versus usual care with
crossover to ECMO as rescue [60, 61]. VV-ECMO has been used successfully to treat
patients with severe COVID-19 [61, 62]. ECMO is generally recommended in patients with
severe COVID-19 and progressive respiratory failure despite PP, neuromuscular blockade
and lung-protective ventilation in the absence of contraindications [63]. Some parameters
that are generally considered an indication for progressive respiratory failure are: 1) PaO2/FIO2
<60 mmHg for >6 h, 2) PaO2/FIO2 <50 mmHg for >3 h or 3) pH <7.20 with PaCO2 >80 mmHg
for >6 h [64]. The decision to start VV-ECMO should be made in the context of the
individual patient and may include considerations such as the duration of mechanical
ventilation (generally <7 days), the presence of indicators of barotrauma, a trajectory of
respiratory failure and hospital system logistics. The median duration of ECMO treatment
in patients with COVID-19 has been 14–20 days and mortality ∼40%. Complications have
included bleeding, thrombosis, haemolysis and oxygenator failure [61, 63, 65]. VV-ECMO
may offer benefit to carefully selected patients with severe COVID-19, but is a
resource-intensive treatment best offered in experienced centres.
Pulmonary vasodilators
Inhaled pulmonary vasodilators including nitric oxide and epoprostenol can improve gas
exchange by selective vasodilation of the pulmonary vasculature in the ventilated parts of
the lung, thereby improving ventilation–perfusion matching [66, 67]. Inhaled pulmonary
vasodilators have not been shown to improve mortality or decrease ventilator days in
ARDS, but have been used as rescue treatments to ameliorate refractory hypoxaemia in
severe hypoxaemic respiratory failure. Several small cohorts of patients with COVID-19
have not reported significant improvements in PaO2/FIO2 after the initiation of inhaled nitric
oxide or inhaled epoprostenol [68–70]. Inhaled pulmonary vasodilators can be trialled as a
rescue therapy or bridging therapy, but treatments with more robust evidence such as PP
and, where available, ECMO should be prioritised.
Pharmacological interventions
Antivirals
Remdesivir is a nucleotide prodrug that terminates viral RNA transcription [71].

Remdesivir reduced recovery time by 5 days in all patients in one study, but not in patients
who needed mechanical ventilation or ECMO at baseline [72]. Results from the largest trial
so far of remdesivir in severe COVID-19 did not show any improvement in mortality,
progression to mechanical ventilation or duration of hospital stay [73]. There does not
appear to be a difference in efficacy between 5 days or 10 days of remdesivir, but few
patients in this study required mechanical ventilation at enrolment, so the optimum
https://doi.org/10.1183/2312508X.10025920 129
duration of remdesivir in critically ill patients is unclear [74]. If there is an effect of

remdesivir, the effect size is moderate and is probably better applicable to treatment on the
ward rather than during ICU admission.
Lopinavir–ritonavir is an antiviral combination, typically used in the treatment and

prevention of HIV [75]. Lopinavir–ritonavir does not appear to improve mortality,
progression to mechanical ventilation or duration of hospital stay in COVID-19 [76]. A
small study suggested that it may reduce time in the ICU by 5 days in severe COVID-19 [77],
but the RECOVERY trial showed no evidence for benefit in COVID-19 patients on IMV,
although the confidence intervals for estimated effect sizes were wide [78].
Favipiravir is an influenza antiviral that inhibits viral RNA polymerase [79]. In a small,
open-label randomised trial recruiting patients with moderate COVID-19, favipiravir
resulted in a 2-day reduction in time to clinical cure [80]. Data from a small nonrandomised
study indicated that favipiravir may result in faster virus clearance and resolution of
radiological findings compared with lopinavir–ritonavir, as well as fewer adverse events [81].
Further RCTs of favipiravir in severe COVID-19 are needed to assess effectivity.
Antibiotics
A systematic review and meta-analysis found that 14% of ICU patients have bacterial
coinfection (95% CI 5–26%) [82]. However, up to 71% of patients receive antibiotics,
indicating inappropriate administration of antimicrobials [83]. Elevated procalcitonin is
uncommon in COVID-19 but does appear to increase with increasing disease severity [84].
This could be due to bacterial coinfection, as patients with suspected bacterial coinfection
have poorer outcomes [83], but it could also be due to the COVID-19 disease process.
Therefore, procalcitonin alone should not be used to diagnose bacterial coinfection. Other
signs of coinfection include a change in symptoms (e.g. new pyrexia), new leucocytosis
and/or neutrophilia, or new radiological consolidation [85]. Antibiotic stewardship should
be maintained when managing COVID-19 in the ICU to reduce the risk of multiresistant
organisms developing [86]. Routine use of antibiotics is not recommended in COVID-19,
and antibiotics should only be used if there is a suspected bacterial coinfection.
Anticoagulation
Coagulopathy is common in COVID-19, and the degree of coagulopathy increases with

disease severity: D-dimer levels and prothrombin times are increased in ICU patients and
nonsurvivors [46, 87, 88]. Venous thromboembolism rates are higher in COVID-19 patients
admitted to the ICU than in non-COVID-19 patients [89, 90]. Furthermore, prophylactic
anticoagulation was associated with a 4-fold decreased risk of pulmonary embolism in severe
COVID-19 [91]. There are limited data comparing the effectiveness of different prophylactic
anticoagulants. Expert consensus is that LMWH is preferable to unfractionated heparin, as
unfractionated heparin requires frequent blood tests to monitor the activated partial
thromboplastin time, which increases healthcare worker exposure to COVID-19 [92]. There is
a lack of evidence supporting the routine use of therapeutic anticoagulation in COVID-19,
and there are now emerging reports of major haemorrhagic events in patients receiving
therapeutic anticoagulation [93]. Furthermore, a preliminary report of a large RCT indicates
that therapeutic anticoagulation does not improve outcomes [94]. Taken together,
prophylactic anticoagulation should be utilised in COVID-19, and therapeutic anticoagulation
should only be used if there is suspected/confirmed venous thromboembolism.
130 https://doi.org/10.1183/2312508X.10025920
Steroids
The value of corticosteroids in ARDS has been widely debated [95, 96]. Despite a strong
pathophysiological rationale for controlling an excessive immune response, there were
initial hesitations in using steroids in severe COVID-19 pneumonia [97]. Consistent with
data following MERS-CoV infection [98], studies suggested that steroids increase the viral
load in patients with SARS-CoV-1 [99, 100]. Furthermore, steroids were associated with
higher mortality in patients with severe influenza infection [101].
Early steroid treatment

Prior to the COVID-19 pandemic, several studies investigated steroids in ARDS. In a recent
multicentre RCT, patients with moderate-to-severe ARDS were randomised to receive
dexamethasone (20 mg once daily for days 1–5, and 10 mg once daily for days 6–10) or
placebo. The mean number of ventilator-free days was higher in the dexamethasone group,
suggesting that early administration of dexamethasone could reduce the duration of
mechanical ventilation and overall mortality in patients with established moderate-to-severe
ARDS not related to SARS-CoV-2 [96].
Dexamethasone
The RECOVERY study showed that use of dexamethasone 6 mg for 10 days reduced 28-day
mortality compared with the standard of treatment in patients who required ventilatory support
[102]. Even so, this study had limitations because it was a pragmatic open-label study. The
CoDEX (COVID-19 dexamethasone) trial, a Brazilian multicentre RCT, was conducted to
evaluate the efficacy of dexamethasone in patients with moderate-to-severe ARDS due to
COVID-19 and showed a statistically significant increase in the number of ventilator-free days
(days alive and free of mechanical ventilation) over 28 days [103]. There is robust evidence to
recommend dexamethasone 6 mg·day−1 orally or intravenously for 10 days (or until discharge
from hospital) for all patients requiring supplemental oxygen. In ICU patients, the optimal
dosage could be higher, and one could consider a maximum dose of dexamethasone 20 mg·day−1
i.v. for 5 days (followed by 10 mg dexamethasone), but comparative evidence is currently lacking.
Studies comparing moderate- and high-dose steroids are expected soon. A higher dose might
increase the number of ventilator-free days, but will probably also result in more side-effects.
Other steroids
Future studies should evaluate whether there is a class effect or only a specific drug effect of
dexamethasone [104]. In the case of a lack of dexamethasone, other corticosteroids at
equivalent doses are recommended.
Anti-IL-6 treatment
IL-6 is a central pro-inflammatory cytokine involved in the innate immune response. Higher
initial plasma concentrations are associated with higher mortality in critically ill COVID-19
patients. Furthermore, there is a difference in IL-6 trajectory between survivors and
nonsurvivors [105]. Nevertheless, plasma IL-6 levels are lower in patients with COVID-19-
related ARDS than with ARDS due to other causes [106]. Tocilizumab and sarilumab are
recombinant humanised anti-IL-6 receptor monoclonal antibodies that block downstream
signalling and reduce inflammation. Tocilizumab was found to reduce mortality in patients
with a CRP level >75 mg·L−1 in the RECOVERY trial [107]. The REMAP-CAP
(Randomized embedded multifactorial adaptive platform for community-acquired
pneumonia) trial showed similar results in patients admitted to the ICU for organ support,
https://doi.org/10.1183/2312508X.10025920 131
irrespective of CRP plasma concentrations [108]. In a planned meta-analysis conducted by

the WHO that included over 10 000 patients, administration of IL-6 antagonists was
associated with reduced mortality. Taken together, IL-6 antagonists are recommended in
critically ill patients with COVID-19 on ICU admission, if not administered beforehand.
Complications during intensive care of patients with COVID-19

infection
A wide variety of complications have been observed in critically ill patients with COVID-19
[109]. It is important to clarify that it is unclear for most of these complications whether
they are a result of the COVID-19 infection itself or a consequence of critical illness in
general. Irrespective of the exact cause, it is important to be aware of the potential
multiorgan involvement during the course of disease.
Neurological complications
COVID-19 patients can exhibit various neurological sequelae with rates ranging from 15%
to 65% [110, 111]. Symptoms range from headache, encephalopathy, dizziness, dysgeusia
and anosmia to severe cognitive impairment, stroke, movement disorders, motor and
sensory deficits, myopathy and seizures [110–112]. A higher incidence of neurological
symptoms is observed in critically ill versus noncritically ill patients with COVID-19, with
delirium/acute confusion being the most prevalent [110, 112].
For characterisation of COVID-19 encephalopathy, a spectrum of magnetic resonance imaging

(MRI) findings has been observed. These findings include leptomeningeal enhancement, medial
temporal lobe signal abnormalities, nonconfluent multifocal white matter hyperintense lesions
and/or bilateral frontotemporal hypoperfusion [111, 113–116]. Imaging should be obtained
when clinically indicated, and little has been added with the addition of lumbar puncture.
Frequent reorientation, supportive care and time have proven to be the most effective therapy.
Ischaemic strokes have been reported in both severe and nonsevere COVID-19 illness, but
are often correlated with systemic signs of inflammation such as CRP [117, 118]. Strokes
seem more severe, more frequent and possibly occur in younger patients than otherwise
observed [117, 119]. Microbleeds and haemorrhagic strokes have also been reported [115, 116].
The observation of bleeding and clotting is further addressed in the Vascular complications
section. Stroke prevention should be centred around mitigating risk with patient-specific
anticoagulation and imaging investigations.
Peripheral nerve pathologies have been described, including critical illness polyneuropathy
and myopathy possibly directly related to COVID-19, but a direct viral mechanism has
not been found [110, 111]. There are case reports of acute demyelinating polyneuropathy
(i.e. Guillain–Barré syndrome and Miller Fisher syndrome) [120, 121]. Management should
follow conventional treatment guidelines and focus on supportive care. There is no
indication that these complications occur more frequently than in other viral illnesses.
Cardiac complications
Direct cardiac damage from COVID-19 is less apparent than initially feared. There are data
that indicate increased risk of arrhythmias in COVID-19, but this is confounded by the use
132 https://doi.org/10.1183/2312508X.10025920
of arrhythmogenic agents such as hydroxychloroquine and is not felt to be a viral effect

[122–124]. While there are studies reporting evidence of cardiomyopathy in COVID-19
seen on cardiac MRI and pathology, this link is not clearly established [115, 125–128].
While COVID-19 causes increased thrombosis generation and endothelial inflammation,
the apparent incidence of myocardial infarction has not increased. Standard cardiac
surveillance is recommended for ICU patients.
Pulmonary complications
Nonresolving ARDS is frequently seen in COVID-19 patients. These patients maintain a low
PaO2/FIO2 ratio and nondependent ground-glass opacities are evident on a chest CT scan. On
biopsy, there have been several observed histopathological patterns including acute fibrinous
and organising pneumonia, diffuse alveolar damage, fibrosis and organising pneumonia
[129–131]. ARDS related to COVID-19 persists longer than influenza virus infection, and
while the proportion of patients requiring intubation was the same, the length of time for
COVID-19 patients was significantly longer and was associated with lower rates of extubation
and a higher all-cause mortality [132]. At hospital presentation for COVID-19, the incidence
of coinfection with community-acquired pneumonia is low at ∼3% [133–135]. However,
during hospitalisation, especially in the ICU, this incidence increases. Coexisting bacterial
pathogens range from Streptococcus pneumoniae and Staphylococcus aureus to Pseudomonas
aeruginosa, Escherichia coli and Acinetobacter baumannii, with continued S. aureus presence
[133, 135, 136]. Fungal infections including Aspergillus and Candida species have also been
observed, but the rate of fungal infections is controversial, as reports vary from 1% to 20%
[133, 134, 137–139]. Several reports highlight Aspergillus coinfections and refer to the entity as
coronavirus-associated pulmonary aspergillosis [139–141]. There is controversy surrounding
the incidence, as there is no good reference standard for invasive Aspergillus infection in the
absence of radiological signs and host factors. Furthermore, high rates of coinfection have not
been identified in autopsy series [128, 129, 139, 142, 143]. Currently, there is no
recommendation to use antibacterial or antifungal treatments as “prophylaxis”. However, as
the hospital course lengthens, the pre-test probability for such infections increases, and
therefore investigation for invasive fungal or coexisting bacterial infections is encouraged.
Pneumothoraces have been reported in 1–2% of hospitalised patients with COVID-19,

either spontaneously or during mechanical ventilation. However, development of a
pneumothorax does not appear to correlate with poorer clinical outcomes [137, 144].
Particular attention should be paid to optimising driving pressures and increasing ventilator
synchrony during mechanical ventilation to reduce the risk of iatrogenic pneumothorax.
Gastrointestinal and hepatic complications
There is involvement of the digestive tract in COVID-19, with nearly 20% of patients
exhibiting diarrhoea and >40% experiencing nausea or vomiting [145–147]. Direct liver
injury has been identified both radiographically and on laboratory testing [148, 149].
SARS-CoV-2 cellular receptors are present mainly on cholangiocytes rather than hepatocytes,
Kupffer cells or intrahepatic immune cells [150, 151]. Physicians should be aware of hepatic
steatosis, acute hepatitis and cholestasis that are increased with COVID-19 [152, 153].
The overall prevalence of liver dysfunction related to COVID-19 is low [154]. The degree of
abnormal liver function tests as well as radiographic abnormalities has been associated with
https://doi.org/10.1183/2312508X.10025920 133
the severity of lung injury [148, 149]. Medications with high degrees of liver toxicity are
frequently used in critically ill patients [148]. Special attention should be paid to
medication use, dose and duration with concern for liver injury.
Renal complications
The rates of acute renal injury are high in the general COVID-19 hospitalised population
(∼20%) and occur in up to 90% of mechanically ventilated patients [155, 156]. While the
mechanism for renal impairment is multifactorial including cardiorenal syndrome and
sepsis, there are some data indicating direct renal tubular epithelium and podocyte
involvement [115, 157, 158]. Given this degree of derangement, there is a high need for
renal replacement therapy in patients who are critically ill with COVID-19. Renal
replacement therapy should be given in relation to conventional triggers, as there has been
no evidence to suggest otherwise.
Vascular complications
Endothelial dysfunction, coagulopathy and complement activation are likely to be

important mechanisms of organ injury related to COVID-19 [159]. These mechanisms
probably play a role in injury to the brain, heart, lungs and kidney, both on the venous and
the arterial side, given the propensity towards forming microscopic and macroscopic clots
[128, 129, 160, 161]. There appears to be an increased risk of thrombosis in patients with
COVID-19-related ARDS when compared with other ARDS due to other respiratory
viruses. Specifically, the estimated incidence of pulmonary embolism in ICU patients ranges
from 30% to 50% [162–165]. The prognosis worsens and the incidence of thrombosis
increases when patients are found to have abnormal coagulation parameters [87, 166].
While there have been calls to increase doses of thromboprophylaxis, there has been no
clear evidence to support this or higher therapeutic goals in these patients to date.
COVID-19 is associated with a coagulopathy, unique from disseminated intravascular

coagulopathy (DIC), characterised by elevated fibrinogen, D-dimer, mild thrombocytopenia
and slight prothrombin time prolongation [167]. COVID-19 coagulopathy may be driven
more by inflammatory changes as well as endothelial damage. Patients with COVID-19 can
develop overt DIC, but this is probably related to critical illness. Bleeding is rare in
COVID-19 patients [87, 163, 167]. Management is supportive, focusing on treating the
underlying critical illness correction of coagulopathies in the presence of bleeding.
Post-ICU syndrome in COVID-19
Post-ICU syndrome encompasses the range of physical, cognitive and mental sequelae of
critical illness, which may persist for months or years following hospital discharge [168].
Critical illness is a multisystem disorder that may manifest with hypoxia, hypotension,
systemic inflammation, nutritional deficiency and glucose dysregulation, and ICU
admission typically involves prolonged immobilisation, sleep disruption, and the use of
sedation and analgesia. Survivors of critical illness are consequently at risk of organ-specific
complications, functional disability and psychiatric disorders, including depression, anxiety
and PTSD [169]. ICU mortality appears to be improving over the course of the current
pandemic, which may be attributable to lung-protective ventilation strategies, steroids and
effective resource utilisation [170]. Results from ongoing pharmaceutical trials may further
134 https://doi.org/10.1183/2312508X.10025920
improve COVID-related ICU survival [102]. Thus, as COVID-related critical illness

survivorship increases and the incidence of COVID-19 continues to rise, early recognition
and management of COVID-19 sequelae is a clinical priority.
Persistence of symptoms following the acute phase of COVID-19 illness, referred to as

“long COVID” or “post-COVID”, is increasingly described [171, 172], and medium-term
post-hospitalisation data are emerging. An early report identified that 87% of patients
reported at least one persistent symptom at face-to-face clinical follow-up 2 months after
COVID-19 symptom onset, with fatigue (53%) and dyspnoea (43%) most commonly
observed [171]. Similarly, at 2 months post-discharge, high burdens of persistent fatigue
(68%), sleep disturbance (57%) and breathlessness (32%) were observed by another group
of investigators [173]. This was in line with the findings obtained through telephone
interviews at 2 months post-discharge, and reported comparably high burdens of new or
worsened fatigue and breathlessness, more prevalent in those admitted to the ICU (fatigue
72%, breathlessness 66%) [174]. Functional limitation is also described, with 46% of
patients reporting persistent functional impairment, compared with the pre-COVID-19
baseline, at 2 months post-discharge [173]. Exercise limitation has also been reported, with
a slow (<0.8 m·s−1) 4-m gait speed observed in 38%, 52% below the lower limit of normal
for 1-min sit-to-stand repetitions and 35% exhibiting exertional SpO2 by ⩾4% [173].
Speculative causes underpinning these observations include persistent systemic
inflammation [175], pulmonary inflammation or fibrosis and associated restrictive lung
defects [176], and muscle weakness and wasting as a consequence of both the systemic
manifestation of acute COVID-19 and contextual limitations on exercise as a result of
governmental policies on social distancing and lockdown. The psychological impact of
severe COVID-19 following hospital discharge should not be underestimated, with anxiety,
depression and PTSD reportedly affecting up to 42%, 31% and 28% of patients,
respectively [173, 177].
Long-term COVID-specific post-ICU outcomes remain largely unknown, and results

from multicentre clinical trials, such as the PHOSP-COVID (Post-hospitalisation
COVID-19 study: a national consortium to understand and improve long-term health
outcomes) trial (identifier ISRCTN10980107), are eagerly awaited. However, patients
admitted to the ICU are likely to face similar challenges to the general ICU cohort, and
we can apply lessons learned from outcomes following ARDS and previous coronavirus
outbreaks. Evaluation of ARDS survivors at 3, 6 and 12 months post-discharge identified
persistent impairments in lung function, 6-min walk distance and quality of life [178, 179].
These sequelae were attributed to muscle weakness and wasting caused by critical illness
neuromyopathy, but could not be related to pulmonary fibrosis. Functional impairment
may be present 5 years after index hospitalisation [180]. Six months following
hospitalisation with SARS-CoV-1, survivors exhibited respiratory muscle weakness,
functional limitation, reduced quality of life and impaired lung function, with lower FVC,
total lung capacity and transfer factor of the lung for carbon monoxide (TLCO) observed in
those requiring ICU admission [181].
There is an expanding body of evidence describing multidisciplinary in-ICU measures that

mitigate the long-term effects of critical illness, which may be applied to COVID-19
patients. Early exercise, mobilisation and daily sedation holds are associated with improved
functional status and muscle strength at hospital discharge and shorter duration of
mechanical ventilation and ICU admission [182, 183]. Measures should be taken to avoid/
minimise delirium, which is associated with adverse post-ICU outcomes. When required,
https://doi.org/10.1183/2312508X.10025920 135
sedation should be light (assessed with validating scoring systems, such as the Richmond
Agitation–Sedation Scale) and interrupted daily to facilitate patient arousal [184]. This
approach reduces drug accumulation and side-effects, and improves long-term physical,
psychological and neurocognitive outcomes. Opioids should be avoided in pain
management when possible, as they are associated with delirium, respiratory depression
and prolonged ICU admission [185]. Sleep disruption can be minimised by reducing
nocturnal light and noise, the use of orientation boards and clocks, and by implementing
assist-control ventilation overnight.
Following hospital discharge, survivors of critical illness should routinely be offered

patient-centred multidisciplinary post-ICU support and clinical care, based on the
aetiology and severity of the index critical illness and premorbid characteristics and
comorbidities [186]. The THRIVE taskforce was established to improve care for survivors
of critical illness and their families, and involves clinician education and patient-led peer
support [187, 188]. Rehabilitation programmes, which may be delivered in hospital or at
home, should be offered routinely at discharge, and have been shown to improve
functional status and quality of life at 6 months post-discharge [169]. Post-ICU outpatient
evaluation may be beneficial to critical illness survivors, and should integrate
neurocognitive and psychological support. We recommend that these holistic principles be
applied to survivors of severe COVID-19 as well. In the current absence of robust,
prospective data on long-term COVID-19 sequelae, guidance from international societies,
including the European Respiratory Society, may be implemented to develop
post-COVID-19 services locally [189]. Based on these recommendations, post-COVID-19
ICU follow-up services should involve a clinical review of pulmonary and extrapulmonary
sequelae by a trained physician, and incorporate radiological, physical function,
neurocognitive and psychological screening, with onward specialist referral where
appropriate [190]. Delivery of such services must be pragmatic in the current environment
where clinical resources (healthcare staff, equipment, space) are under immense pressure
and where conventional services (including lung function and rehabilitation) are limited by
infection control precautions aimed at reducing nosocomial virus transmission. Regular
service evaluation is recommended, and an adaptive model of care that considers the
physical, psychological and social needs of the local population and emerging
post-COVID-19 data should be adopted.
Conclusion
In this chapter, we have described the ICU management of patients with severe COVID-19
infection. In general, the approach is very similar to the management of patients with
severe non-COVID-19-related ARDS. One of the major advances is the proven effectiveness
of treatment with steroids in COVID-19 patients. However, the mortality, morbidity and
long-term consequences of COVID-19 remain significant. In the coming period, we are
likely to learn more about the effective treatment of this devastating disease and hopefully
further improve outcomes.
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Disclosures: S. Ananth has nothing to disclose. A. Aujayeb has nothing to disclose. S.B. Brosnahan has
nothing to disclose. L.D. Bos reports receiving the following, outside the submitted work: a Young Investigator
grant from the Dutch Lung Foundation; a Public–Private Partnership grant from the Dutch Lung Foundation
and Health Holland; and grants from the Dutch Lung Foundation (Dirkje Postma Award), the IMI COVID19
initiative and from the Amsterdam UMC fellowship. R.F. D’Cruz has nothing to disclose. D. López-Padilla has
nothing to disclose. A. Lubinsky has nothing to disclose. H.S. Kulkarni reports receiving the following, outside
the submitted work: grants from the National Institutes of Health, the Department of Defense and Alexion
Pharmaceuticals; and personal fees for work on an Advisory Board from inThought Research
(inDemic). T. Marín reports receiving the following, outside the submitted work: grants from the Spanish
Society of Pulmonology and Thoracic Surgery (SEPAR) and the Catalan Society of Pulmonology (SOCAP) for a
Clinical Fellowship in Non-invasive Ventilation, Bolonia; travel and accommodation expenses for the European
Respiratory Society Respiratory Failure and Mechanical Ventilation Congress 2020, Berlin; and receipt of
loaned medical material from Phillips, BREAS and Pulmovista. E. Swingwood has nothing to disclose.
https://doi.org/10.1183/2312508X.10025920 143
| Chapter 9
Clinical features and acute
management in children
Katherine Longbottom1, Elizabeth Whittaker2 and Justin Penner3
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 [https://doi.org/10.1183/2312508X.10024320].
@ERSpublications
In most children, COVID-19 is asymptomatic or mild. Paediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2 is more severe: >40%
have myocardial dysfunction and need inotropic support. Collateral pandemic effects
are significant. https://bit.ly/3sYBXEZ
Epidemiology
Children account for ∼1–2% of reported cases of SARS-CoV-2 infection worldwide [1–5]. In
population-based screening for detection of SARS-CoV-2 RNA using reverse transcriptase
PCR (RT-PCR), the incidence is lowest in children <10 years of age [6, 7]. Accordingly,
SARS-CoV-2 seroprevalence increases with age. A pooled seroprevalence of 2.28% (95% CI
1.1–3.56) in children up to 19 years of age was observed in 23 countries worldwide by August
2020, compared with an all-age seroprevalence of 3.38% (95% CI 3.05–3.72) [8].
1
Paediatric Infectious Diseases, Imperial College Healthcare NHS Trust Children’s Services, London, UK. 2Paediatric Infectious Diseases,
Imperial College, London, UK. 3Paediatric Infectious Diseases, Great Ormond Street Hospital For Children NHS Trust, London, UK.
Correspondence: Elizabeth Whittaker (e.whittaker@imperial.ac.uk)
144 https://doi.org/10.1183/2312508X.10024320
FEATURES AND MANAGEMENT IN CHILDREN | K. LONGBOTTOM ET AL.
The majority of children with reported acute SARS-CoV-2 infection are asymptomatic or
have mild disease [9–11]. Severe disease and mortality are observed in children with
associated comorbidities [11, 12]. As described in adults, children of ethnic minority
groups appear to be over-represented in cases of both COVID-19 and paediatric
inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)
[13–15]. This over-representation of marginalised ethnic minority groups has been seen in
both Europe and the USA.
The impact of variants of concern, particularly B1.617.2 (delta), on paediatric populations

is of imminent importance as social gatherings and education open up to pre-pandemic
capacity. A study analysing weekly hospitalisations of children (0–17 years) in mid-August
2021 demonstrated significantly higher rates of childhood hospitalisation in the USA,
coinciding with increased population prevalence of the delta variant. In adolescents,
admission rates were five times greater than in June 2021, whereas in those aged 0–4 years,
weekly hospitalisations were 10 times those seen in June 2021 and 10.1 times higher in
unvaccinated adolescents compared with fully vaccinated adolescents. Levels of severe
COVID-19 in children and adolescents (requiring paediatric ICU (PICU) admission),
however, were not noted to be higher when comparing 1 March 2020–19 June 2021
( pre-delta) versus 20 June 2021–31 July 2021 ( post-delta) [16].
Neonates
Overall, mothers and neonates infected with SARS-CoV-2 do well. Nonetheless, this
remains a period of high risk for severe infection, given both the maternal and neonatal
state of relative physiological immunosuppression. Vertical transmission of SARS-CoV-2 is
rare but has been reported in several case series from China [17–19], the UK [20] and the
USA [21]. Mother-to-child transmission is estimated to occur in ∼2% of maternal
SARS-CoV-2 infections [20, 21].
A large UK-based maternity unit study identified 427 cases of SARS-CoV-2 infection in
86 293 pregnant women between 1 March and 14 April 2020. Women in the third trimester
(81% of cases), in Afro-Caribbean and ethnic minorities, overweight women, obese women,
those with maternal age ⩾35 years and women with pre-existing cardiorespiratory
conditions and/or diabetes were more likely to be admitted with COVID-19 [20]. In this
multicentre study, 41 maternal admissions required critical care and four of these required
extracorporeal membrane oxygenation (ECMO), with five maternal deaths (maternal
mortality 5.8 per 100 000 maternities, 95% CI 1.9–13.5). There were four pregnancy losses,
and 63% of pregnancies were born pre-term (<37 weeks), of which 12% were attributed
directly to SARS-CoV-2 infection. Twelve infants tested positive for SARS-CoV-2, with 50%
of these in the first 12 h of life [20].
Only a small number of reports have confirmed SARS-CoV-2 in breast milk [22], and it
has yet to be determined whether this represents a possible route of mother-to-child
transmission or whether these cases simply represent inactive virus or virus colonisation of
the breast surface. In a Chinese study of in utero transmission, two term neonates
presented with vague symptoms of lethargy and fever, subsequently testing positive for
SARS-CoV-2, whereas the third, a pre-term neonate, presented with significant early-onset
symptoms of respiratory distress and evidence of pneumonia on radiography [17]. None of
the three positive early neonatal infections had evidence of virus replication in amniotic
https://doi.org/10.1183/2312508X.10024320 145
fluid, cord blood or breast milk [17], whereas the larger UK study [20] did not evaluate
these samples. Two separate case reports have demonstrated positive IgM antibodies in
neonates born to women with SARS-CoV-2 infection and negative SARS-CoV-2 PCR in
vaginal secretions, suggesting probable in utero as opposed to perinatal transmission [23, 24].
Significant expression of ACE2 receptors has been demonstrated in placental and fetal tissue,
supporting the potential biological plausibility of maternal–fetal in utero transmission [25].
SARS-CoV-2 has been isolated in both amniotic [26] and placental [27] tissue. Investigation
of potential antenatal transmission evaluating at a minimum RT-PCR of nasal/respiratory
and rectal swab sampling is important early after birth in order to differentiate from
post-partum acquisition.
Children and adolescents
The majority of data on acute SARS-CoV-2 infection in children are based on hospitalised
cases, and there is a paucity of data on nonhospitalised infected children. One systematic
review concluded that the proportion of asymptomatic children ranged from 14.6% to 42%.
Fever and cough appear to be the most commonly described symptoms; proportions with
fever ranged from 46% to 64.2% and with cough from 32% to 55.9%. A variety of other
“flu-like symptoms” are experienced in children in up to 20% of cases, including
rhinorrhoea, sore throat, headache, fatigue/myalgia and gastrointestinal symptoms
including diarrhoea and vomiting [28]. Overall, children and adolescents make up a small
proportion of hospitalised COVID-19 cases.
The International Severe Acute Respiratory and Emerging Diseases Consortium (ISARIC)
conducted a large multicentre observational study in the UK of children (<19 years) [10].
They reported on 651 children admitted to hospital with a median age of 4.6 years
(interquartile range 0.3–13.7) of whom 35% were <1 year. Three phenotypes were
identified: a discrete respiratory illness, a mucocutaneous enteric illness, and a less common
isolated neurological presentation. PICU admission was required in 18%. Younger children
(<1 month) and older children (10–14 years) were more likely to be admitted to the PICU
with an OR of 3.21 (95% CI 1.36–7.66; p=0.008) and 3.23 (95% CI 1.55–6.99; p=0.002),
respectively. All deaths (0.96%, six out of 627 children for whom outcome data were
available) had comorbid conditions [10]. A large multicentre European observational study
showed similar results, with 8% requiring PICU admission with a very low overall mortality
rate (0.69%) [12]. Younger infants (<1 month) and those with pre-existing conditions were
equally more likely to require PICU admission, and 16% of this cohort were completely
asymptomatic [12]. Increasing rates of asymptomatic infection with age in children was
shown in the original COVID-19 epicentre in Wuhan, where all children <1 year (n=31)
were symptomatic, whereas rates of asymptomatic disease increased steadily with age [29].
However, similar to neonates, older teenagers appear to be at higher risk of more severe
disease when hospitalised, as shown in a Washington cohort [30]. Critically unwell
teenagers were over-represented compared with those hospitalised but not critically unwell
(17.3 versus 3.6 years; p=0.04) [30].
The Paediatric Tuberculosis Network European Trials Group (PTBNET), who surveyed
symptoms in 582 cases of COVID-19 in children (<18 years), revealed fever as the most
common presenting complaint (65%), in line with several other large cohort studies [12].
This was followed closely by upper and lower respiratory tract symptoms (54% and 25%,
respectively). Studies consistently report low levels of hypoxaemia requiring oxygen
146 https://doi.org/10.1183/2312508X.10024320
supplementation [2, 31, 32]. Abdominal pain was a presenting symptom in 40% of
COVID-19 pneumonia, whereas 50% and 60% presented with diarrhoea and vomiting,
respectively, in a cohort with primary respiratory disease at Great Ormond Street Hospital,
UK [33]. In this population, two patients developed thrombosis, secondary to a hypercoagulable
state similarly recognised in the adult population [33].
When chest radiography was performed in the PTBNET study, approximately half of
children with a positive SARS-CoV-2 PCR showed evidence of pneumonia [12]. The
distribution of symptoms and patterns of radiological findings in European and USA
cohorts at presentation were very similar to a Chinese cohort of 1391 children where 12%
of asymptomatic children had evidence of pneumonia on chest radiography [29].
Radiographic findings vary across studies and are likely to be a result of clinical
decision-making thresholds to perform chest radiography and/or CT. A range of both
unilateral and/or bilateral patchy shadowing is described, with those most unwell rarely
showing radiographic signs of ARDS. In one study, younger children (<3 years) were found
more commonly to have bilateral findings on chest CT, whereas older children (>6 years)
more commonly had unilateral lung consolidation [34]. Radiographic findings do not
necessarily correlate with clinical status and physical examination findings, as both
asymptomatic children and those with no clinical respiratory signs may show radiographic
changes consistent with pneumonia.
Elevated CRP (19%) was most common in those with pneumonia, but overall CRP was low [35].
Findings of comparatively low CRP and procalcitonin were consistent across studies and
age groups. A large Italian multicentre study corroborated relatively normal biochemical
findings for children who presented with a range of symptoms and phenotypes excluding
PIMS-TS [32]. Lymphopenia is inconsistently shown across studies of COVID-19
pneumonia [32]. GONZALEZ-CORTES et al. [36] further demonstrated no difference in
biochemical markers (white cell counts, lymphocyte counts and CRP) between those
children requiring ventilation and those who did not. However, a PICU cohort from Great
Ormond Street Hospital, UK, was found to consistently have elevated CRP, ferritin, LDH
and D-dimer [37]. In contrast, markers of systemic inflammation in PIMS-TS, in particular
CRP, are ubiquitously elevated. Children with severe disease have been shown to have
elevated IL-6. However, levels of systemic cytokines (IL-1, IL-4, IL-6 and TNF-α) in
mild-to-moderate disease were generally low. IL-10 was increased in 14% of mild-to-
moderate cases [38]. Nevertheless, cytokine profiles have been done sparsely and may not
be a true representation of localised lung inflammation.
Gastrointestinal manifestations
Gastrointestinal symptoms are the most commonly reported symptoms after fever and cough.
Paediatric case series with confirmed SARS-CoV-2 infection report gastrointestinal symptoms
in 10–33% of cases [2, 5, 10, 12]. One European study described a group of children with
gastrointestinal but without respiratory symptoms (7%) [12]. SWANN et al. [10] described a
discrete cohort of children with mucocutaneous enteric symptoms, including children with
acute SARS-CoV-2 infection and those meeting the criteria for PIMS-TS.
Gastrointestinal symptoms are reported in 80–100% of patients with PIMS-TS [14, 39–41],
and 90% of children treated for PIMS-TS in PICUs in the UK had at least one abdominal
symptom [42]. In a UK case series, 45% of children experienced vomiting, 53% abdominal
https://doi.org/10.1183/2312508X.10024320 147
pain and 52% diarrhoea [43]. In a French cohort, abdominal symptoms were noted to
occur early in the course of illness before the onset of mucocutaneous features. Peritoneal
effusions and aseptic peritonitis all resolved after treatment [41]. In a UK cohort, patients
with intra-abdominal lymphadenopathy, inflammatory fat throughout the mesentery and
thickening of the terminal ileum were managed with immunomodulation and did not
require surgical intervention [44].
Case reports of small-bowel obstruction and intussusception in patients with SARS-CoV-2

suggest an association [45, 46]. During the first wave of the pandemic, the rates of complicated
appendicitis increased in comparison with previous years, with a longer mean duration of
symptoms. In three hospitals across New York City, rates of perforation were 45% compared
with 27% in the preceding 5-year period (OR 2.23, 95% CI 1.29–3.85; p=0.005) [47]. Among 71
children with appendicitis cared for at a children’s hospital in New Jersey, SARS-CoV-2-positive
patients had a higher rate of appendiceal perforation than SARS-CoV-2-negative patients (50%
versus 36.1%), suggesting that both delayed presentation and an exaggerated immune response
to SARS-CoV-2 may account for increased perforation rates [46].
Neurological manifestations
Neurological symptoms are reported in up to 43% children with SARS-CoV-2. Headache,

altered mental status and weakness are the most common [48]. Headache is reported in 8–
28% of children [5, 11, 12]. In the UK, a cluster of patients with confusion and seizures
was identified [10]. There are few case reports of seizures in children associated with
SARS-CoV-2.
Headache, meningism, vision changes, altered mental status, encephalopathy, brainstem

and cerebellar signs, muscle weakness and abnormal reflexes are all reported in
PIMS-TS [39, 40, 49]. In New York, 30–47% with PIMS-TS experienced neurological
symptoms [39, 40]. In a review of 186 cases across the USA, 6% experienced severe
neurological involvement, including encephalitis, aseptic meningitis, demyelinating
disorders, seizures and coma [14]. Splenium signal changes on magnetic resonance
imaging of the brain, an excess of slow-wave activity on electroencephalogram, and mild
myopathic and neuropathic changes on nerve conduction studies and electromyography
have been described [49].
Guillain–Barré syndrome [50, 51], acute disseminated encephalomyelitis, myelitis, neuritis,

autoimmune encephalitis, stroke [52] and intracranial hypertension [53] have also been
reported in children in association with SARS-CoV-2. Whether or not this association is
causative requires further investigation.
Cardiac manifestations
Myocarditis, pericarditis, heart failure, cardiogenic shock, cardiac arrhythmia and

pulmonary hypertension are all reported in children with SARS-CoV-2 who do not meet
the criteria for PIMS-TS [54].
Myocarditis has been observed in children of all ages and can be fulminant. Viral particles
of SARS-CoV-2 have been detected in the myocardium of children with sudden cardiac
148 https://doi.org/10.1183/2312508X.10024320
death, suggesting direct myocardial damage [55]. Myocardial involvement in the absence of
PIMS-TS has been demonstrated microbiologically in a 2-year-old with myocarditis and
SARS-CoV-2 isolated on myocardial biopsy [56]. The CAKE (Critical coronavirus and kids
epidemiologic) study reported on four children with myocarditis in the setting of
symptomatic SARS-CoV-2 infection, none of whom had evidence of previous cardiac
disease [57]. The average time from initial SARS-CoV-2-attributable symptoms to cardiac
manifestations was 3.5 days. All four children survived to hospital discharge. A multitude of
pan-cardiac echo findings including systolic dysfunction, probably secondary to cardiac
stunning, have been described in PIMS-TS.
Renal manifestations
The presence of ACE2 receptors in the kidney may explain renal injury with SARS-CoV-2.
This is in addition to pre-renal and iatrogenic renal insults during illness. Direct renal
injury may result from dysregulation of the immune system and complement activation,
direct viral injury, and/or thromboinflammation and microangiopathy resulting in
endovascular damage. Case reports of COVID-19-associated rhabdomyolysis causing acute
kidney injury (AKI) in children are also described [58, 59], and in one report this occurred
in the absence of typical fever and respiratory symptoms [60].
Critically ill children with COVID-19 have been shown to have the greatest propensity for
AKI, sometimes requiring renal replacement therapy. WANG et al. [61] describe three out
of 238 critically ill children requiring continuous renal replacement therapy who were
also treated with plasma exchange, only one of whom made a full renal recovery [61].
The utility of eculizumab in the context of SARS-CoV-2-induced renal thrombotic
microangiopathy has been proposed [62]. A UK single-centre paediatric cohort mimicked
these findings, demonstrating that 46% of hospitalised children testing positive for
SARS-CoV-2 had an AKI, of whom 93% were admitted to the PICU [63]. Not
surprisingly, children with preceding vomiting and diarrhoea in the setting of SARS-CoV-2
are more commonly found to have AKI [44]. AKI is an equally common finding in the
context of PIMS-TS, and is similarly more common in those requiring PICU care. In a
multicentre study of PIMS-TS patients admitted to the PICU in the UK, 41.4% had
evidence of raised serum creatinine above the upper limit of age-dependent reference
values [64].
Dermatological manifestations
A Spanish cohort of 375 patients with dermatological manifestations outlined five main
categories of skin phenotypes: acral erythema-oedema with vesicles/pustules (19%), which
is more common in children, vesicular eruptions (9%), urticarial lesions (19%),
maculopapular rashes (47%), and livido or necrosis (6%) [65]. Chilblain-like lesions of the
peripheries seem to be associated with SARS-CoV-2 in young people. A cohort of seven
children with chilblains and no other systemic symptoms of SARS-CoV-2 confirmed
isolated endovascular inflammatory and vasculitic manifestations of SARS-CoV-2 [66]. All
seven children were found to be positive for SARS-CoV-2 on biopsy of the lesions.
Consistently, case reports/series comment on spontaneous resolution of skin manifestations
without treatment. In patients with PIMS-TS, a polymorphous rash is described in over
half of patients [38, 39, 42].
https://doi.org/10.1183/2312508X.10024320 149
Comorbidities and risk
A retrospective cohort analysis of patients admitted to a single UK centre revealed no

increase in admissions with COVID-19 in those children categorised as medically
vulnerable [67]. Likewise, a cross-sectional seroprevalence study of 485 children with a
variety of immunocompromising conditions found a similar SARS-CoV-2 seroprevalence
in immunocompetent and immunosuppressed children. None of the immunocompromised
patients with detectable antibodies or who was positive on RT-PCR had more than mild
disease, suggesting similar outcomes to the general paediatric population [68]. This is in
contrast to a multicentre European study, which showed increased risk of admission to
hospital and the PICU in children with comorbidities, in particular those with complex
neurological and neurodevelopmental delays [12].
A report from oncology centres in Lombardy, Italy, described no deaths in oncology

patients from COVID-19, despite high death rates in the region. Nevertheless, changes and
delays to therapy were common, affecting almost 50% [69]. A large paediatric oncology
centre in New York reported similar reassuring findings: 11% of exposed or symptomatic
children tested positive for SARS-CoV-2, of whom only a single child required
hospitalisation without PICU admission [70]. A large UK conglomerate of paediatric
oncology centres described only 54 positive cases, with 28% and 63% having asymptomatic
and mild disease, respectively [71]. No deaths or PICU admissions were reported in this
cohort. Data on patients with acute lymphoblastic leukaemia and those undergoing
stem-cell transplantation exposed to and/or testing positive for SARS-CoV-2 are reassuring,
with limited poor outcomes as a direct result of SARS-CoV-2 infection [69, 72, 73].
A large tertiary care cardiac transplant centre in New York, one of the largest in the USA,
following hundreds of paediatric patients, has equally provided reassuring data on
SARS-CoV-2 in children with heart transplants where only four patients presented with
mild-to-moderate disease [74]. A multicentre analysis of 26 patients with different
solid-organ transplantations and SARS-CoV-2 concluded that those with solid-organ
transplants undergo a similar clinical course to immunocompetent children [75].
A single case report of SARS-CoV-2 in a cystic fibrosis patient described an asymptomatic

clinical course [76]. This has been corroborated by a larger analysis of 105 children with
cystic fibrosis and SARS-CoV-2 infection: 24 required hospital admission, six required
supplementary oxygen and two required NIV, with no SARS-CoV-2-attributable
deaths [77]. A pan-European survey of centres treating children with severe asthma
advocated for a relaxation of shielding, as cases of severe COVID-19 in children with
asthma, even those with the most difficult to treat phenotype, were very uncommon,
mimicking trends in the general paediatric population [78].
Despite the wide use of immunosuppression, a large cohort study of children with
inflammatory bowel disease reported no significant increased risk of severe disease with
SARS-CoV-2 [79]. Analysis of a SARS-CoV-2 outbreak on a paediatric dialysis unit equally
showed no increased risk in this group of medically vulnerable children [80]. Analogous
findings of a larger multicentre study of children with kidney disease showed no increased
risk of severe disease, and thus the authors advocate against shielding in this population
[81]. Likewise, children with primary immunodeficiencies have remained relatively spared
of severe COVID-19 [82].
150 https://doi.org/10.1183/2312508X.10024320
Acute management of SARS-CoV-2 infection in children
As the majority of children experience asymptomatic or mild disease, supportive home

therapy with oral fluids and antipyretics is all that is required. Initial reports of increased
severity with ibuprofen have not been verified, and both nonsteroidal anti-inflammatory
drugs and paracetamol may be used. Wheeze has not been a predominant feature in children
with COVID-19, but normal management with oral steroids and bronchodilators should be
instituted. Hospitalisation is indicated when there is a need for enhanced supportive therapy,
such as intravenous fluids or ventilatory support for those with severe respiratory disease.
There may be a lower threshold for admission of clinically extremely vulnerable children
with COVID-19, such as those with complex neurodisabilities and a history of severe
recurrent respiratory tract infections. Oxygen therapy via mask or nasal prongs is
recommended for hypoxia, with escalation to NIV support, or invasive ventilatory support
as required. Where possible, children should be nursed in single rooms or in
negative-pressure ventilation rooms where available, and appropriate PPE and infection
control measures instituted. There is limited evidence on the benefit of antiviral or
immunosuppressive drugs in paediatric populations, and much has been extrapolated from
adult clinical trials. In vitro, animal and human studies of remdesivir have shown some
benefit in moderately unwell adults with COVID-19, but there are no efficacy data in
children to date. Remdesivir has been approved for use in hospitalised adults and paediatric
patients ⩾12 years and ⩾40 kg in a variety of settings. It may be used with caution in
younger hospitalised patients on a case-by-case basis on compassionate grounds use only.
Data from the RECOVERY (Randomised evaluation of COVID-19 therapy) trial, a large,
multicentre, randomised, open-label trial performed in the UK, has led to the
recommendation of use of corticosteroids for adults with moderate-to-severe COVID-19
who were mechanically ventilated or required supplemental oxygen at enrolment. No
benefit of dexamethasone was seen in patients who did not require supplemental oxygen at
enrolment [83]. The safety and efficacy of steroids have not been evaluated in children with
COVID-19. Dexamethasone may be beneficial in paediatric patients who require ventilatory
support, while use in other children who require oxygen therapy should be considered on a
case-by-case basis. Antibiotics should be used only if there is a suggestion of coinfection,
based on usual practice.
Tocilizumab, a human anti-IL-6 monoclonal antibody, appears to be effective in the

treatment of adults with extensive and bilateral lung involvement, according to the
REMAP-CAP (Randomized embedded multifactorial adaptive platform for community-
acquired pneumonia) and RECOVERY trials, but as yet there are no data in children. It
may be used with caution on a case-by-case basis in children after consultation. Trials
evaluating other monoclonal antibody formulations and anti-inflammatory therapies in
children, including synthetic SARS-CoV-2 antibody cocktails, anti-IL-1, anti-TNF and
janus kinase ( JAK) inhibitors, are ongoing.
A variety of other investigational treatments have been examined in randomised and

nonrandomised studies without confirmed benefit. These include azithromycin,
hydroxychloroquine, convalescent plasma and lopinavir/ritonavir, among others. Although
few children were included in these studies, it is unlikely that these treatments would have
benefit in a younger population.
https://doi.org/10.1183/2312508X.10024320 151
Post-infectious complications of SARS-CoV-2 in children
Subsequent to the first wave of the pandemic, clusters of children presenting with unusual
multisystem inflammatory conditions emerged, initially in reports in the UK and Italy [43,
84]. This syndrome, which had overlapping features of other childhood inflammatory
conditions such as Kawasaki disease (KD) and toxic shock syndrome (TSS), became known
as PIMS-TS, or multisystem inflammatory syndrome in children (MIS-C) [85–87].
PIMS-TS appears to follow infection with SARS-CoV-2 with a 3–6-week delay. The disease
is characterised by multiorgan involvement, which can lead to shock, heart failure, a
requirement for intensive care and, in some cases, inflammation of the coronary arteries,
and which may be fatal in a small proportion of cases. Although a number of studies
exploring the pathophysiology of this study are underway, the mechanisms underlying
PIMS-TS remain poorly understood.
Children with PIMS-TS present with fever and a variety of mucocutaneous features
(conjunctival injection, mucosal erythema, maculopapular rashes) (figure 1), gastrointestinal
involvement (abdominal pain, diarrhoea, vomiting), neurological involvement (confusion,
headaches, and lethargy) and cardiac involvement in 40–50% (figure 2).
In a systematic review of 688 cases of PIMS-TS, myocardial dysfunction and heart failure were
observed in 52–53%. Overall, 56.7% of the 75.6% patients admitted to critical care presented
with shock requiring inotropic support [54]. In a paediatric cohort from across Europe with
PIMS-TS and identified cardiac complications (n=286), a reduced left ventricular ejection
fraction was present in over half. The most common cardiac complications were shock
(40.2%), ECG changes (35.3%), pericardial effusion (24%) and coronary artery dilatation
(24.1%) [88]. Reported ECG changes included abnormal ST- and T-wave segments, a
prolonged PR interval, heart block, a prolonged QT interval and ventricular arrhythmias. The
Figure 1. Examples of conjunctival injection (upper panels) and maculopapular rashes on the hands and
abdomen (lower panels) of a child with COVID-19.
152 https://doi.org/10.1183/2312508X.10024320
majority of coronary artery changes included ectasia and mild aneurysms. To date, only a
handful of giant aneurysms have been reported worldwide. The majority of patients with
PIMS-TS have elevated cardiac troponin and natriuretic peptide. VALVERDE et al. [88]
demonstrated a statistically significant correlation between the degree of cardiac and
biochemical parameter elevation and the requirement for intensive care support (p<0.05).
Definition
1. Fever, inflammation and single
or multiorgan failure
All Persistent fever >38.5 °C
2. Exclusion of any other Oxygen requirement
microbial cause Some Hypotension
3. SARS-CoV-2 PCR positive or
negative
(with some additional features
below)
Headache/
confusion
Cough Conjunctivitis
Sore throat Lymphadenopathy
Respiratory
symptoms Syncope
Vomiting
Rash
Abdominal
Diarrhoea pain
Hands/feet
Tests swelling
D-dimer
Ferritin
CRP
Neutrophils (often)
Differentials
Albumin Kawasaki disease
Lymphocytes Toxic shock syndrome
Sepsis
MAS
Abnormal fibrinogen
Figure 2. Infographic prompt for signs, symptoms and case definition of paediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2. MAS: macrophage activation syndrome.
Figure reproduced with kind permission of Don’t Forget the Bubbles (dontforgetthebubbles.com).
https://doi.org/10.1183/2312508X.10024320 153
Mortality rates of up to 1.8% are reported, although most patients recover within the first
weeks of illness. In the majority, the ejection fraction returns to normal by the time of
hospital discharge. RODRIGUEZ-GONZALEZ et al. [54] reported cardiac sequelae in the form of
mild myocardial dysfunction or coronary artery aneurysms in only 5.5% of children,
whereas VALVERDE et al. [88] reported that most coronary artery abnormalities (64 out of
69; Z-score >2) persisted to hospital discharge. Longitudinal studies are required to
determine the long-term outcome for these patients.
To date, management of these children is based on retrospective, observational data and

expert opinion extrapolated from treatment evidence for KD and TSS. Consensus statements
suggest the role of supportive care (fluids, vasoactive drugs, and ventilatory support or renal
therapy when warranted), with various immunomodulatory therapies having a role, including
corticosteroids, i.v. immunoglobulin (IVIG), and monoclonal antibodies against IL-1
(anakinra), IL-6 (tocilizumab) and TNF-α (infliximab) [89]. The Best Available Treatment
Study of 614 children and adolescents with suspected PIMS-TS concluded that illness
trajectory and recovery did not differ significantly based on the primary treatment utilised:
IVIG, steroids alone or a combination [90]. Conversely, the Overcoming COVID-19
consortium showed that initial treatment with IVIG plus corticosteroids was associated with a
lower risk of cardiovascular dysfunction and inotropic support than IVIG alone (n=518) [91].
A French national surveillance study also found that a combination of IVIG and steroids led
to lower rates of treatment escalation, inotropic requirements and shorter stays in the PICU
compared with treatment with IVIG alone [92]. The role of thromboprophylaxis with
antiplatelet agents (aspirin) and LMWH is also unclear. RCT data are urgently required.
Short- and medium-term outcomes of paediatric patients with PIMS-TS, even those with
the most critical illness, are reassuring. Muscle weakness, fatigue and psychological trauma
from hospitalisation are reported as the most common sequelae, stressing the importance
of holistic multidisciplinary care during follow-up [93].
COVID-19 vaccinations in children and adolescents
Various vaccines, utilising different vaccine technologies, have received emergency approval
worldwide in adult populations. The Pfizer/BioNTech and Moderna nucleoside-modified
mRNA vaccines are the most widely studied in paediatric populations leading to universal
adolescent (⩾12 years) vaccine rollout in some countries. Nevertheless, vaccination
approaches in paediatric populations vary widely.
Recently published studies show that both the Pfizer/BioNTech and Moderna vaccines are
reactogenic and immunogenic in healthy adolescents from 12 years of age [94, 95]. A two-
dose, phase 3 study of the Pfizer/BioNTech vaccine conducted in ∼44 000 people
(⩾12 years) demonstrated vaccine efficacy of 95.0% (95% CI 90.3–97.6%) and after two
doses of the Pfizer/BioNTech vaccine (21 days apart), the geometric mean ratio of
SARS-CoV-2 neutralising antibody titres in participants 12–15 years old relative to
16–25-year-olds was 1.76 (95% CI 1.47–2.1) in a total of 1131 adolescents [95]. Furthermore,
in these phase 2/3 studies, no vaccine-related serious adverse events were reported [95].
Safety and efficacy studies in younger children (<12 years) and in children and adolescents
utilising other established COVID-19 vaccine technology platforms approved in adults are
ongoing. Vaccine side-effects in adolescents are generally similar to those experienced in
adult populations and with other routinely administered childhood vaccines: injection site
154 https://doi.org/10.1183/2312508X.10024320
pain, myalgia and fever are most common. A rare post-COVID-19 vaccine myocarditis,
generally appearing within the first 14 days after vaccination, has been described, and is
more common in young men and boys after the second dose. Several case reports/case
series depict this very rare, presumed inflammatory phenomena to be generally mild and
self-resolving in the vast majority of adolescents, but possible long-term effects such as
fibrosis of inflamed cardiac tissue cannot be ignored [96–98].
A study of 35 691 pregnant women vaccinated against COVID-19 did not demonstrate any
adverse effects on the developing fetus or neonate over and above pre-COVID-19
population data [99]. Efficacy of COVID-19 vaccinations in lactating women and positive
neonatal safety outcomes have also been widely published [100]. Extrapolating knowledge
from other vaccine-preventable illnesses (i.e. pertussis, influenza) in pregnancy and the
positive implications of passive immunisation of the developing fetus, COVID-19
vaccination in pregnancy is likely to reduce neonatal COVID-19 infections and/or severity
of disease.
A third boosting dose to adolescents with severe immunosuppression at the time of initial
vaccination and/or ongoing immunosuppression has been considered in some countries, as
with adolescents deemed clinically extremely vulnerable with conditions such as trisomy 21,
cerebral palsy and complex neurodevelopmental delays.
Universal rollout of COVID-19 vaccinations in children and adolescents, who are generally
considered a low-risk group for severe infection, as well as paediatric booster doses, need to
be balanced against the risks of known and as yet unknown possible adverse vaccine-related
events, and possible disruption of existing childhood vaccination schedules through
diversion of resources, among others. We must also consider the effects on broader society,
such as diminishing worldwide vaccine supplies, the ethical implication of vaccination
equity and redistribution, and the associated risk of variant strain emergence in areas where
vaccination rates among adults are low.
Long COVID
Although it is increasingly recognised that adults experience prolonged symptoms following

infection with SARS-CoV-2 (known as long COVID) [101, 102], it is unknown how many
youth are also experiencing persistent changes in their physical and psychological health
[103]. Parents in a long COVID-19 support group have reported that, following
SARS-CoV-2 infection, their children experienced fatigue, general gastrointestinal issues, sore
throat, headache, and muscle pain or weakness. Other symptoms included fever, nausea,
mood changes, rashes, dizziness, breathing difficulties and/or cognitive blunting [104]. These
reports by parents are supported by limited evidence from case series, describing children
who continue to experience symptoms 6–8 months after COVID-19 diagnosis and who were
unable to fully return to normal schooling activities. In a review of 14 studies of COVID-19
sequelae, of which five included youth without SARS-CoV-2 as controls, two studies
concluded that there was no difference in long-term sequelae between those infected with
SARS-CoV-2 versus those who were not. Nevertheless, studies in this review were generally
deemed of poor quality with variable case definitions and follow-up times [105].
Initial studies from the UK suggest that only a small proportion of children with
SARS-CoV-2 have illness duration >4 weeks. In a prospective cohort study of 1734 UK
https://doi.org/10.1183/2312508X.10024320 155
school-aged children with a positive SARS-CoV-2 RT-PCR result, only 77 out of 1734
(4.4%) had illness duration ⩾28 days, while 25 out of 1379 (1.8%) had symptoms for
⩾56 days [106]. Older children were more likely to have longer duration of symptoms, but
in both groups, symptom burden reduced with time. Although only 15 out of 1734 (0.9%)
in the negative-testing cohort had symptoms for ⩾28 days, these children experienced a
greater symptom burden before and after 28 days than the children testing positive, leading
authors to conclude that a holistic approach for all children with persistent illness during
the pandemic is appropriate [106].
Collateral effects of COVID-19 in children and adolescents
Despite relatively good outcomes of COVID-19 in children and adolescents compared with
adults, collateral effects on the mental and physical health of a developing child or
adolescent must not be overlooked. A reduction in care-seeking behaviours during the
pandemic, particularly for mental health-related issues, has been clearly established and
risks further exacerbating delays in diagnosis and mental health treatment [107]. This
mimics delayed presentation to care for medical problems for fear of virus transmission in
hospital settings [108]. Late presentations have been considered a contributing factor in
child deaths.
Across the UK, fewer children have been referred for child protection assessment. Input
from paediatric community health and social care services has reduced and the
safeguarding role played by school staff has diminished through lack of face-to-face contact.
This raises concern about children’s well-being and missed abuse, especially as increased
incidence and severity of domestic violence have been reported worldwide in countries that
have imposed social isolation measures.
Long-term health and social consequences of the pandemic on children and families are
likely to become even more evident as time passes. It is already recognised that death,
social isolation, illness and malnutrition all have lasting effects on child development, and
as a result, the pandemic risks further exposing social disparities. Worldwide routine
childhood immunisation programmes have been disrupted, leading to concern about
measles outbreaks owning to reduced vaccine coverage. Poverty, domestic violence, child
abuse and neglect, educational attainment gaps and a lack of social opportunity during the
pandemic are likely to exacerbate social inequality for an entire generation of young people
unless rapid and meaningful mitigating steps are taken to curb societal gaps created by
downstream effects of the pandemic. This is especially evident as the disease itself appears
to affect ethnic minorities and the socially vulnerable disproportionately, further
exacerbating baseline inequalities.
COVID-19-related social stigma, anxiety about disclosure of illness and social isolation
of those children testing positive for SARS-CoV-2 further risks marginalisation of
children who are already vulnerable and often stigmatised. Investigation into the
underlying reasons for disproportionate infection rates in ethnic minorities is required
but is likely to be multifactorial. Broadening social supports for vulnerable children and
addressing systemic racism and stigmatisation in addition to campaigns to de-escalate
COVID-19-specific stigma are required. This will also strengthen community support
systems and minimise COVID-19 myths and misunderstanding and will help diminish
vaccine hesitancy.
156 https://doi.org/10.1183/2312508X.10024320
Conclusion
Children account for a minority of cases of SARS-CoV-2 infection. The majority with acute
infection are asymptomatic or have mild disease. Although children with comorbidities
such as complex neurodisability have an increased risk of severe disease, those with
immunosuppression appear to have a similar disease course to the general paediatric
population. Fever and cough are the most common presenting features of acute infection,
but a variety of other symptoms including gastrointestinal, neurological and dermatological
symptoms are experienced. PIMS-TS is observed on average 4 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 inotropic support. Management of PIMS-TS
is based on evidence from KD and TSS with possible immunomodulation and cardiac
protection. RCT data are urgently required. Collateral effects of the pandemic are likely to
have long-term effects on children’s physical and mental health.
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https://doi.org/10.1183/2312508X.10024320 161
| Chapter 10
Imaging
Christian B. Laursen 1,2, Helmut Prosch 3, Stefan M.W. Harders 4,
Casper Falster1,2, Jesper R. Davidsen 1,2,5 and Ádám D. Tárnoki6,7
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.
1183/2312508X.10012421].
@ERSpublications
Thoracic imaging is the standard of care in COVID-19 patients alongside clinical and
laboratory assessment. As typical COVID-19 imaging findings are unspecific, abnormal
imaging results should be critically appraised and correlated in the clinical context.
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T he utility of thoracic imaging for diagnosing pneumonia associated with COVID-19,

the disease caused by SARS-CoV-2, has received significant global attention, with
literature originating in particular from experts in China, the USA and Europe where a
range of thoracic imaging patterns have been recognised and described in affected patients
[1, 2]. SARS-CoV-2 targets cells expressing the ACE2 receptor on their surface. In lung
tissue, the ACE2 receptor is expressed primarily on type II pneumocytes and endothelial
cells. Upon entering the host cell, the virus replicates, which ultimately induces an immune
1
Dept of Respiratory Medicine, Odense University Hospital, Odense C, Denmark. 2Odense Respiratory Research Unit, Dept of Clinical
Research, University of Southern Denmark, Odense C, Denmark. 3Dept of Biomedical Imaging and Image-guided Therapy, Medical
University of Vienna, Vienna General Hospital, Vienna, Austria. 4Dept of Radiology, Odense University Hospital, Odense C, Denmark.
5
South Danish Center for Interstitial Lung Diseases (SCILS), Odense University Hospital, Odense C, Denmark. 6Medical Imaging
Centre, Semmelweis University, Budapest, Hungary. 7Oncologic Imaging and Invasive Diagnostic Centre, National Institute of Oncology,
Budapest, Hungary.
Correspondence: Christian Laursen (Christian.b.laursen@rsyd.dk)
162 https://doi.org/10.1183/2312508X.10012421
IMAGING | C.B. LAURSEN ET AL.
response causing a disruption of the alveolar–capillary membrane, resulting in an influx of

cells into the interstitium and alveolar spaces, leading to oedema, and the formation of
hyaline membranes. This inflammation and oedema lead to a displacement of air from the
alveolar spaces, which allows detection of the disease using thoracic imaging. Involvement
of the lung parenchyma is, however, not always present in COVID-19 or its early disease
phases [3, 4]. As such, although several imaging modalities can be used for the assessment
of patients with possible or proven COVID-19, reverse transcriptase PCR (RT-PCR) testing
is considered to be the reference standard for COVID-19 diagnostic screening rather than
thoracic imaging [5, 6]. The combination of clinical characteristics and imaging may,
however, be used as an alternative if RT-PCR is not readily available or until the result
becomes available [6, 7]. Despite the limitations in diagnosing COVID-19 when compared
with RT-PCR, thoracic imaging is an important cornerstone in the diagnosis, monitoring
and follow-up of patients with COVID-19, and should be considered a standard diagnostic
modality alongside clinical and laboratory assessment to guide clinical decision making in
order to determine the need for hospitalisation and choice of ward the patient is admitted
to (e.g. regular ward, ICU) [6].
An additional aspect to consider is that neither of the thoracic imaging modalities is

optimal for any given clinical scenario or setting, as what is practically feasible in one
context (e.g. ready access to CT in a well-functioning healthcare system) may not be
feasible in another (e.g. limited access to specific types of imaging in a healthcare system
collapsing due to the COVID-19 pandemic). Furthermore, the strengths and limitations of
the different modalities must be assessed in a setting in which limiting additional disease
spread and the safety of healthcare staff also need to be considered [8, 9].
The scope of this chapter is to present a general overview of the current knowledge of the
most common types of thoracic imaging for approaching three major clinical scenarios
involving adult patients with COVID-19, namely initial assessment, monitoring and
follow-up. As such, the chapter does not provide individual detailed descriptions of the
different forms of imaging used, and the use of imaging for assessment of extrathoracic
disease involvement of COVID-19 will only be mentioned briefly when considered relevant.
Whenever possible, references to recent international statements and systematic reviews
have been included in order to provide recommendations for specific settings based on
current evidence as well as more detailed information regarding the specific thoracic
imaging modalities.
Imaging for initial assessment of patients with possible or proven

COVID-19
Point-of-care ultrasound
Upon clinical suspicion of COVID-19, point-of-care ultrasound (PoCUS) has the advantage
of being a fast bedside imaging tool that can serve as a clinical adjunct to the given context
such as triage, diagnostics and monitoring [2]. Additionally, small portable or hand-held
ultrasound machines are ideal for assessing isolated patients in order to limit intrahospital
transport of the patient, disinfection of larger imaging devices and the number of healthcare
staff in contact with the patient [2]. PoCUS is typically used in a focused manner to assess
simple predefined yes/no questions (e.g. presence of pleural effusion) [10, 11]. PoCUS may
also be used to assess one or several organs using a so-called multiorgan approach [2].
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Lung ultrasound
The lung ultrasound (LUS) findings observed in COVID-19 patients are comparable to
what has been described previously in patients with viral pneumonia or ARDS [12–14].
Typical findings present as a continuum, depending on the extent of lung involvement in
the area scanned. In “spared areas” with no lung involvement, TUS findings will typically
be normal. Initial abnormal findings are the presence of B-lines originating from a normal
visceral pleural line reflecting an increased density of the lung parenchyma compatible with
the development of initial inflammation and oedema. With increasing severity, an increased
number of or confluent B-lines will typically be present and the visceral pleural line may
become thickened and fragmented; this appears with increasing prevalence associated with
increasing disease severity and potential development of ARDS (figure 1). Areas with the
presence of B-lines typically correlate with areas with ground-glass opacities (GGOs) on
CT. With further lung involvement, frank consolidation of the lung tissue occurs, appearing
initially as small subpleural consolidations when visualised with LUS. These may increase
in size to larger consolidations, in which air bronchograms may be present [15–21].
In an emergency setting, LUS has a higher diagnostic accuracy than chest radiography for a
wide range of acute respiratory conditions. This has been demonstrated not only to
increase the proportion of patients who will subsequently receive the correct treatment but
also to reduce the time until initiation of relevant interventions [22–27]. In the context of
COVID-19, the diagnostic accuracy of LUS for diagnosing COVID-19 pneumonia and
ARDS also appears to be superior to chest radiography [2, 15, 28]. In COVID-19, LUS
findings of lung parenchymal pathology show good agreement with CT, including
assessment of disease severity, but the overall diagnostic accuracy is still lower than CT due
to a lower specificity [16–18, 28]. In a recently updated Cochrane review, the pooled
sensitivity and specificity for the ability of LUS to diagnose COVID-19 was 86.4% (95% CI
72.7–93.9%) and 54.6% (95% CI 35.3–72.6%), respectively (table 1) [28].
There is no overall consensus regarding the optimal LUS scanning protocol for patients
with respiratory symptoms or patients with possible or proven COVID-19 [10, 22]. Several
protocols and scoring systems have been described and assessed, but studies directly
comparing different protocols are scarce [29]. As lung involvement may be limited to the
posterobasal parts of the lungs in early or mild cases, protocols including assessment of
these areas are of importance when diagnosing patients with less severe symptoms or signs
[21, 29, 30]. The time required to perform LUS will depend on the protocol used and
whether LUS is performed as part of the clinical assessment or as a separately performed
assessment. The time taken to perform focused LUS is typically relatively short and often
reported as ⩽5 min [31, 32]. Studies specifically assessing interobserver variance when
using LUS to assess patients with COVID-19 are still warranted. In ARDS patients with
findings resembling COVID-19, the agreement between observers is generally strong [14].
The use of deep-learning artificial intelligence (AI) systems could potentially help support
the development of a more standardised scanning protocol, assessment and models for the
automatic scoring of LUS data [33, 34].
Cardiac ultrasound
Heart involvement and cardiac complications as part of COVID-19 may occur as a

consequence of hypoxaemia from respiratory failure, hyperinflammation or direct
164 https://doi.org/10.1183/2312508X.10012421
a) b)
c) d)
Figure 1. Examples of different initial lung ultrasound findings in a 42-year-old female patient admitted to
hospital due to COVID-19 pneumonia with respiratory failure. a) An area with no apparent abnormal
findings. No B-lines or consolidations are present. The pleural line (P) appears normal. b) An area with the
presence of B-lines (B), seen as hyperechoic (white), vertical lines originating from the pleural line and
extending profoundly throughout the screen without fading. The pleural line itself appears normal. c) An
area with the presence of B-lines and a thickened and fragmented pleural line. d) An area with the
presence of a small subpleural consolidation (C) seen as a hypoechoic (black), well-defined area just below
the pleural line.
myocardial injury [35–37]. Signs of heart involvement can typically be assessed using
PoCUS principles through focused cardiac ultrasound (FoCUS) or as a comprehensive
transthoracic echocardiograph (TTE). In an international survey of the indications, findings
and impact of TTE in patients with COVID-19, left or right ventricular abnormalities could
be demonstrated in approximately half of the patients in whom TTE was performed.
Among the patients with an abnormal TTE, the abnormalities were considered to be severe
in one out of seven patients. TTE was found to directly impact patient management in
one-third of cases including alterations to disease-specific management, haemodynamic
https://doi.org/10.1183/2312508X.10012421 165
Table 1. Overview of strengths and weaknesses of common thoracic imaging modalities used
for initial assessment of patients with possible or proven COVID-19
Imaging Sensitivity Specificity Strengths Weaknesses

modality (95% CI)# (95% CI)#
LUS 86.4% 54.6% Sensitivity comparable to CT Low specificity

(72.7–93.9%) (35.3–72.6%) No need to move patient No clear standard
Limited number of staff for image storage
exposed and comparison
Fast Observer dependent
Low cost (experience,
No radiation protocol used)
Easily repeatable
Can be expanded to assess
other structures (e.g. heart,
deep veins)
CXR 80.6% 71.5% Acceptable sensitivity Low specificity
(69.1–88.6%) (59.8–80.8%) Can be performed at bedside Patient needs to be
(supine) moved (erect, two
Standard for image storage views)
and comparison More staff exposed
Time use
Radiation exposure
Chest CT 87.9% 80.0% High sensitivity and specificity Patient needs to be
(84.6–90.6%) (74.9–84.3%) Can provide information on moved
relevant differential More staff exposed
diagnosis Time use
Can be supplemented with Costs
assessment for pulmonary Radiation exposure
embolism
Standard for image storage
and comparison
LUS: lung ultrasound; CXR: chest radiography. #: pooled data from [28].
support and the level of care received by the patients [38]. Despite these findings, FoCUS
or TTE are only considered to be part of the mandatory imaging in selected patients
admitted with possible or proven COVID-19 and in whom the findings are believed to
have a direct impact on patient management [37]. It is, however, important to consider
that routine use of FoCUS in patients with acute respiratory failure has been demonstrated
to be able to identify conditions otherwise missed by the clinician, and as such generates a
direct clinical impact [26, 27, 39–42]. The clinical threshold for performing FoCUS or TTE
should generally be low and especially considered as part of standard imaging in patients
presenting with moderate-to-severe COVID-19 or haemodynamic instability [2].
Multiorgan PoCUS
By combining ultrasound assessment of several organ systems (e.g. lungs, heart, inferior
vena cava, deep veins) into one examination using a so-called multiorgan PoCUS approach,
the physician or other healthcare provider is able to assess not only pulmonary
involvement but also possible extrapulmonary involvement in COVID-19 such as
cardiovascular and thromboembolic aspects [2]. Apart from the advantages of obtaining
166 https://doi.org/10.1183/2312508X.10012421
important clinical information from several organ systems at the bedside, the approach also
has the advantage of minimising the number of healthcare staff being exposed to
COVID-19 at the bedside. Whenever possible, obtained images and ultrasound clips should
be stored, as these can be assessed subsequently by more dedicated specialists (e.g. FoCUS
clips assessed by a cardiologist prior to determining the requirement for an additional
TTE), and possibly limit the need for additional and more comprehensive imaging [10, 37].
Proper documentation of initial PoCUS findings alongside stored clips and images are also
of importance if PoCUS, as part of patient monitoring, is repeated during admission or
following discharge.
Chest radiography
In the first reported study on chest radiography findings in COVID-19 patients,

consolidation was the most common finding (47%), followed by GGOs (33%). Peripheral
distribution (41%) and lower-zone distribution (50%) were the most common locations,
with typical bilateral involvement (50%) (figure 2). Pleural effusion was rare (3%) [43].
However, chest radiography findings were normal or presented with only mild pathology in
the majority of patients at baseline [43].
a) b)
c) d)
Figure 2. Course of chest radiography findings in a 52-year-old male patient with COVID-19 pneumonia.
a) Normal chest radiograph performed 11 months prior to admission with COVID-19. b) Chest radiograph
performed upon admission due to suspected COVID-19 and mild hypoxic respiratory failure. Bilateral lung
opacities are present. c) Chest radiograph performed 4 days after admission due to progressive respiratory
failure with the need for intensive care treatment and respiratory support. The bilateral lung opacities have
progressed significantly. d) Chest radiograph performed as part of outpatient follow-up, ∼2 months after the
admission date. The bilateral opacities have regressed, but opacities with a reticular pattern are still present.
https://doi.org/10.1183/2312508X.10012421 167
In a larger study, the authors defined a characteristic COVID-19 pattern as the presence of
bilateral patchy or confluent, band-like GGOs or consolidation in a peripheral and mid- to
lower lung zone distribution [44]. If the chest radiograph showed pleuropulmonary
abnormalities other than the previously mentioned characteristics, it was assigned to the
nonspecific category and grouped according to type of abnormality (mass-like, upper lung
zone predominant, diffuse, ill-defined bibasilar, focal/unilateral, effusion). A chest
radiograph without any apparent pleuropulmonary abnormality was labelled negative.
Overall, 10% of the chest radiographs exhibited the characteristic COVID-19 appearance,
57% exhibited the nonspecific appearance and 33% were considered to be without
pulmonary abnormalities. The authors concluded that chest radiography, while low in
sensitivity, can be highly suggestive of COVID-19 in patients whose chest radiograph
exhibits characteristic COVID-19 findings, when used in combination with clinical
characteristics [44].
The findings of these two studies are supported by the previously mentioned Cochrane
review, in which the pooled sensitivity and specificity for the ability of chest radiography to
diagnose COVID-19 was 80.6% (95% CI 69.1–88.6%) and 71.5% (95% CI 59.8–80.8%),
respectively (table 1) [28]. As such, based on sensitivity, chest radiography is inferior to
LUS and CT for the initial assessment of patients with suspected COVID-19 [28]. The low
sensitivity of chest radiography is especially of clinical importance in patients with mild
COVID-19 or early in the disease [5].
Recently, the use of deep-learning AI systems for chest radiograph assessment in patients
with COVID-19 has also been described. In two reports from north-western USA and one
report from The Netherlands, three different deep-learning AI systems yielded promising
results in terms of their area under the receiver operating characteristic curve (AUC).
DeepCOVID-XR classified 300 random test images (134 positive for COVID-19) and reached
an AUC of 0.88, comparable to the consensus of five radiologists (AUC=0.85) [45].
CV19-Net classified 500 random test images (250 positive for COVID-19) and reached an
AUC of 0.94, outperforming each of three radiologists, who did not perform continuous
scoring [46]. Finally, CAD4COVID-XRay classified 454 patient images (223 positive for
COVID-19) and achieved an AUC of 0.81, thereby achieving results with a high agreement to
radiologists’ interpretations at different cut-off values [47]. As such, the use of AI systems for
chest radiograph assessment in patients with COVID-19 indeed has a future clinical
potential, especially to provide a more rapid assessment, or if assessment by a radiologist is
not readily available. Prospective studies assessing the diagnostic accuracy as well as the
clinical impact are, however, still warranted.
CT
The first CT manifestations in COVID-19 are GGOs, reflecting the initial inflammation
and oedema of the lung parenchyma with subsequent displacement of air from the alveolar
spaces [3, 4]. In some patients, the “crazy-paving” sign is observed as a combination of
ground-glass and superimposed reticular abnormalities. As more and more air is displaced
from the alveolar spaces by this process, the lung parenchyma becomes denser, leading to
consolidations as seen on CT (figures 3 and 4). A particular finding in COVID-19 is an
enlargement of pulmonary vessels, which is presumably caused either by cytokine-induced
vasodilation or thrombosis of small vessels (figure 3e). The described CT findings are
usually multifocal (70%) and are observed with a bilateral (79%), basal and peripheral
168 https://doi.org/10.1183/2312508X.10012421
a) b) c)
d) e)
Figure 3. Common CT patterns in patients with COVID-19. a) Ground-glass opacities (arrowhead). b) “Crazy
paving”, a combination of ground-glass and superimposed reticular abnormalities. c) Consolidations.
d) Band-like opacities in perilobular distribution. e) Enlarged pulmonary vessels (arrowhead).
predominance [48–52]. In some patients, a bronchovascular or a diffuse distribution

pattern has been described [52–54]. Pathological changes typically found in cases of
COVID-19-mediated acute lung injury include a wide spectrum of histological patterns
ranging from diffuse alveolar damage to organising pneumonia, which can be observed as
GGOs and/or consolidation on CT [55]. CT may show the “reverse halo sign” (an irregular
opacity with a dense peripheral ring of consolidation and a central area of GGO) in the
case of an organising pneumonia pattern in 13–32% of patients [1].
Importantly, there are a few CT findings that are only rarely observed in COVID-19
pneumonia including tree-in-bud, centrilobular nodules, lobar or segmental consolidation,
lung cavitation and pleural effusions [48, 52, 54]. These findings do not exclude COVID-19
pneumonia but raise the likelihood of alternative diagnoses, or may point towards
complications secondary to COVID-19 pneumonia such as superinfection or evolvement of
heart failure.
In the previously mentioned Cochrane review, the pooled sensitivity and specificity for the
ability of CT to diagnose COVID-19 was 87.9% (95% CI 84.6–90.6%) and 80.0% (95% CI
74.9–84.3%) (table 1), respectively, with CT being superior to chest radiography and LUS
for the initial assessment of patients with suspected COVID-19 [28]. Due to patient-related
as well as institution-related concerns over the increased use of CT, leading radiological
societies have, however, discouraged the use of CT as a COVID-19 screening tool [5].
In order to systemise the CT diagnosis of COVID-19 and to ease the prediction of the
probability of COVID-19 pneumonia, a number of assessment schemes have been proposed
since the outbreak of the disease [1, 56–58]. Of these systems, probably the most
commonly used is the COVID-19 Reporting and Data System (CO-RADS) developed by
the Dutch Radiological Society [56]. In CO-RADS, the probability of COVID-19
pneumonia is categorised on a scale from 1 (very low) to 5 (very high) [56]. Importantly,
https://doi.org/10.1183/2312508X.10012421 169
a) b)
c) d)
Figure 4. Course of CT findings in a 48-year-old male patient with COVID-19 pneumonia. a) Early stage at
first presentation of the patient showing focal ground-glass opacities (GGOs) and consolidations in the lung
periphery. b) CT scan performed 4 days later showing more extensive GGOs (progressive stage). c) Peak
stage. A CT scan performed 14 days after disease onset showing a combination of GGOs and consolidations.
The distortion of the airways seen at this stage, which may be mistaken for a sign of irreversible fibrosis, is
transient and reverses on longer-term imaging. d) Late stage, characterised by a gradual decrease in the
consolidations and GGOs.
the diagnostic performance of CO-RADS to a large extent depends on the presence of

symptoms and the pre-test probability, which is in essence the overall prevalence of a
positive PCR [59]. In symptomatic patients from a population with a high prevalence
(42%) of RT-PCR-positive COVID-19, 89% of patients classified as CO-RADS 5 were
diagnosed with COVID-19 compared with 9% of patients classified as CO-RADS 1 [59].
In contrast, in populations with a low prevalence of the disease (5%), COVID-19 was only
diagnosed in slightly more than 30% of patients with a CO-RADS score of 5 [59]. While
CT achieved reasonable results in diagnosing COVID-19, the combination of imaging and
clinical characteristics proved to be superior, with an AUC of 0.914 [7].
In addition to diagnosing COVID-19 pneumonia, CT is also used to predict the prognosis

of patients. Several severity scores have been proposed to predict admission to the ICU and
survival [60–65]. Although the scoring systems vary in detail, they evaluate the extent of
the disease by assessing the overall extent of involvement of the lung parenchyma or by
lobe or segment [3]. The creation and interpretation of CT scoring systems is impaired by
comorbidities such as emphysema or pre-existing cardiovascular diseases. A recently
published model could improve the AUC predicting severe outcome at 1 month follow-up
from 0.64, when just using clinical parameters, to 0.69 when also including the extent of
pneumonia and the coronary calcium score on CT [65].
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AI has shown promise for use in determining both the diagnosis, disease quantification
and severity assessment, and the prognosis determination of COVID-19 pneumonia, with
respect to both radiography and CT [66]. These software-based quantitative methods can
assess the total lung involvement as well as the percentage of GGOs and consolidation,
which has been associated with disease progression [67]. Importantly, however, most of the
published studies on AI in COVID-19 suffer from significant methodological issues
regarding the applied machine-learning methodology, nonrepresentative training sets, a lack
of external validation and/or a retrospective study design. One large study investigating
2212 studies published on this topic up to October 2020 concluded that, due to
methodological issues, none of the investigated studies was of potential clinical use [68].
Magnetic resonance imaging
Recent studies have shown promising results with lung magnetic resonance imaging (MRI),
demonstrating excellent concordance with chest CT in visualising typical features of
COVID-19 pneumonia, and especially in patients where radiation exposure should be
avoided (e.g. pregnant patients, children) [69]. MRI was found to be very sensitive for GGOs,
consolidation and interlobular septal thickening. Moreover, diffusion-weighted imaging might
be helpful in the evaluation of a pulmonary active inflammatory process [70].
Imaging for monitoring patients with COVID-19
LUS
In patients with COVID-19 with pulmonary involvement, LUS can be used to monitor
disease progression, as well as to diagnose complications such as pneumothorax,
superimposed bacterial pneumonia or pulmonary embolism [2, 22, 71]. LUS can easily be
repeated at the bedside and does not necessitate transport of the patient to another
department for more advanced imaging, and simultaneously reduces the number of
healthcare workers exposed to COVID-19 [2, 9]. As such, LUS monitoring has been
demonstrated to reduce the supplementary need for chest radiography and CT in patients
admitted with COVID-19 [9]. Progression of LUS findings has been correlated with clinical
and radiological deterioration and can thus accurately monitor the evolution throughout its
spectrum of severity, from cases with mild respiratory involvement to critically ill patients
with manifest severe respiratory failure [2, 21, 72–76]. When compared with chest
radiography and CT, the high feasibility of LUS and no use of radiation allows easy access to
daily monitoring with the potential to detect early signs of possible patient deterioration or
complications, prior to other clinical signs developing [21]. However, it is important to
stress that, despite being a sensitive tool to detect progressive pulmonary involvement,
significant overlap exists in the typical LUS findings observed in progressive lung
involvement in COVID-19 and the typical LUS patterns of important differential diagnoses
such as pulmonary oedema, bacterial pneumonia and pulmonary embolism [2, 19, 22, 76].
Thus, progressive LUS findings in patients with COVID-19 should be carefully integrated
with other clinical information and the results of other imaging and diagnostic tests
(e.g. blood samples, microbiology) [2, 77]. Despite being seen as a useful tool for monitoring
admitted patients with COVID-19, there is still no international consensus on which LUS
monitoring protocol or scoring system should be preferred for monitoring patients with
COVID-19 [2]. Prospective studies validating and assessing the clinical impact of using
specific predefined LUS score changes to guide clinical management are still warranted.
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Chest radiography
Several chest radiography severity scores have been proposed as COVID-19 prognostic and
monitoring tools to guide clinical decision making in patients being admitted to hospital
[78–82]. The severity of chest radiography findings based on severity scoring typically peak
at days 10–13 following the onset of symptoms [78]. The typical pattern at presentation is
bilateral mid- and lower-zone peripheral lung opacities, with lung opacities gradually
increasing in extent and density, with consolidative changes becoming the prevalent pattern
at the time point with the highest score [5, 78]. If chest radiography is used as a
monitoring tool, a daily chest radiograph is generally not recommended, but some authors
recommend using repeated chest radiographs every 3–4 days [78]. When compared with
CT, chest radiography is a more feasible imaging modality for monitoring patients
admitted with COVID-19; however, LUS and whole-body PoCUS still remain the most
feasible imaging modalities for patient monitoring. Both CT and whole-body PoCUS
additionally have the advantage of being superior to chest radiography in the diagnosis of
important complications of COVID-19 (e.g. pneumothorax, thromboembolic disease,
systolic heart failure) [2, 5, 41, 71].
CT
The variety of CT manifestations can be explained partly by individual response patterns and
by the temporal course of the disease [51, 83]. While in the first few days of the disease CT
scans are either normal or show only limited GGOs, CT scans performed 5–8 days after the
onset of symptoms show more extensive GGOs in combination with a crazy-paving pattern
[51]. At the peak of the disease, 9–13 days after disease onset, prevalent findings will typically
be a combination of GGOs and consolidations, which parallel the evolution of acute lung
injury [51]. The peak stage is then followed by a late absorption stage, which is characterised
by a gradual decrease in consolidations and GGOs (figure 4d). In some patients, this gradual
decrease in the parenchymal abnormalities can take several weeks. However, in some patients,
GGOs and consolidations transform into more reticular opacities over weeks and may be
associated with fibrosis, volume loss, architectural distortion and traction bronchiectasis [66].
These persistent CT abnormalities have been reported 60 days after onset of COVID-19 in
77% of individuals, and in 63% after 100 days [84]. The most commonly observed residual
parenchymal abnormalities have been reported to be GGOs, reticular abnormalities and
parenchymal bands (figures 4 and 5) [84].
In addition to classic pulmonary manifestations of COVID-19, CT might play a role in

diagnosing ARDS and superimposed pneumonia-related abnormalities. Moreover,
cardiovascular, neurological and abdominal manifestations have also been observed in
COVID-19 patients [66, 85]. SARS-CoV-2 may also target endothelial cells, which may lead
to endothelial damage and endotheliitis, which can, in turn, lead to activation of the
coagulation cascade and ultimately to a local thrombus formation or thromboembolic events.
A high incidence of pulmonary embolism was reported during the first weeks of the outbreak,
with incidences in hospitalised patients ranging from 4.8% to 85% [86, 87]. Local thrombus
formation in small pulmonary vessels was described in small autopsy series and may also be
the explanation for pulmonary ischaemic areas as observed on pulmonary dual-energy CT
angiography in the absence of visible thrombosis [4, 88, 89]. Spectral contrast-enhanced CT
pulmonary blood volume maps show the perfusion defects in the territory of dilated vessels.
In situ thrombosis of the pulmonary arteries was supported by cohort studies that
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a) b)
c) d)
Figure 5. Long-term course of CT findings in a 52-year-old male patient with COVID-19 showing a gradual
decrease in the CT findings at a) 2 weeks, b) 3 weeks, c) 14 weeks and d) 24 weeks after disease onset.
demonstrated clots being disproportionately located in the distal pulmonary vasculature (with
lower rates in proximal pulmonary arteries) along with lower-than-expected rates of
concurrent DVT [66, 90, 91]. Consequently, an elevated D-dimer level alone does not
confirm the suspicion of pulmonary embolism in COVID-19 patients, but such studies are
warranted in patients with disproportionate dyspnoea or a suddenly deteriorating clinical
picture [92]. According to the British Thoracic Society’s suggestion, the term “pulmonary
embolism” should be avoided with those with just segmental and/or subsegmental changes,
and instead the changes should be described and then noted that these may represent
pulmonary embolism or immunothrombosis (e.g. “filling defect is noted; whether or not this
represents embolus or immunothrombosis is uncertain”) [92].
Coronary CT angiography plays a role in the assessment of coronary atherosclerosis in low-

to intermediate-risk patients with chest pain [66]. Moreover, multisystem inflammatory
syndrome in children can cause coronary arterial aneurysms in about 10% of hospitalised
children, which can also be verified by coronary CT angiography [66].
Abdominal involvement in COVID-19 includes ACE2 receptor-expressing cells in organs

such as the liver, biliary tree, gastrointestinal tract and abdominal vasculature [66, 93]. Such
complications include superior mesenteric artery and portal vein thrombosis, and
infarction of abdominal organs (e.g. bowels, spleen, kidneys). Common abdominal CT
abnormalities include colorectal and small-bowel wall thickening, a fluid-filled colon, and
infarction of the kidney, spleen or liver, ischaemic enteritis and rarely pancreatic injury
(oedema and mild peripancreatic fluid collection) [66, 93].
https://doi.org/10.1183/2312508X.10012421 173
MRI
Cardiac manifestations of COVID-19 infection include myocarditis, acute myocardial

infarction and coronary artery aneurysms. Myocarditis might develop in both symptomatic
and asymptomatic COVID-19 patients and can be demonstrated by cardiac MRI. About
45–78% of patients who underwent cardiac MRI within a few weeks of COVID-19
infection had MRI abnormalities, including oedema, a lower left ventricular ejection
fraction, late gadolinium enhancement and pericardial effusion [66, 94–96]. Virus infection
of coronary endothelium can contribute to the increased rate of myocardial infarction in
COVID-19 patients [97].
MRI has a role in the investigation of COVID-19 patients with neurological symptoms and
may occur in up to 3–5% of patients [98]. The most common neuroimaging abnormalities of
COVID-19 patients include olfactory bulb abnormalities, white matter hyperintensities, acute/
subacute ischaemic and haemorrhagic stroke, encephalopathy and leptomeningeal enhance-
ment; however, their direct relationship with COVID-19 infection remains unclear [66].
Positron emission tomography
18
F-fluorodeoxyglucose (18F-FDG) positron emission tomography CT (PET-CT) imaging is
not recommended as a first-line imaging modality in COVID-19 patients [69]. In a number
of case reports on COVID-19, pneumonia was detected as an incidental finding on routine
18
F-FDG PET-CT examinations due to radiotracer accumulation in COVID-19-associated
pulmonary lesions in otherwise subclinical or asymptomatic patients due to lymphadenitis.
Accordingly, use of PET-CT for other clinical indications may yield the earliest detection of
nascent infection in otherwise asymptomatic individuals [69].
Imaging for assessment of COVID-19 sequelae
Currently, little is known about the long-term consequences of COVID-19 pneumonia.

At present, no evidence-based guidelines have been published describing the optimal use of
thoracic imaging for assessing patients with possible pulmonary sequelae to COVID-19.
As such, when performing imaging for assessment of COVID-19 sequelae, it is important
to be aware that the pathogenetic significance of imaging patterns and their corresponding
long-term clinical significance are still unknown [99]. Few international protocols based on
expert recommendations are currently available for the long-term follow-up of patients
recovering from COVID-19. The most detailed is the recommendation issued by the British
Thoracic Society in May 2020 for the clinical radiological follow-up of COVID-19-certified
pneumonia patients [92]. In a study on CT findings in 114 patients 6 months after disease
onset, fibrotic-like changes were observed in 35% of patients [100]. Long-term follow-up is
required to determine whether reticulation found in long-term follow-up examinations may
correspond to irreversible lung fibrosis or is part of reversible COVID-19 sequelae. Recent
studies have shown that risk factors for developing fibrosis include elderly male patients
with more severe symptoms, a longer time spent in the ICU, higher serum CRP and IL-6
levels, and a higher maximum CT score [101, 102]. CT studies have shown that irregular
edges and parenchymal bundles might predict the development of pulmonary fibrosis at an
earlier disease stage [102]. Lung single-photon emission CT detects perfusion-mismatched
defects in early post-COVID-19 patients with hypoxia, suggestive of pulmonary
thromboembolism [103].
174 https://doi.org/10.1183/2312508X.10012421
Further research areas
Despite several studies assessing the use of imaging in COVID-19, diagnostic accuracy
studies performed in accordance with the Standards for Reporting of Diagnostic Accuracy
(STARD) reporting guidelines and directly comparing different forms of imaging are still
scarce [28]. Additionally, several studies of thoracic imaging have focused on imaging as a
first-line diagnostic test for COVID-19 itself rather than for diagnosing COVID-19 with
pulmonary involvement (e.g. pneumonia, ARDS) [28]. The diagnostic accuracy varies
significantly depending on whether chest imaging is used as a true first-line diagnostic test
for possible COVID-19 or whether it is used in conjunction with RT-PCR testing or
following a positive RT-PCR test to determine the presence or absence of lung
involvement. Most of the published studies derive from settings with a high COVID-19
prevalence due to the nature of the pandemic. Thus, studies are warranted assessing the
diagnostic accuracy, and especially the extent of false-positive tests, in low COVID-19
prevalence settings where patients may possess varied causes of respiratory failure. Such
scenarios may reflect future conditions in which immunity and vaccination have
significantly reduced COVID-19 prevalence.
The spectrum of long-term pulmonary consequences of COVID-19 pneumonia is

currently unknown. We do not know whether an asymptomatic infection may induce
chronic organ effects in some predisposed patients, which partly explains why follow-up
protocols including CT have not yet been developed. As several questions regarding the
long-term sequelae of COVID-19 remain unanswered, further research studies should
elucidate the role of CT to predict prognosis of COVID-19 pneumonia, especially in
future pandemic waves due to ongoing mutations of SARS-CoV-2. Moreover, it remains
unclear whether long-term pulmonary manifestations are irreversible. Cardiovascular
complications such as thromboembolism should also prompt further investigation.
Further studies are also required in the field of lung MRI in order to avoid the burden
of radiation in severely ill COVID-19 patients who require frequent chest imaging
follow-up.
Several studies have described the use of deep learning and AI systems for assessing the
images and data obtained from the most commonly used thoracic imaging modalities in
patients with COVID-19 [33, 34, 45, 58]. The results are generally promising, but,
alongside the more classical use of thoracic imaging being assessed by a clinician or
radiologist, prospective studies also including clinical data from a low COVID-19
prevalence setting are warranted.
Conclusion
Thoracic imaging is an important cornerstone in the diagnostics, monitoring and

follow-up of patients admitted to hospital with COVID-19. The most commonly used
forms of thoracic imaging such as LUS, chest radiography and CT all have acceptable
sensitivities for the detection of COVID-19 with lung involvement but are disadvantaged
by the detection of positive findings regarded as unspecific. Consequently, imaging results
should always be critically appraised and related to the given clinical context. Further
studies are still warranted, especially assessing optimal use of thoracic imaging for
monitoring COVID-19 patients during admission and for assessment of possible
pulmonary COVID-19 sequelae.
https://doi.org/10.1183/2312508X.10012421 175
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Disclosures: C.B. Laursen reports receiving the following, outside the submitted work: royalties for
educational materials (books, web-based learning platforms) from Munksgaard, Denmark; and payment or
honoraria for lectures, presentations, speakers’ bureaus, manuscript writing and educational events from
AstraZeneca A/S for the Foredrag ved 6th Nordic Respiratory Science Forum (11 February 2021).
C.B. Laursen is Chair of the European Respiratory Society Ultrasound Group. H. Prosch reports receiving the
following, outside the submitted work: payment or honoraria for lectures, presentations, speakers’ bureaus,
manuscript writing and educational events from Boehringer Ingelheim, AstraZeneca, MSD, BMS, Roche and
Novartis; and support for attending meetings and/or travel reimbursement from Boehringer Ingelheim.
S.M.W. Harders reports receiving payment for lectures on interstitial lung disease from Boehringer
Ingelheim, outside the submitted work. C. Falster reports receiving payment as a lecturer in ultrasound for
emergency physicians in training, outside the submitted work. J.R. Davidsen has nothing to disclose.
A.D. Tárnoki reports receiving payment or honoraria for lectures from Boehringer Ingelheim, outside the
submitted work. A.D. Tárnoki is the Secretary of the European Respiratory Society Imaging Group.
https://doi.org/10.1183/2312508X.10012421 179
| Chapter 11
Post-COVID-19 sequelae
Andrea Gramegna1,2, Marco Mantero1,2, Francesco Amati 3,4
,
Stefano Aliberti 3,4 and Francesco Blasi 1,2
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 [https://doi.
org/10.1183/2312508X.10024420].
@ERSpublications
Post-COVID-19 sequelae are not fully understood but can affect various organs and vary
from mild manifestations to irreversible and progressive organ damage. Intersected
multidisciplinary programmes of clinical evaluation and research are needed. https://
bit.ly/3sYBXEZ
O ver the past 18 months, many aspects of both acute infection as well as post-acute and
long-term effects of COVID-19 have been extensively studied. When we consider the
clinical data in ARDS and our current understanding of the pathophysiology of
SARS-CoV-2 infection, the possibility of pulmonary sequelae is not surprising. It has been
reported that patients who have experienced ARDS, regardless of any aetiology, have
impaired lung function as well as reduced exercise capacity and quality of life for ⩽5 years
after the event [1]. Similarly, patients who survived severe influenza A (H7N9) reported
long-term lung disability and psychological impairment 2 years after discharge from the
hospital [2]. Two prospective studies examined the long-term pulmonary outcomes among
SARS-CoV-1 survivors and confirmed a significant decrease of gas diffusion and exercise
capacity, along with persistent radiological abnormalities over a 2-year follow-up [3].
Conversely, comparisons with other systemic viral diseases, such as West Nile fever, Ebola
virus and measles, suggest that patients might suffer from additional long-term
extra-cardiorespiratory complications, including cardiovascular, neuropsychiatric and
metabolic sequelae [4–6].
1
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy. 2Dept of
Pathophysiology and Transplantation, University of Milan, Milan, Italy. 3Dept of Biomedical Sciences, Humanitas University, Milan,
Italy. 4IRCCS Humanitas Research Hospital, Milan, Italy.
Correspondence: Francesco Blasi (francesco.blasi@policlinico.mi.it)
180 https://doi.org/10.1183/2312508X.10024420
POST-COVID SEQUELAE | A. GRAMEGNA ET AL.
Characterisation of the underlying mechanisms of long-term COVID-19 sequelae is still

ground for ongoing research; sequelae may result from irreversible organ damage during
the acute infection phase, or may reflect the manifestations secondary to a persistent
hyperinflammatory state or ongoing viral activity with poor host antibody response.
This chapter presents a summary of the evidence available as at October 2021 regarding
the different manifestations and severity of post-COVID-19 sequelae in adult patients.
Recurrence, relapse and readmission after recovery
Recurrence and relapse of COVID-19
Re-infection with SARS-CoV-2 has emerged as a possible outcome after full recovery from
COVID-19. Several authors have reported that patients might present with a new positive
respiratory sample after previous negative results. TO et al. [7] reported a real case of
COVID-19 recurrence; they documented re-infection by a different strain of SARS-CoV-2
with IgG seroconversion. Conversely, KANG et al. [8] analysed 292 re-positive cases from
South Korea; patients were asymptomatic or reported minor symptoms and the authors
concluded that new positive samples were probably due to previous false-negative
laboratory tests or persistent viral shedding rather than real re-infection.
A systematic review of published evidence identified 1350 similar cases [9]. The
re-positivity occurred mainly in asymptomatic patients; interestingly, only 5.6% of
patients were pyrexial mean±SD 34.5±18.7 days after the initial onset of symptoms.
Fortunately, the outcome was favourable in the majority of cases (96.7%) and only 2.1%
died. GIDARI et al. [9] evaluated a total of nine re-positive patients and inoculated six new
positive respiratory samples in Vero-E6 cells showing no growth and negative PCR
results. This suggests an absence of live virus in re-positive patients who, therefore,
should be considered not contagious. The authors hypothesised that this phenomenon
was due to prolonged RNA persistence in the upper respiratory tract [9]. A meta-analysis
of potential COVID-19 recurrence included >30,000 publications and analysed patient
data for age, sex, time of re-occurrence or relapse of symptoms, and a persistent
SARS-CoV-2 PCR test [10]. Relapse occurred after a mean±SD of 34±10.5 days of
recovery. This group reported persistent positive SARS-CoV-2 results 39±9 days after the
initial positive testing. Relapse predominantly occurred in older individuals with an
anergic immune response. There were no reports of any clinical re-infections after a
70-day period following initial infection.
Readmission and death in post-COVID-19
Readmission and death after hospital discharge contribute to the burden of the disease. An
observational study based in a large multihospital system in Michigan (USA) included 2179
hospitalised patients and reported readmission and death within 60 days of discharge in
19.9% and 9.1% of patients, respectively [11]. The most common reasons for readmission
were COVID-19 (30.2%), sepsis (8.5%), pneumonia (3.1%) and heart failure (3.1%); patients
with readmission were older and 22.6% required admittance to the ICU.
When compared with other common diseases, rates of readmission within 60 days were lower
for COVID-19 than for pneumonia and heart failure (27% versus 31.7% and 37%, respectively),
https://doi.org/10.1183/2312508X.10024420 181
while rates of readmission within 10 days were higher than those for pneumonia or heart
failure (13.4% versus 9.7% and 8.8%, respectively) [11]. This observation suggests a period
of higher frailty and the risk of worse outcomes immediately after clinical recovery.
Proposed definitions and classifications of post-COVID-19 sequelae
Time-based definition
The acute phase of COVID-19 was defined by HUANG et al. [12] as the time between
symptom onset and hospital discharge, but could be extended to clinical recovery for those
who did not require hospitalisation. However, the post-COVID-19 phase is often difficult
to define. Studies aimed at investigating symptoms and health consequences in the
post-COVID-19 phase included hospitalised patients with a mean follow-up period of
3 months after discharge [13–15].
Recently, the WHO defined post-COVID-19 sequelae as the presence of symptoms in a

patient with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months
from the onset of COVID-19, with symptoms lasting ⩾2 months and not explained by an
alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive
dysfunction and other symptoms that generally have an impact on everyday functioning.
Symptoms may persist from the COVID-19 acute phase, or relapse after a period of initial
recovery [16].
To our knowledge, the largest cohort with the longest follow-up duration assessing the
long-term complications of COVID-19 in adult patients is composed by 1733 individuals
from Wuhan, China [12]. The authors reported that only 10.8% and 24% of patients had
no symptoms at 3 and 6 months, respectively, after symptom onset, suggesting that the
long-term health consequences after COVID-19 may occur in a not insubstantial number
of patients for a relatively long time [12, 17]. To date, no studies exist with a longer
follow-up period in these patients. Investigating predictors of post-COVID-19, SUDRE et al.
[18] found that symptoms in the first week of the acute phase including fatigue (OR 2.83,
CI 2.09–3.83), headache (OR 2.62, CI 2.04–3.37), dyspnoea (OR 2.36, CI 1.91–2.91), hoarse
voice (OR 2.33, CI 1.88–2.90) and myalgia (OR 2.22, CI 1.80–2.73), were associated with
ongoing symptoms at day 28 after recovery. Patients were also at a higher susceptibility of
long-term symptoms if they reported more than five symptoms in their first week and were
of female sex and/or older and/or had an elevated BMI. These results are consistent with a
recent systematic review and metanalysis, which reported that 80% of patients with
COVID-19 had evidence of one or more symptoms associated with post-COVID sequelae,
which commonly included fatigue (58%), headache (44%), attention disorder, (27%), hair
loss (25%) and dyspnoea (24%) [19].
Symptoms after recovery from the acute phase are shown in figure 1.
Severity-based definition
Post-COVID-19 sequelae can be classified according to their severity into mild, moderate
and severe non-reversible sequelae.
182 https://doi.org/10.1183/2312508X.10024420
Acute phase COVID recovery Post-COVID-19
Fatigue Days
80%/38%
Cough 10 20 30 40 50 60 70 80 90 100 180
67.8%/70% Fatigue 80% Dyspnoea Fever 73% Dyspnoea 54% Dyspnoea 36% Fatigue/muscle
Cough 70% 74.3% Cough 17%/70% Post-activity Cough 36% weakness 63%
Dyspnoea
60%/18% Loss of appetite Night sweats 63% polypnoea 16% Sleep disorder Sleep
52% 28% difficulties 26%
Loss of appetite Dyspnoea 58%
52% Dysgeusia 50% Pain 24% Hair loss 22%
Pain 54%
Dysgeusia 50% Chest pain 50% Night sweats 24% Smell disorder
Fatigue 50%
11%
Chest pain 50% Headache 50% Hyposmia/anosmia 43% Hyposmia/
anosmia 19% Joint pain 9%
Joint pain 50% Myalgia 50% Diarrhoea/vomiting 41%
Diarrhoea/ Decreased
Headache Anosmia 41% Sleep disorder 39%
vomiting 9% appetite 8%
13.6%/50% Diarrhoea 29% Chest pain 21% Taste disorder
Myalgia 50%/ Brain fog 7.2%
Dyspnoea 28% Anosmia 17% 7%
14% Fever 0%
Rhinitis 27% Rhinitis 12% Dizziness 6%
Fever 43.8% Fatigue not
Red eyes 23% Dysgeusia 10% Diarrhoea or
Anosmia 41% reported
Sputum 18% Red eyes 10% vomiting 5%
Diarrhoea
Vertigo 17% Sputum 9% Chest pain 5%
29%/3.8%
Headache 9% Sore throat 4%
Sputum 18%/
33% Myalgia 6% Skin rash 3%
Dizziness 17% Myalgia 2%
Sore throat Headache 2%
13.8% Low grade fever
Nausea 5% <1%
Figure 1. The frequency and evolution of post-COVID-19 sequelae. Numbers presented with a slash show
the range in percentage of symptoms reported in different studies.
Mild sequelae include persistent but reversible symptoms with no need of treatment. They
are present in most patients at 3 and 6 months after recovery and are usually attributed to
systemic hyperinflammation (fatigue, arthralgia and myalgia, headache) or are related to
respiratory involvement (dyspnoea, cough), which might reflect multiple mechanisms,
including specific organ damage and the deconditioning that follows weeks of bed rest and
low physical activity [15, 17].
Moderate sequelae require active intervention in terms of diagnosis and treatment but are
generally treatable and reversible. These complications are often neurological and include
tinnitus, dementia, depression, anxiety and obsessive-compulsive disorder (OCD) [17].
Severe sequelae are rare and are represented by chronic organ failure, such as
cardiovascular events including myocarditis, renal failure or pulmonary fibrosis. These
effects are usually long-term and are not reversible, they are potentially progressive, and
they are a consequence of organ damage that has occurred during the acute phase [17].
Older patients and patients with severe manifestations during the acute phase are more at
risk of moderate or severe sequelae [12, 17].
The management of moderate and severe post-COVID-19 sequelae often requires further
investigation and benefits from a multidisciplinary approach in order to provide a
comprehensive individualised approach to treatment for those affected [20].
https://doi.org/10.1183/2312508X.10024420 183
Organ-based definition
Late sequelae in COVID-19 can involve several organs causing different syndromes
resulting from distinct pathophysiological processes. It is currently accepted that respiratory
complications and cardiovascular involvement are the two main determinants of mortality
and morbidity during the acute infection phase; thus, it has been hypothesised that either
long-term pulmonary or long-term cardiac dysfunction is most likely to occur. A detailed
description of the different organs involved in the post-COVID-19 phase follows, according
to classification of the cardiorespiratory and extra-respiratory sequelae.
Table 1 summarises the respiratory and extra-respiratory symptoms in the post-COVID-19

period reported by different authors.
Cardiorespiratory sequelae
Respiratory sequelae
Pulmonary fibrosis
Pulmonary fibrosis is a known sequela of severe lung damage secondary to many
aetiologies including respiratory infections [25].
Radiological and histological findings of pulmonary fibrosis were reported following lung
involvement during SARS-CoV-1 and MERS, two respiratory viruses that share many
similarities with SARS-CoV-2. ZHANG et al. [3] recently published a 15-year follow-up
analysis in a cohort of SARS-CoV-1 survivors and reported interstitial abnormalities in
4.6% of patients. Consistently, current evidence suggests the occasional occurrence of
progressive fibrotic lung disease as a serious complication of COVID-19, rarely requiring
lung transplantation [26–28].
Pathophysiological mechanisms underlying this complication remain unknown, but

immune activation and alveolar epithelial injuries might lead to an aberrant reparative
response with accumulation of fibroblasts and excessive deposition of collagen [25].
Whether and in what proportion pulmonary fibrosis results from a combination of direct
viral insult, pro-inflammatory cytokine storm and ventilatory-induced lung injury is still a
matter of debate.
Early in the pandemic, ZHOU et al. [29] reported fibrotic changes in 21 (33.9%) out of 62
patients, with this occurrence more likely in the advanced phase (8–14 days after the onset
of symptoms) than in the early phase of the disease (⩽7 days after the onset of symptoms).
Similar fibrotic changes noted upon high-resolution CT (HRCT) of the chest were reported
in 11 (17.5%) out of a cohort of 63 COVID-19 patients recovering from COVID-19 in
Wuhan, China [30].
A multicentre prospective study based in Norway analysed the CT scans of 103 patients,
including 15 ICU patients, at 3 months who had previously been admitted to hospital due
to COVID-19 [21]. The authors described persistent ground-glass opacities as the most
common radiological findings in 25% and parenchymal bands, as an indicator of early
progression to pulmonary fibrosis, in 19% of their overall cohort.
184 https://doi.org/10.1183/2312508X.10024420
https://doi.org/10.1183/2312508X.10024420
Table 1. Symptoms before, during and after the COVID-19 acute phase
Symptoms First author Before Onset 20 37 60 3 100 6

[ref.] days days # days months days months
Dyspnoea mMRC LERUM [21] All 54%

grade >0 ICU 42%
No ICU
56%
p=0.526
SONNWEBER [22] 58% 36%
Dyspnoea mMRC HUANG [12] 26%
grade >1
Dyspnoea mMRC SONNWEBER [22] 4%
grade >3
Dyspnoea PROMIS WEERAHANDI [23] 30.9%, median 74.3%, median
score score 0 (IQR 0–1) score 3 (IQR 0–5)
Dyspnoea CARFI [15] ∼60% ∼43%
KAMAL [24] 28%
Fatigue CARFI [15] ∼80% ∼50%
KAMAL [24] 72.8%

HUANG [12] 63%
Cough SONNWEBER [22] 70% 36%
CARFI [15] ∼70% ∼17%
Sputum CARFI [15] ∼18% ∼9%
Fever SONNWEBER [22] 73% 0%
KAMAL [24] 11.1%
HUANG [12] <1%
Anosmia CARFI [15] ∼41% ∼17%
Dysgeusia CARFI [15] ∼50% ∼10%
HUANG [12] 7%
Hyposmia/anosmia SONNWEBER [22] 43% 19%
HUANG [12] 11%
Rhinitis CARFI [15] ∼27% ∼12%
Red eyes CARFI [15] ∼23% ∼10%
Diarrhoea or SONNWEBER [22] 41% 9%
vomiting HUANG [12] 5%
185
Continued
186

Table 1. Continued
Symptoms First author Before Onset 20 37 60 3 100 6

[ref.] days days # days months days months
Diarrhoea CARFI [15] ∼29% ∼4%

Night sweats SONNWEBER [22] 63% 24%
Pain SONNWEBER [22] 54% 24%
Chest pain CARFI [15] ∼50% ∼21%
KAMAL [24] 28.9%
HUANG [12] 5%
Joint pain CARFI [15] ∼50% ∼23%
KAMAL [24] 31.4%
HUANG [12] 9%
Headache CARFI [15] ∼50% ∼9%
KAMAL [24] 28.9%
HUANG [12] 2%
Migraine KAMAL [24] 2.8%
Myalgia KAMAL [24] ∼50% ∼6%
HUANG [12] 2%
Sore throat CARFI [15] ∼30% ∼7%
HUANG [12] 4%
Lack of appetite CARFI [15] ∼52% ∼8%
https://doi.org/10.1183/2312508X.10024420
Dizziness CARFI [15] ∼17% ∼6%

HUANG [12] 6%
Tinnitus 16.7%
Sleep disorder SONNWEBER [22] 39% 28%
HUANG [12] 26%
Hair loss HUANG [12] 22%
Skin rash HUANG [12] 3%
Anxiety KAMAL [24] 38%
Dementia KAMAL [24] 28.6%
Depression KAMAL [24] 28.6%
Blurred vision KAMAL [24] 17.1%
mMRC: modified Medical Research Council dyspnoea scale; IQR: interquartile range. #: range 30–43 days.
A systematic review reported the presence of HRCT alterations in 35% of patients after a
period of 60–100 days since the onset of the acute phase [20]. Interestingly, HRCT
alterations were associated with ventilator treatment.
Furthermore, interstitial lung alterations improved over time in the majority of patients,
with a significant reduction of ground-glass opacities and reticulations at CT scan 90 days
after recovery [26].
Post mortem series and autopsy reports confirm these radiological findings [31–33]. GRILLO
et al. [34] described a series of lung cryobiopsies from eight patients with severe COVID-19
who died in the ICU, with observed marked fibrotic lung parenchymal remodelling,
characterised by fibroblast proliferation, airspace obliteration and micro-honeycombing.
The epidemiological impact of COVID-19-related pulmonary fibrosis is uncertain.
Risk factors for COVID-19-related pulmonary fibrosis include age, disease severity and
length of stay in ICU, as well as a history of smoking and chronic alcoholism [35].
Regarding age, interstitial lung diseases are more often reported in older individuals and
rarely occur before 50 years of age [36]. Similar results were observed following SARS-CoV-1
and MERS infections, with a higher risk of developing pulmonary fibrosis described in
older patients [37, 38].
Regarding the severity of the disease, this definition is secondary to a comprehensive

clinical evaluation, including pulmonary manifestations, the presence of comorbidities and
alterations of laboratory findings [14]. Firstly, the extent of lung injury is known to
correlate with fibrotic changes [39]. Secondly, observational data suggest that patients with
COVID-19 and secondary pulmonary fibrosis are more likely to have had longer exposure
to systemic therapies such as anti-virals and intravenous steroids than the non-fibrosis
group, thus suggesting a more severe disease in the latter group [40]. Thirdly, some
biomarkers of disease severity, including LDH levels, have been demonstrated to correlate
with a higher risk of pulmonary fibrosis in both SARS-CoV-1 and MERS survivors [38, 41].
The length of mechanical ventilation is both a surrogate of disease severity and an

established risk factor for ventilator-induced lung injury, which might lead to increased
prevalence of pulmonary fibrosis in survivors [42].
Currently, prospective data on the risk of developing pulmonary fibrosis cease at 6 months
and the epidemiology of patients developing this sequela remains uncertain. Multicentre
longitudinal studies are needed to further elucidate the progression of COVID-19-related
pulmonary fibrosis and the rationale for the use of long-term steroids or antifibrotic agents.
Level of evidence: Low. Small observational studies.
Lung function decline and dyspnoea

Anomalies of lung function at the time of discharge, especially in terms of decreased gas
diffusion, have been reported in a number of patients.
Early analysis from a cohort of 110 patients in Guangzhou, China, noted a reduction in
diffusing capacity of the lung for carbon monoxide (DLCO) in 51 (47.2%) individuals, total lung
https://doi.org/10.1183/2312508X.10024420 187
capacity in 27 (25%), forced expiratory volume in 1 s in 15 (13.6%) and FVC in 10 (9.1%)

[43]. Unsurprisingly, impairment in gas diffusion and lung capacity increased with worsening
severity, i.e. 30.4% in mild disease, 42.4% in pneumonia and 84.2% in severe pneumonia.
KANG et al. [8] described the first retrospective multicentre cohort at 3 months reporting
reductions in DLCO in 25% of individuals.
Lung function alterations are also reported to persist for 60–90 days after recovery [13].
A recent multicentre observational study that aimed to monitor cardiorespiratory sequelae
in post-COVID-19 patients highlighted that one-third of patients displayed a reduced lung
diffusion capacity 100 days after recovery [43]. However, lung volume and gas diffusion
capacity progressively recover 3–6 months after the acute phase in both general ward and
ICU patients [12, 21].
The reduction in gas diffusion is likely to reflect COVID-19 pneumonitis and could
contribute to persistent dyspnoea in the following weeks and months.
Dyspnoea is present in more than half of patients after the acute phase of COVID-19, with
a modified Medical Research Council dyspnoea scale (mMRC) Grade of >0 in 43–54% of
cases with mild-to-severe disease [21, 44]. Dyspnoea is also reported in the absence of
significant lung function alterations or radiological findings, and is probably related to
cardiorespiratory, neuromuscular and psychological factors [22]. The percentage of patients
with post-COVID-19 dyspnoea significantly reduces over time, from 68% of patients at day
60 to 36% after 3 months, with only 4% of patients reporting severe ongoing breathlessness
(mMRC Grade 3–4) [22].
Post-activity polypnoea is one of the most common post-COVID-19 symptoms and has
been interpreted as a patient-reported variation of dyspnoea [20]. The application of
cardiopulmonary exercise testing in a study of persistent dyspnoea highlighted the
argument that deconditioning might play a major role, as indicated by exercise-induced
hyperventilation, lower peak oxygen uptake (V’O2) and lower ventilatory efficiency [44–46].
Level of evidence: Moderate. Multicentre observational studies.
Cardiac sequelae
Previous experience with SARS-CoV-1

Although COVID-19 is a novel disease with no data on long-term outcomes, similarities
with the 2003 SARS-CoV-1 epidemic might shed some light on this issue. It was reported
out of 25 recovered SARS-CoV-1 patients, the majority (68%) still showed alterations in
lipid profiles 12 years after infection [46]. Unspecified cardiovascular alterations with poor
quality of life were present in 40% of this cohort [46].
Level of evidence: Low. Single observation study.
Diastolic dysfunction and rare sequelae

Diastolic dysfunction has been reported as a common cardiac alteration after COVID-19
recovery. A recent prospective, multicentre study systematically evaluated cardiopulmonary
damage in patients recovering from COVID-19 and reported a high rate of diastolic
dysfunction (60% and 55% of all patients at 60 and 100 days after diagnosis, respectively) [22].
188 https://doi.org/10.1183/2312508X.10024420
The same observational study by SONNWEBER et al. [22] reported rare cardiological
complications, including pulmonary hypertension in 10% of subjects, pericardial effusion
in 6% and reduced left ventricular ejection fraction in only four subjects.
Recently, postural orthostatic tachycardia syndrome has been reported in a case series of
three patients >3 months after the acute phase of COVID-19 [47]. The real clinical burden
is still unclear as we lack long-term follow-up and prospective observational studies aiming
to explore this outcome.
Level of evidence: Moderate. Prospective multicentre observational studies.
Myocardial inflammation
Myocardial inflammation has been reported in 58% of a series of unselected patients who
recovered from COVID-19 independently of the severity of the acute phase [48].
Cardiovascular magnetic resonance scans showing myocardial inflammation signs are still
seen at a median of 71 (interquartile range 64–92) days after recovery. However, data about
the evolution of this condition are not available after this time, indicating the need for
prospective observational studies [49].
Level of evidence: Low. Case series and one prospective observational study with a high
level of technological assessment.
Systemic hypertension
The onset of systemic hypertension during the acute phase of COVID-19 has been the
subject of some discussion and has been associated with worsening of the respiratory
condition, as well as modulation of the renin–angiotensin–aldosterone system by
SARS-CoV-2 [50]. It is still unclear whether this form of hypertension is reversible in the
medium term from the resolution of the viral infection or involves the need for chronic
clinical and therapeutic management.
Expert opinion: No evidence is available.
Extra-cardiorespiratory sequelae
Persistent changes in coagulation factors
During the acute phase and mainly in severe cases, pro-inflammatory cytokine signalling,
which includes IL-1, IL-6 and TNF-α, contributes to the activation of the coagulation
cascade [12].
The pro-coagulation state could be the cause of the high rate of thromboembolic
complications during COVID-19, occurring in 35–45% of patients [51].
D-dimer remained elevated in 23% of patients 3 months after recovery from COVID-19,
but pulmonary embolism was documented in only one of eight patients at 3 months [22].
No DVT of the lower limbs was documented in a 6-month follow-up study of 390 patients
who underwent lower limb vein ultrasound [12].
https://doi.org/10.1183/2312508X.10024420 189
It could be concluded that the post-COVID-19 period is not characterised by the same
thromboembolic risk as the acute phase, and an increased or persistently elevated D-dimer
should be carefully evaluated before performing diagnostics to exclude a venous
thromboembolism event.
Level of evidence: Low. Two observational studies that did not evaluate all patients with
actual gold standard tests for pulmonary embolism or DVT.
Olfactory and gustative dysfunction
Olfactory and gustative alterations are frequent during the acute phase, accounting for
⩽70% of patients after 48 h of onset of systemic symptoms [52]. Female sex and patients
with mild presentation of COVID-19 are reported to be more predisposed to develop these
alterations [53].
These alterations had resolved in only 44% of patients 5–8 days after recovery, and a
complete recovery was reported after the 8th day in 72.6% [47]. CHO et al. [54]
documented complete resolution at day 10 of anosmia and dysgeusia in 71.8% and 83.3%
of patients, respectively.
Level of evidence: Low. Case reports and one systematic review of case series.
Asthenia and fatigue
Asthenia and fatigue are among the most commonly reported persistent symptoms in the
post-COVID-19 period, accounting for 70% of patients at the time of hospital discharge.
Fatigue is still common during the follow-up period, reported in 40.3–50% of patients
3 months after the acute phase [52, 55].
In an observational study, fatigue and muscle weakness have been reported in 63% of
overall patients and in 81% of patients requiring HFNC and mechanical ventilation during
the acute phase [12]. In their observational study at 6 months, HUANG et al. [12] documented
asthenia and fatigue to be amongst the most persistent symptoms at the end of follow-up.
Intense fatigue is also described as part of the newly defined “post-COVID-19 syndrome”,
characterised by mild symptoms in the acute phase and recurrence of symptoms during
follow-up [56]. Post-COVID-19 syndrome usually self-limits and resolves within 8 weeks.
The hypothesis is that this complication might be secondary to the dysautonomous
alterations and inadequate inflammatory response described after Epstein–Barr virus
infection and post-chikungunya syndrome [57]. The authors do not provide indications for
specific treatment, but rehabilitation, psychological support and counselling can be useful
to aid recovery [56, 58].
The persistence of symptoms over 3 months, however, should be investigated further, as the
viral infection could act as the trigger for an underlying disease state, such as an
autoimmune disease [58].
Level of evidence: Low. One single prospective observational study.
190 https://doi.org/10.1183/2312508X.10024420
Peripheral neuropathy
Neurological sequelae were described in the context of previous outbreaks of SARS-CoV-1

and MERS. The most frequent manifestations were peripheral neuropathy, myopathy,
Bickerstaff brainstem encephalitis and Guillain–Barré Syndrome, with the onset of
neurological syndromes appearing 2–3 weeks after respiratory symptoms [59, 60].
Long-term neurological sequelae following other coronavirus infections are well

documented; for example, in a study demonstrating a high prevalence of previous
coronavirus infection in 48% of patients affected by multiple sclerosis [61].
SARS-CoV-2 can spread to the central neural system via a retrograde axonal transport from
peripheral nerves, such as the olfactory nerve, or via the blood stream [62]. This observation
demonstrates that SARS-CoV-2 has the same neurotrophisms as other species and provides a
rationale for the occurrence of long-term neurological sequelae after COVID-19 [63].
The similarity between the different coronavirus-related diseases highlights the opportunity
for close surveillance in patients recovering from COVID-19. A multidisciplinary
perspective would be beneficial here, with neurological monitoring.
Expert opinion: No evidence is available.
Neurocognitive alterations
In a prospective observational study, KAMAL et al. [16] reported dementia in 28.6% of COVID-19
survivors in a North-African population. Unfortunately, the study design makes it difficult to
assess whether cognitive alterations were present before COVID-19 and whether dementia was
caused by SARS-CoV-2 itself or whether it was secondary to associated conditions, such as social
isolation, hospitalisation and the acute worsening of physical comorbidities [16].
Recent studies have reported the presence of neurological symptoms 4 months after the
acute phase; this was also seen in patients who did not required hospitalisation [64]. The
term ‘brain fog’ has been used to describe a nonspecific cognitive disorder reported in 7.2%
of patients with post-COVID-19 sequelae and in 81% of patients who specifically reported
neurological symptoms that persisted after the acute phase [64, 65]. A possible mechanism
that could explain the development of brain fog is the presence of a high viral load
affecting the central nervous system and, specifically, the neuronal mitochondria in patients
with COVID-19 [66]. However, confinement and stressful conditions during the
COVID-19 outbreak have been associated with worsening neuro-cognitive symptoms, and
this has also been noted in patients without COVID-19 but with a previous diagnosis of
mild cognitive impairment or dementia, making the correlation between SARS-CoV-2
infection and cognitive symptoms a challenge to investigate [67].
Level of evidence: Moderate. Data from prospective studies.
Psychological and psychiatric alterations
The burden of neuropsychiatric sequelae after COVID-19 is not completely known because
of the highly variable period of time from viral infection to the onset of post-acute
psychiatric manifestations [59].
https://doi.org/10.1183/2312508X.10024420 191
The previous outbreaks of SARS-CoV-1 and MERS were associated with an increase in
psychiatric disorders, including PTSD (54.5%), depression (39%), chronic pain disorder
(36.4%), panic disorder (32.5%) and OCD (15.6%) [68].
Previous infection with different strains of HCoV is frequently noted in patients with a
recent psychotic episode, suggesting a possible relationship between viral infection and
psychosis, which may also occur in SARS-CoV-2 [69].
Data about psychiatric sequelae after COVID-19 are less extensive, but a retrospective study
reported anxiety, depression and OCD in the 38%, 28.6% and 4.9%of patients, respectively,
during follow-up [16].
Anxiety or depression have been reported in 23% of patients 6 months after recovery;
female sex and severe disease were associated with psychiatric manifestations, but it is not
known whether they are secondary to the systemic stress following the acute phase or
whether they are due to the direct role of the SARS-CoV-2 infection [12, 70, 71].
Patients who experienced prolonged invasive mechanical ventilation were more at risk of
delirium after ICU discharge, and this complication could significantly increase the length
of hospitalisation [71].
Level of evidence: Low. Observational studies.
Dermatological manifestations
The incidence of dermatological complications during the acute phase varies from 4.9% to
20% across different studies [72, 73].
Erythematous rash and urticaria are the most frequent manifestations, probably mediated by
T-cell immunity activation and degranulation of mast cells. Skin infection is less likely as it has
never been possible to demonstrate the presence of SARS-CoV-2 in skin cells [74]. In the
post-COVID-19 period, skin rash is described in 3% of patients within 6 months of recovery [12].
Chilblain-like lesions, ischaemic lesions and ecchymotic acral lesions have also been described
during COVID-19, probably secondary to the alterations of coagulation homeostasis [75].
Another sequela is telogen effluvium: abundant hair loss occurring weeks or months after a
systemic stressor [76–78]. The most probable trigger is the high level of pro-inflammatory
cytokines during COVID-19; but another possible cause is the use of heparinoids in the
acute phase [79]. Patients at higher risk of this complication were women (78.5%) with a
median (range) age of 47.4 (15–88) years, regardless of the severity of the acute disease. Hair
loss usually starts 4 weeks after onset of the infection, with a mean±SD duration of 57.1±18.3
days. The majority of patients reported a high level of emotional stress due to infection,
with hair loss contributing to increased apprehension about their health status [79].
Hair loss is usually self-resolving, although it is still reported in 22% of patients 6 months
after recovery [12, 78]. The use of vitamin B seems to reduce the duration of hair loss;
topical minoxidil 5% was used in a single case with a previous diagnosis of androgenetic
alopecia, but without clear evidence of efficacy [12, 78, 79].
Level of evidence: Low. Single-centre and multicentre prospective observational studies and
case series.
192 https://doi.org/10.1183/2312508X.10024420
Gastroenteric persistent alterations
Gastrointestinal symptoms are common, with diarrhoea (3.8–34%), nausea or vomiting

(3.9–10.1%), and abdominal pain (1.2%) the most commonly reported during the acute
phase [80]. These complications are probably secondary to direct viral infection and
damage to the gastrointestinal cells [80].
Diarrhoea, nausea and vomiting persist during the post-COVID-19 period, with slow
improvement during the 6 months after recovery [12, 43].
Level of evidence: Low. Studies that specifically focus on gastroenteric alteration in the
post-COVID-19 period are lacking.
Liver function alterations
Elevation of liver enzyme and bilirubin is described during the acute phase, particularly in
severe cases and in the presence of abnormal systemic inflammation or hypoxic injury [81].
This alteration resolves spontaneously during clinical improvement and is not reported in
the post-COVID-19 period [82].
Level of evidence: Low. Data come from studies about the acute phase.
Renal failure
Acute renal failure has been described during COVID-19 and it has been hypothesised that
it can persist or evolve into chronic alteration after recovery [12, 83]. In 13% of cases, renal
impairment could develop in the post-COVID-19 period in patients without renal function
alterations in the acute phase [12, 83].
On the basis of these data, renal function and diseases during the post-COVID-19 should
be evaluated.
Level of evidence: Low. Case series and one single large prospective observational study.
Conclusion
COVID-19 can cause long-term sequelae in patients. Fatigue, headache, attention disorder,
hair loss and dyspnoea appear to be the most frequent symptoms in this patient group. The
severity of post-COVID-19 sequelae is usually related to the severity of COVID-19 infection
during the acute phase; increasing age and comorbidities are also potential risk factors for
long-term sequelae. There is, however, a subset of patients with an initially low
symptomatic burden in the acute phase and a prolonged symptomatic period after initial
recovery from the virus. Post-COVID-19 is usually self-resolving but it potentially
compromises quality of life and the resumption of daily activities for several weeks.
Long-term follow-up studies are needed to describe the evolution and possible
interventions to treat or reduce the impact of this condition of “long COVID” in
post-COVID-19 patients.
https://doi.org/10.1183/2312508X.10024420 193
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196 https://doi.org/10.1183/2312508X.10024420
| Chapter 12
Post-COVID-19 rehabilitation
Sally Singh1,2
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 [https://doi.org/10.1183/2312508X.
10024520].
@ERSpublications
A significant number of individuals fail to fully recover after initial SARS-CoV-2
infection. The demand for multidisciplinary and individualised rehabilitation may be
high. Integrated models of care need to be developed and evaluated as a priority.
https://bit.ly/3sYBXEZ
T he need to support the rehabilitation of individuals post-COVID-19 is becoming

increasingly evident and a growing challenge for the rehabilitation community. This
chapter will discuss the common symptoms reported in the post-COVID-19 population that
could be favourably influenced by a rehabilitation programme. The process of rehabilitation
will be debated and possible pathways identified. The challenge, of course, is the lack of
literature describing the process and outcomes of rehabilitation for the post-COVID-19
population. The post-COVID-19 disease burden has recently been defined by the National
Institute of Health and Care Excellence (NICE) as follows: “Post-COVID-19 syndrome: signs
and symptoms that develop during or after an infection consistent with COVID-19,
continue for more than 12 weeks and are not explained by an alternative diagnosis” [1].
This gives some structure to potential management strategies for this population.
This chapter will cover the rehabilitation of the individual post-COVID-19 but will not
address the rehabilitation that may occur in the ICU or on a ward to facilitate discharge
1
Dept of Respiratory Science, University of Leicester, Leicester, UK. 2University Hospitals of Leicester NHS Trust, Leicester, UK.
Correspondence: Sally Singh (ss1119@le.ac.uk)
https://doi.org/10.1183/2312508X.10024520 197
(ICU management is discussed in more detail elsewhere in the Monograph [2]). Pulmonary
rehabilitation offers a structured programme that facilitates a reduction of symptoms in
patients with chronic lung disease, and may offer a potential recovery pathway, albeit
adapted for those with post-COVID-19 symptoms.
Background
Since the outbreak of the pandemic, the rehabilitation needs of the COVID-19 survivor
have been anticipated. Initially, the rehabilitation focus was around the post-ICU
population, referencing the previous data describing the need of this population [3].
However, over the following few months it became clear that there was an increasing
demand for rehabilitation services for those hospitalised irrespective of the need for
mechanical ventilation, and more recently, evidence is emerging that those who managed
the acute phase of the illness in the community report a similar profile of symptoms [4].
Rehabilitation services are predicted to face unprecedent demand, although models of care
are yet to be described and evaluated.
Individuals presenting with other complex rehabilitation needs alongside a recent

SARS-COV-2 infection may be best suited to a more specific rehabilitation programme; for
example, complex trauma or neurological disease. There are reports of more serious
side-effects that have been attributed to SARS-CoV-2 infection; these require further
investigation and treatment prior to engaging with a recovery programme or again may
indeed be best suited to existing programmes, depending upon the symptom burden. The
most obvious example currently would be a thrombotic event as a direct consequence of a
SARS-CoV-2 infection, such as a stroke or myocardial infarction. It might be pertinent to
direct individuals to be referred to either cardiac or stroke rehabilitation; both services are
well developed in high-income countries. These existing pathways will not be included in
this chapter; details of these programmes can be found in national and international
guidelines [5–7].
Symptom burden
The early data describing post-COVID-19 symptoms focused on the post-ICU population
and referred to the wide literature describing the impact of ARDS. ICU-acquired weakness
is a common feature of ARDS, and early reports suggested that critically ill patients with
post-COVID-19 syndrome were no different [8]. The recovery of this weakness may extend
over 5 years [2]. Some studies reported significant cognitive impairment after ICU
discharge, with incidence as high as 70–100%, which can persist even at 5 years. Depression
is also well documented post ICU as is PTSD [3]. The proportion of people
post-COVID-19 who are discharged from ICU is a smaller proportion of the hospitalised
post-COVID-19 population, and it could be speculated that the impact of SARS-CoV-2
infection in conjunction with the negative impact of an ICU stay would lead to a greater
symptom burden compared to those who were admitted or those who were managed in the
community. This has indeed been demonstrated in a large cohort study that was stratified
according to the level of inpatient care [9]. We do know that the effect of previous
respiratory viruses, such as MERS and SARS, is significant. A systematic review
demonstrated the impact across a broad range of outcomes commonly deployed in a
pulmonary rehabilitation programme, such as exercise capacity, health-related quality of life
198 https://doi.org/10.1183/2312508X.10024520
REHABILITATION | S. SINGH
(HRQoL), depression, anxiety, fatigue and pain. The review catalogued the impact of
infection at varying time points post-discharge, and it was clear that the impact was evident
at 12 months post discharge [10]. The cohorts recruited post SARS/MERS were much
younger than those conventionally recruited to a pulmonary rehabilitation programme,
demonstrating the indiscriminate impact of these respiratory viral infections.
There have been numerous reports of the symptoms observed at the point of hospital
admission and at follow-up. During the acute phase, the common symptoms appear to be
cough, breathlessness and fatigue. Initial reports of post-COVID-19 disease were limited to
the post hospital discharge population and described a complex symptom burden [11].
More recently, there has been data from wider communities post-COVID-19; specifically,
the large datasets use data acquired through Facebook groups or dedicated mobile apps
collecting data [4]. The distribution and clusters of these symptoms are largely unexplored
and we don’t fully understand whether there is a propensity for groups of symptoms. The
challenge for many individuals is the fluctuating nature of the symptoms: a patient-led
survey (n=640) identified that 89% of respondents identified that “symptoms fluctuated in
intensity and frequency” and 70% of the respondents selected “new symptoms appeared at
different times.” The survey described the early phase of the disease but its findings may
well be true for those several weeks on from the initial infection [12]; this was echoed in a
large qualitative study [13].
Perhaps not surprisingly, and consistent with chronic lung disease, the burden of symptoms
appears to be unrelated to the degree of lung damage. A study of individuals hospitalised and
assessed ∼6 weeks post-discharge showed a dissociation between chest radiograph changes
and symptom burden [14]. Despite the resolution of radiological abnormalities, scores of
breathlessness increased compared with pre-infection levels; symptoms of fatigue, sleep
disturbance, anxiety and depression also increased. A large dataset from Wuhan (China)
followed up a cohort on average 186 (175–199) days following symptom onset. Fatigue or
muscle weakness was noted in 63% of the cohort; 26% reported sleep difficulties and 23%
reported anxiety or depression. Exercise capacity was measured using the 6-min walk test
(6MWT) (mean distance 495 m, mean age 57 years); 23% of the cohort had a walking
distance less than the lower limit of the normal range [15]. Data reporting the incremental
shuttle walking test (ISWT) as an outcome measure demonstrated a similar protracted
disability, with the cohort achieving a mean±SD 46.2±35.8% of age-matched predicted at
5 months post-discharge [9]. Other symptoms with a prevalence of >10% in the Wuhan
cohort included hair loss (22%) and smell disorder (11%). Less frequently reported symptoms
were palpitations (9%), joint pain (9%), loss of appetite (8%), taste disorder (7%) and
dizziness (6%) [15]. Data from a UK post-hospital cohort echoed these findings, with >90%
having at least one persistent symptom at the median follow-up time of 5 months. At that
time-point, only 29% of patients felt fully recovered. The most commonly reported symptoms
included pain, fatigue, physical slow down, poor sleep, muscle weakness, breathlessness and
short-term memory loss. Importantly almost 20% were no longer working [9].
The symptom burden from community-managed SARS-CoV-2 infections is less clear.

Early self-reported data recorded through a purpose-built app identified ∼10% of people
who reported experiencing prolonged symptoms for >3 weeks, with ∼2% symptomatic at
3 months [16]. A large community study, again in the UK, reported much larger numbers:
almost 20% of participants remained symptomatic at 12 weeks [17]. Data from a study of
younger adults (aged 16–30 years) managed in the community reinforced this, noting that
52% (32 out of 61) had symptoms at 6 months [18].
https://doi.org/10.1183/2312508X.10024520 199
Predicting the characteristics of those most likely to present with enduring symptoms
suggests that being female and of increasing age increases the likelihood of symptoms,
whilst being non-white is less likely to be associated with persistent symptoms [19].
The rehabilitation model
The need for a supported rehabilitation service for those with post-COVID-19 syndrome is
undeniable; the overall demand is less clear [20].
The rehabilitation model has not been defined or evaluated for the post-COVID-19
population. There are existing models of rehabilitation that are established across many
countries, notably pulmonary and cardiac rehabilitation, that support the rehabilitation needs
of those with chronic lung disease and cardiac disease, respectively. The model of cardiac and
pulmonary rehabilitation is remarkably similar, comprising individually prescribed and
progressed exercise and education to support self-management. There is strong evidence that
these structured, centre-based and supervised programmes can favourably influence exercise
intolerance, HRQoL, anxiety, depression and breathlessness [21, 22].
Respiratory clinicians are of course familiar with pulmonary rehabilitation, a package of

care that is multidisciplinary and comprises a broad range of healthcare professionals,
including physiotherapists, nurses, doctors, psychologists, dietitians and occupational
therapists. Pulmonary rehabilitation has a very strong evidence base [21–23] and is
equally successful beyond the rigours of clinical trials [24]. Furthermore, data confirms
that the results are not compromised in those with multiple comorbidities that may be
more reflective of the post-COVID-19 individual [25]. The evidence confirms that in
chronic respiratory disease, rehabilitation improves exercise capacity, breathlessness,
anxiety, depression [26, 27], fatigue [28] and cognition [29]. Equally, a series of
Cochrane reviews examining cardiac rehabilitation confirmed gains in exercise capacity
and HRQoL [30], and a similar review in chronic renal disease confirmed similar gains
in walking capacity, cardiovascular dimensions (e.g. blood pressure and heart rate),
HRQoL and some nutritional parameters [31]. For those with end-stage renal disease,
exercise training has resulted in improvements in fatigue, anxiety, depression and
physical activity [32]. It is likely that the needs of the post-COVID-19 individual extend
beyond those commonly reported in the respiratory or cardiac population. Services will
need to collaborate or integrate to collectively address the needs of the post-COVID-19
population.
One significant difference in the data for both cardiac and pulmonary rehabilitation
compared with the post-COVID-19 population is the average age of the group. Early data
from the first wave of SARS-CoV-2 in a UK cohort of discharged patients indicated that
the age of subjects was <70 years [33], a much lower mean age than values commonly
described in pulmonary rehabilitation studies. This means that the challenge of supporting
a return to work needs to be addressed [15, 34].
There have been indications that an adapted pulmonary rehabilitation programme may form
a foundation for the generation of a service for the post-COVID-19 population [35, 36]. It is
important that this is not to the detriment of the traditional participants of pulmonary
rehabilitation. Many of the symptoms reported align with those commonly observed in the
usual pulmonary rehabilitation population, notably breathlessness, reduced functional
200 https://doi.org/10.1183/2312508X.10024520
capacity, anxiety and depression [4]. Figure 1 presents the commonly reported symptoms
that are ameliorated by a rehabilitation programme, alongside those that might not be, but
could be with an adapted programme.
Fatigue is an important symptom of post-COVID-19 syndrome but not necessarily the

focus of rehabilitation in the chronic respiratory population. Interestingly, it is a domain of
the Chronic Respiratory Questionnaire (CRQ) [37] and an item on the COPD Assessment
Test (CAT) questionnaire [38]. There have been reports describing the impact of fatigue in
COPD and the value of pulmonary rehabilitation [28]. A recent study specifically explored
the impact of rehabilitation in the COPD population and patients categorised by the
severity of their fatigue prior to the intervention. Overall, the fatigue score improved
significantly (using the subjective fatigue subscale of the checklist individual strength) [39].
There was an important shift from those reporting severe fatigue pre-intervention (79.4%)
to post-intervention (33.0%); the remainder reported mild (33.6%) or normal levels of
fatigue (33.4%). Looking at the group who responded to the fatigue score, at baseline, there
were differences in their fatigue and HRQoL scores when compared with nonresponders.
There were no differences observed in baseline demographics, baseline anxiety, depression,
lung function, 6MWD or dyspnoea ( p-values >0.01). There is so much that we don’t yet
understand about the experience of fatigue for the post-COVID-19 population and we do
not know if post-viral fatigue is the same as fatigue associated with chronic respiratory
disease, or resembles the patterns observed in those with chronic fatigue syndrome or
9 Strong evidence 9 Potential benefit ? Unlikely X No evidence
PR COVID-19
rehabilitation
Fatigue 9 9
Muscle weakness 9 9
Breathlessness 9 9
Exercise intolerance 9 9
Cough 9 9
Depression 9 9
Anxiety 9 9
Sleep disturbances ? ?
Hair loss X X
Joint pain ? 9
? ?
Palpitations
X X
Smell disorder
? ?
Loss of appetite
Figure 1. Symptoms treated with a conventional pulmonary rehabilitation (PR) programme and the
additional challenge presented by the individual post-COVID-19.
https://doi.org/10.1183/2312508X.10024520 201
myalgic encephalomyelitis. It is an area of concern with respect to exercise therapy but to

date there is no evidence in either direction supporting or disputing the value of
exercise-based therapy in the individual with fatigue post-COVID-19 [40].
The psychological impact of previous respiratory pandemics has been described, with data
identifying high levels of anxiety and depression [10]. In addition, there are reports of
PTSD [10] stigmatisation and the almost inevitable fear associated with death and infecting
others [41]. These mental health problems seem to have different time courses, with the
fear of dying and infecting others being short lived compared with the other consequences.
Data that looked more widely at the previous SARS and MERS pandemics suggested that
these outbreaks were associated with a significant psychiatric burden during the immediate
acute infection and for an extended period after discharge [42]. The European Respiratory
Society (ERS)/American Thoracic Society (ATS) interim guidance on rehabilitation for
those discharged from hospital strongly recommended that survivors of COVID-19 with
symptoms of psychological distress (assessed using questionnaires) at 6–8 weeks after
discharge from the hospital should receive a formal psychological assessment [43].
The mental health symptoms reported in those with post-COVID-19 are, of course,
compounded by the emotional distress associated with the social isolation from family and
friends that is a consequence of the national lockdowns and restrictions that are/have been
severe and prolonged. It would seem reasonable to speculate that in certain communities
there is stigma associated with SARS-CoV-2 infections and further social isolation,
compounding the emotional disturbance.
Referral
Individuals discharged from hospital and those who have managed their infection in the
community who experience ongoing symptoms and/or a limitation in function and/or
challenges returning to work should be referred for assessment of their physical, cognitive
and mental impairment. Ideally, this should be a single point of access to an interdisciplinary
team that can simultaneously address recovery needs rather than a protracted and sequential
interaction with healthcare professionals to support recovery of single symptoms.
The pathway to rehabilitation services is usually a referral from a medical practitioner;

referral of COVID-19 patients would be no different and candidates could be referred from
primary or secondary care. Irrespective of the source of referral, it is important to confirm
that there are no outstanding symptoms post-COVID-19 that require either diagnosis,
assessment or intervention. It is also important that the referrer has ruled out new disease
or worsening symptoms of a previous disease, requiring further intervention. There are
currently few exclusion criteria for recovery pathways for the individual post-COVID-19; if
there is reduced exercise capacity that warrants consideration for an exercise-based
intervention, the usual considerations would apply [44]. Individuals presenting from
nursing homes, with severe frailty, in the end-of-life period and with palliative care needs,
are unlikely to benefit from a structured rehabilitation programme. It is important to note
that many candidates for rehabilitation programmes will have no prior lung disease or
indeed any other long-term conditions. Therefore, the aims will not be the usual goals of a
pulmonary rehabilitation programme: to reduce the burden of symptoms. Rather, the aim
will be to alleviate symptoms completely and facilitate a full recovery and return to
economic productivity (see table 1 for inclusion and exclusion criteria). A screening tool
202 https://doi.org/10.1183/2312508X.10024520
Table 1. Inclusion and exclusion criteria for post-COVID-19 rehabilitation
Inclusion criteria # Exclusion criteria
Patients with a prolonged hospital stay who Patients admitted with COVID-19 but presenting
received care on ICU with/without invasive predominantly with problems relating to
mechanical ventilation, high flow of oxygen neurological, cardiac, renal or polytrauma, or
therapy or NIV. other body systems. These patients may be
Patients presenting with respiratory better suited to alternative, specific,
symptoms with an inpatient stay with/ predefined rehabilitation pathways e.g.
without evidence of pneumonia. complex neurological or stroke rehabilitation.
Patients with persistant symptoms most likely Patients presenting with fall-related injuries
due to COVID-19 but who did not require should be referred to appropriate local
hospital admission. Many of these patients fall-prevention services.
may not have been tested for COVID-19 and Patients presenting with COVID-19 with
diagnosis will have been made on best coexisting active cancer requiring treatment
clinical judgement. Other medical decisions and plans, would be best initially
conditions that may present with similar managed on the cancer pathway.
symptoms need to be excluded. Patients presenting a) from nursing homes,
b) with severe frailty, c) in the end-of-life
period and d) with overwhelming palliative
care needs may not benefit from this
rehabilitation intensity, nature and style and be
better managed using alternative pathways.
Patients with persistant rehabilitation needs
requiring inpatient multidisciplinary
rehabilitation following a prolonged or severe
hospital admission. The proposed
rehabilitation detailed here does not replace
this but may take place at a later date.
Those with suspected active COVID-19 infection,
particularly if COVID-19 was not confirmed
during an initial influenza-like illness.
#
: the main referral criteria will be persistent symptoms associated with post-COVID-19 from a
number of routes. Reproduced and modified from [62] with permission.
has been proposed to help those referring into a service to identify those with most need of
a supported recovery [46].
Assessment of the post-COVID-19 survivor
When?
One important concern about the timing of any post-COVID-19 rehabilitation is the risk
of spreading the virus further. It is likely that any post-COVID-19 rehabilitation will extend
beyond the period of infection and likely spread, although this is not the case for inpatient
rehabilitation and all the necessary precautions should be followed. Infection-control
policies will likely be unique for each country/institution and should be observed at all
stages of the journey through the rehabilitation programme.
The timing of the post-COVID-19 assessment for a recovery intervention has not yet been
confirmed; for those post ICU, there are established pathways and this is usually delivered
https://doi.org/10.1183/2312508X.10024520 203
6–8 weeks post discharge [47]. The proportion of post-ICU patients in the broader
post-COVID-19 population is small; the majority will have been hospital (ward) admissions
or community-managed infections. The consensus document developed with the support of
the ERS/ATS early in the pandemic, proposed that formal rehabilitation should be considered
6–8 weeks post discharge from hospital [48]. The NICE guidance suggests that those
post-hospital admission should be called 6 weeks post discharge to check on symptoms, and
where necessary, individuals should have access to multidisciplinary rehabilitation
programmes. It is the general consensus that access to multidisciplinary rehabilitation should
be considered at any point 4–12 weeks post infection. Importantly, it should be noted that a
proportion of patients will fully recover, although this may take ⩽3 months [49].
Where?
Once all of the medical investigations have been completed, the assessment of an
individual’s needs can occur in primary care, secondary care or community facilities.
The COVID-19 recovery team
There is little guidance on the composition of the multidisciplinary team, and it is likely
that this will evolve as we learn more about the complexities of the post-COVID-19
symptoms. As a minimum, guidance has proposed the following [1]:
• A physiotherapist
• An occupational therapist
• Psychological support/expertise (counsellor/psychologist/psychiatrist)
As part of the wider team, the following professional groups or services should be
considered:
• Chronic fatigue service

• Speech and language therapists
• Dietitians/nutritionists
• Exercise physiologists
• Balance service
• Tinnitus services
• Pain specialists
• Cardiovascular rehabilitation teams
• Pulmonary rehabilitation teams
• Neuro-rehabilitation teams
There is no accredited training for those likely to be involved in COVID-19 recovery

programmes, but as a collective team, the expertise should allow for the development of an
integrated holistic recovery programme for the individual.
Components of assessment
There is no core dataset for pulmonary rehabilitation. A core outcome dataset has been
proposed for post-ICU research on ARDS and comprises the following measures that reached
consensus [50]: EQ-5D [51], the 36-item Short-Form Health Survey (SF-36) [52], the Hospital
204 https://doi.org/10.1183/2312508X.10024520
Anxiety and Depression Scale (HADS) [53] and the Impact of Events Scale–Revised [54], or
“mental health” outcomes. Whilst there was no consensus, by the pre-defined threshold, for
measures of cognitive function, muscle function, nerve function, physical function, and
pulmonary function, it would be recommended to include these measures. In the UK, there is
a nationally agreed dataset for pulmonary rehabilitation, which includes measures of process
and clinical effectiveness [24]. The outcome measures include exercise capacity (6MWT/
ISWT) [55, 56] and HRQoL (CRQ/CAT) [37, 38]. This selection of variables is the minimum
dataset and is usually enhanced with measures of psychological well-being, nutritional status,
peripheral muscle strength, balance, activities of daily living and, possibly, measures of physical
activity. For research, the assessment purposes may be more extensive than those for clinical
service. The assessment of the post-COVID-19 individual should be holistic and personalised.
The catalogue of symptoms reported requires comprehensive assessment beyond that typically
conducted in a pulmonary rehabilitation programme [24].
Exercise capacity
The 6MWT [56] and the ISWT [57] are likely to be suitable measures of exercise capacity
in the post-COVID-19 population. There are some studies that describe baseline
performance in a post-hospital population ∼6 months post discharge [9, 15]. In a review
that considered previous respiratory pandemics, AHMED et al. [10] highlighted a significant
reduction in exercise capacity recorded using the 6MWT at ⩽12 months post infection,
which fell well below predicted reference values. Similarly, early 12-month data from the
current pandemic suggested that despite a reduction in the number of post-COVID-19
symptoms reported in the 6–12-month time period, there was no significant difference in
the distance completed in the 6MWT between these two time points [57].
The data reinforces the need to assess the level of disability and develop a programme to
support a recovery of function. Irrespective of the exercise test selected, it is important to
document the reason for termination (for example, breathlessness, fatigue, pain), heart rate
and oxygen desaturation [56].
Quality of life
There may be the opportunity to develop a novel instrument to understand the impact of
COVID-19 for the individual. In the absence of a disease-specific measure, a generic
quality of life scale; for example, the EQ-5D or the SF-36 may be appropriate [51, 52]. The
EQ-5D has been shown to be responsive to pulmonary rehabilitation [58], and a minimal
clinically important difference has been defined. The EQ-5D has reported in cohort data
and early rehabilitation studies [36], as has the SF-36 [59]. The CAT has been widely used
in pulmonary rehabilitation [37, 38]. It assesses eight items: cough, sputum, chest tightness,
breathlessness, activity limitation, confidence leaving the home, sleep and energy. These
items have significant overlap with the commonly reported symptoms for individuals
experiencing COVID-19. Early data have demonstrated that the scale may be appropriate
for assessing the impact of COVID-19 [36]. A mean±SD score of 6.9±6.2 has been suggested
as a normal reference value. For the post-COVID-19 population (on average 32-days post
discharge), the mean (interquartile range) score was 10 (5–16) for the group, 9 (5–14) for
those with no pre-existing lung disease and 13 (8.75–18.75) for those with pre-existing lung
disease ( predominately asthma and COPD). There was no relationship between the CAT
score and the time since discharge (r=−0.14, p=0.13).
https://doi.org/10.1183/2312508X.10024520 205
Fatigue
Fatigue is a common symptom of many chronic diseases, and there are a number of
questionnaires that have established psychometric properties.
Commonly used scales to assess fatigue are: the Functional Assessment of Chronic Illness
Therapy-Fatigue Scale (FACIT) [60]; the Fatigue Severity Scale [61]; the Chalder fatigue
Scale [62]; and a visual analogue scale for fatigue.
The Chalder fatigue score was reported in a follow-up study of a group of individuals
discharged from hospital post-COVID-19 [63]. In a relatively young cohort (49 years old),
∼10 weeks after initial COVID-19 symptoms, just over half reported persistent fatigue;
there was no association between the severity of the initial infection and the degree of
fatigue reported.
In another cohort, the FACIT was reported [64]. Around 4 weeks post discharge the mean
±SD FACIT score was 27.7±13.9, with 54% demonstrating “severe fatigue”. But again, there
were no statistically significant differences in those with/without severe fatigue in length of
stay or number of days ventilated.
Post-exertional symptom exacerbation (PESE), also called post-exertional malaise, may be a

feature of post-COVID-19 for a number of individuals. It is characterised by disabling fatigue
or exhaustion, difficulty thinking, pain and exercise intolerance, all made worse by exertion;
exertion does not necessarily mean physical exertion but can be linked to both emotional and
cognitive stress. The symptoms can occur immediately or may become obvious ⩽24–72 h
after the initiating activity. Evaluation of PESE commonly relies on subjective assessment; for
example, the DePaul Symptom Questionnaire [65], although a 2-day cardiopulmonary
exercise test (CPET) protocol has been described, with the observation that maximal exercise
performance on day 2 is compromised compared with day 1 [66]. It is unlikely that CPET is
available and questionnaires deployed, with team members being vigilant during the
rehabilitation programme for signs and symptoms of PESE. The symptom of fatigue may
influence the choice of rehabilitation programme; given the burden of travelling to centres for
a supervised programme, a home-based programme may be preferred.
Anxiety and depression
The most commonly reported measure in the field of pulmonary rehabilitation is the
HADS, with thresholds of 8–10 indicating borderline symptoms and ⩾11 indicating
abnormal symptoms of anxiety and/or depression [53]. Other questionnaires might include
the Generalised Anxiety Disorder Assessment-7 (score 0–4: minimal anxiety; score 5–9:
mild anxiety; score 10–14: moderate anxiety; score >15: severe anxiety) [67] and the Patient
Heath Questionnaire-9 [54, 68].
Muscle weakness
Skeletal muscle weakness is commonly documented post ICU [3]. The simplest measure of
limb muscle strength used clinically is the Medical Research Council scale [69]. It does
have its limitations and therefore measures using equipment are more able to accurately
measure muscle strength; this would include the 1-repetition maximum or using
dynamometry to measure isometric muscle force.
206 https://doi.org/10.1183/2312508X.10024520
Cognitive function
Post-COVID-19 cognitive function may be disrupted and referral to a specialist may be

necessary. The Montreal Cognitive Assessment test is widely used [70]; however, the
consensus document authored by the ICU community that was previously noted did not
reach consensus on the choice of outcome measure for the assessment of cognitive function
[50]. There are some data that suggest pulmonary rehabilitation can improve cognitive
function, where there is disruption [29]. If the individual has high levels of anxiety and
depression, an assessment of post-traumatic stress would be advised and the appropriate
referral triggered.
Additional components that may be considered as part of the initial assessment aligning
with post-COVID-19 symptoms are: pain (particularly new pain) in terms of location and
intensity; disrupted smell and taste; sleep quality; dizziness and tinnitus; and problems with
voice, communication and swallowing. These are not commonly addressed as part of a
pulmonary rehabilitation programme but with appropriate collaboration with a wider
multidisciplinary team, appropriate treatment and advice can be integrated into the
programme. Importantly, occupation and return to work need to be addressed and
supported by linking with local occupational health teams to support the transition back to
work. Data from a post-hospital cohort indicated that almost a fifth of individuals
experienced a change in occupation as a consequence of changing health status [9].
Complications of SARS-CoV-2 infection to consider at the time of assessment
There are two significant consequences that have been recorded that should be considered
at the time of the initial assessment: thromboembolic events and myocarditis. There should
be a medical review of rehabilitation candidates to exclude significant pathologies that
require further treatment, and the rehabilitation team should be vigilant. The rehabilitation
team should be aware of previous DVT, pulmonary embolism or myocarditis during the
acute phase of the disease. At each session, the team should enquire about new or
worsening symptoms of chest pain or shortness of breath.
Autonomic dysregulation is emerging as a feature of post-COVID-19 syndrome for some

individuals, which can manifest as an abnormal heart rate response.
Postural orthostatic tachycardia syndrome is characterised by an increased and sustained

heart rate of ⩾30 beats·min−1 within 10 min of standing. Symptoms include chest pain,
palpitations and reduced exercise capacity. This may not be a contraindication to
rehabilitation but may require further specialist intervention and support [71].
Similarly, breathing pattern disorder may not be a contraindication for symptom-based

exercise therapy but may require additional support from physiotherapists. A summary of
breathing pattern disorders and possible interventions has been described, but not in the
context of COVID-19 [72].
Acute DVT and pulmonary embolism
An increase in the prevalence of venous thromboembolic events (DVT and pulmonary

embolism) has been observed in SARS-CoV-2, especially in participants with more severe
https://doi.org/10.1183/2312508X.10024520 207
disease. Advice embedded in the British Thoracic Society (BTS) document, describing
adaptations to pulmonary rehabilitation, proposes that prior to the exercise component of
rehabilitation [45], individuals with acute venous thromboembolic disease should receive
therapeutic anticoagulation and should confirm that there has been no adverse bleeding
as a consequence.
Myocarditis
SARS-CoV-2 infection can result in a wide range of cardiovascular complications, including

arrythmias, heart failure, acute coronary syndrome or myocarditis. It would be expected
that these should be identified and managed prior to a rehabilitation assessment;
throughout the subsequent programme, staff must remain observant. If myocarditis has
been confirmed it would be recommended to delay exercise training and revaluate for
safety at follow-up. Current guidance recommends that moderate- and high-intensity
exercise should be avoided for a period of 3–6 months [73]. Other components of the
rehabilitation programme may proceed independently.
Safety considerations
Conduct of an assessment, and any face-to-face rehabilitation, must be guided by local and
national infection-control procedures. For those following a face-to-face programme,
patients should be observant of COVID-19-related symptoms and call prior to attending.
Equipment should be cleaned as guided by local regulations.
Format of the intervention
As there are few reports of rehabilitation interventions in the post-COVID-19 population, it

is relatively early days for systems to adapt. There seems to be consensus around
pulmonary rehabilitation being a potential service model to deliver an effective intervention
for both the community [74] and post-discharge [75, 76]. A survey conducted early in the
pandemic concluded that pulmonary rehabilitation may be a suitable intervention but
would require further integration and engagement with a wider multidisciplinary team.
Contributors from the survey represented a wide range of healthcare professionals, beyond
the pulmonary rehabilitation team [77].
Data from the SARS/MERS pandemic describes successful rehabilitation in a small group of
patients [78]. A range of options is likely to emerge, from supervised inpatient programmes
through to light-touch digital interactions. The duration of the programme is likely to
mirror that of a pulmonary rehabilitation programme, with a component of supervised
exercise and educational sessions. There is currently little evidence of the effectiveness of
therapeutic exercise strategies in the post-COVID-19 population. Until data suggests
otherwise, the principles of exercise prescription as applied to all long-term conditions
remain. Individuals post-COVID-19 are likely to terminate exercise for a variety of reasons,
including breathlessness, pain and fatigue (muscle weakness, general fatigue). Fatigue is a
commonly reported symptom of post-COVID-19, and although it may be explained by
muscle deconditioning, it is also common for fatigue to be described as an overwhelming,
debilitating and sustained sense of exhaustion which compromises the ability to function
and carry out daily activities. The best approach for improving exercise performance in
those suffering from significant fatigue is unclear, and much debated. A common-sense
208 https://doi.org/10.1183/2312508X.10024520
approach would be to be guided by the individual, similar to the approach taken with the
breathless patient, where symptom-titrated exercise is routinely delivered by trained
healthcare professionals.
The educational sessions are likely to overlap with those offered in pulmonary rehabilitation.
However, there will need to be additional support covering fatigue, fear and worry, sleep
disturbances, taste and smell abnormalities, and returning to work (table 2). The latter is
relevant because the data suggest that those recovering post-COVID-19 are of working age.
Importantly, the way in which support is delivered needs to be considered; if there is

cognitive impairment, advice needs to be in bitesize pieces and reinforced with written
handouts.
Table 2. An example of the education programme for post-COVID-19 rehabilitation
COVID-19 disease education

Disease knowledge and possible symptoms
Infection control/social distancing/masks
Respiratory care
Management of breathlessness
Management of cough
Information on ambulatory and long-term oxygen therapy#
Information on tracheostomy care#
Fatigue management
Sleep hygiene
Pacing strategies, energy conservation
Gradual resumption of activities
Psychological care
Management of anxiety and depression
Information on delirium#
Cognitive impairment#
Information on PTSD#
Musculoskeletal problems and pain management
Muscle deconditioning and strength training
Pain management advice
Activities of daily living/functional performance
Management of neuropathy with information on ulceration and infection control#
Nutritional management
Education on diet enrichment#
Smell and taste retraining#
Speech and communication
Swallow retraining#
Voice control#
Cognition and speech#
Social issues
Return to driving
Return to sexual relationships
Social isolation/loneliness
Vocation
Return to work
Return to caring/parenting
#
: where relevant.
https://doi.org/10.1183/2312508X.10024520 209
Early indications are that supervised programmes appear to be feasible, but the data are
from small cohorts and some reports describe interventions very early post discharge when
you might anticipate some natural recovery. Nevertheless, data are encouraging, with few
dropouts [35, 79]. Delayed intervention has been described, again in a small cohort, where
there were surprisingly few dropouts and outcome measures were encouraging [36]. These
studies reported no adverse events or worsening of symptoms. In fact, the study by DAYNES
et al. [36] plotted the changes in fatigue against changes in exercise capacity; the majority
of patients reported improvements in both outcomes. Of course, RCTs are required to
establish the true benefit.
A technology-based solution might offer an alternative approach. A telehealth programme

would seem realistic particularly during a government lockdown. One case study reported
that this approach would be acceptable, at least for those willing to engage with technology
[80]. A digital low-intensity intervention should be able to deliverer an intervention at scale
and pace.
NHS England have developed You COVID Recovery (www.yourcovidrecovery.nhs.uk) to

offer such a solution. The site has been constructed by a wide range of healthcare
professionals, alongside individuals with lived experience of COVID-19. The ambition is to
roll the programme out across England. Access to the site will be facilitated by a healthcare
professional after an initial assessment and, importantly, as with all interventions,
continued supported by a healthcare professional will maximise success.
A smart phone app with a heart rate monitor and healthcare professional follow-up has
been evaluated in an RCT. Significant improvements in exercise capacity and HRQoL were
seen [59].
It is likely that to meet the demand of rehabilitation, a menu of options will be required
that allows for a personalised approach to meet individual needs.
Conclusion
There is going to be a tidal wave of demand for rehabilitation services for those with
post-COVID-19 symptoms. The need is evident now but will be heightened as the world
emerges from the acute phase of the pandemic. Pulmonary rehabilitation teams are well
placed to make a significant contribution to the recovery of these individuals, and to
support a full return to previous levels of well-being and a return to economic productivity.
Over the next few years, data will emerge describing effective strategies, but in the
meantime, we rely on expert consensus to guide the programmes.
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https://doi.org/10.1183/2312508X.10024520 213
| Chapter 13
Clinical trials during the
pandemic: research design
and lessons
Hani Abo-Leyah and 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 [https://doi.org/10.1183/2312508X.10005521].
@ERSpublications
The COVID-19 pandemic has required a substantial coordinated international effort to
develop effective treatments and vaccines, leading to an acceleration in innovation in
clinical research with the rapid adoption of pragmatic, open, adaptive trials https://bit.ly/
3sYBXEZ
T he devastating consequences of widespread SARS-CoV-2 infection demanded an

urgent response from the scientific community [1–3]. COVID-19 posed a significant
risk of mass mortality, collapse of healthcare systems and unprecedented economic damage
[4–7]. Urgent questions of global importance needed to be answered. Expert opinion could
Ninewells Hospital and Medical School, Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.
Correspondence: James D. Chalmers ( j.chalmers@dundee.ac.uk)
214 https://doi.org/10.1183/2312508X.10005521
CLINICAL TRIALS | H. ABO-LEYAH AND J.D. CHALMERS
not meet this demand. Nevertheless, expert opinion was all that was available in early 2020,
and unproven treatments were prescribed widely to patients across the globe, based on
in vitro observations, theory and prior experience with other viruses [8–10].
Of the more important lessons learnt from previous pandemics were that therapies need to
be evidence based and that interventional clinical trials were needed to determine effective
therapies and preventative treatments [11, 12].
Thousands of clinical trials have been registered since the start of the pandemic, and some
have had a major impact on the global management of COVID-19 [13]. In this chapter, we
will look back at the extraordinary year of interventional clinical trials and reflect on how
this experience will challenge established research models. As the issues surrounding the
development of therapeutics and vaccines are quite distinct, this chapter focuses primarily
on the development of therapeutics.
Empiricism versus evidence-based medicine
Antivirals, anti-inflammatory drugs, convalescent plasma, anticoagulation and various

other approaches were introduced into clinical practice prior to there being an evidence
base supporting them [14, 15]. Hydroxychloroquine is an example of a drug that was
prescribed widely across the globe in an unmonitored fashion before the completion of any
clinical trials investigating its efficacy in COVID-19 [16]. Hydroxychloroquine and
combination treatment of hydroxychloroquine and azithromycin were advocated largely on
the basis of in vitro data, followed by uncontrolled case series with a high risk of bias
[17–20]. These were by no means the only drugs used empirically during the pandemic.
The psychological impact of the first few months of the pandemic on front-line clinicians is
likely to be the subject of study for years to come, but it is clear that, faced with an
overwhelming health problem, many clinicians felt the need to act, even in the absence of
evidence [21]. A multicentre Italian study of severe COVID-19 patients requiring
ventilatory support gives an indication of the extent of “off-label” drug use during the first
wave. In this study, nearly one-third of patients received anakinra, 5–9% received
tocilizumab, 97% received hydroxychloroquine, 55% received lopinavir-ritonavir, 2–4%
received remdesivir, 42–50% received corticosteroids, 94–96% received antibiotics and 29%
received anticoagulation [22].
Although this gives an example from a single study, it reflects widespread practice globally
at the time. While clinicians may feel substantial pressure not to deprive patients of
treatments that may theoretically provide benefit, there are two main consequences of this
widespread empirical prescribing. The first is potential harm through side-effects, as the
safety of treatments has not been established [23]. The second is the impeding of
randomised studies that could establish the safety and efficacy, because background
therapies will render patients ineligible and patients may be unwilling to be randomised in
an environment where treatments are offered outside trials.
There is a therefore a delicate balance of ethical and practical considerations when

considering how to treat patients in the absence of evidence. Most, however, agree that the
optimal approach is to offer patients enrolment into rigorously conducted randomised
trials where there is clear equipoise, as was the case for all interventions in the early stages
of the pandemic [24, 25].
https://doi.org/10.1183/2312508X.10005521 215
Pre-pandemic preparation
SARS-CoV-2 is the third novel coronavirus to cause a major outbreak of severe respiratory
disease in the past two decades. SARS-CoV-1 emerged in November 2002 and disappeared
2 years later. MERS was identified in September 2012 and continued to cause sporadic and
local outbreaks [26].
Despite this trend of a novel coronavirus causing a major outbreak every ∼10 years,
European pandemic preparedness was focused on a predicted influenza pandemic. In
response to the 2009 H1N1 pandemic, only seven countries in the WHO European region
published revised pandemic preparedness plans [27].
There was a distinct lack of clinical trials during the 2009 pandemic. This was thought to
be more to do with a lack of preparation than a lack of need. Accordingly, the International
Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) preparedness
platform was set up (https://isaric.org/) [28]. The collaboration identified four types of
study that were needed in a future pandemic: 1) clinical characterisation studies, 2) drug
trials that had to be adaptive and responsive, 3) vaccination trials and 4) convalescent
plasma trials. ISARIC developed protocols that were ready to be deployed to serve these
types of clinical trials [28–30]. Indeed, all four study types occurred during the COVID-19
pandemic, and the preconceived protocols were utilised to facilitate the rapid rollout of the
large platform trials that we discuss later in the text.
The Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE)

consortium (www.prepare-europe.eu/) is another example of a pandemic preparedness
platform conceived since the 2009 influenza epidemic. PREPARE aimed to create a
common European research infrastructure covering over 1200 European sites. Training
delivered at these sites aimed to prepare for a rapid, coordinated research response to any
emerging epidemic. The REMAP-CAP (Randomized embedded multifactorial adaptive
platform for community-acquired pneumonia) study was born out of the PREPARE
consortium and has played a key role in critical care research during the COVID-19
pandemic [31, 32].
There is little doubt that without pre-COVID-19 studies investigating the biology of novel
coronavirus infection, we would not have seen such unprecedented progress over the past
12 months in understanding the basic science that underpins any clinical trial. For the past
two decades, research laboratories have studied the origins of the novel coronaviruses,
mechanisms of their infection route and replication, mechanisms of their spread to target
organs and sites of viral shedding [33–35]. Furthermore, the clinical trial response was
aided in great part by the rich modern history of research into the inflammatory pathways
that occur in acute and chronic lung infection [36]. As soon as common mechanisms were
identified in COVID-19, drug targets were rapidly identified to test novel therapies [37].
Organisations such as the WHO also significantly aided the initial set-up and standardisation
of clinical trial designs by publishing master protocols containing recommended clinical trial
end-points and study designs including power calculations for sample size estimation prior to
and during the early part of the pandemic [38]. This has resulted in a large proportion of
published trials utilising similar end-points, such as the WHO ordinal scale for clinical status.
This has benefits in terms of interpretation of trials but also aids the pooling of data in
meta-analyses such as those required for clinical guidelines [39].
216 https://doi.org/10.1183/2312508X.10005521
Research coordination: the case of the UK
Research initiatives were initiated in every country internationally during the pandemic
with important initial trials reporting results from China [40, 41], and trials then moving
to Europe, North America and more widely as the pandemic moved. It is not possible to
review trial activity in every country globally, but it is widely acknowledged, at the time of
writing, that the UK has made a major contribution to the international understanding of
COVID-19, particularly in the field of clinical trials [13, 17, 42]. The reasons for this have
been widely discussed, but explanations for the success of clinical trials in the UK include
an integrated national health system covering the entire country, and an existing national
research infrastructure through the National Institute for Healthcare Research (NIHR),
which meant that from the beginning of the pandemic nearly all hospitals and many
nonsecondary care environments had trained and experienced clinical research staff
available to support trials [43]. This existing infrastructure gave the UK a substantial
advantage in delivering trials. Alongside this, the UK’s strategy for prioritising research is
worthy of discussion. A recognised problem internationally at the start of the pandemic
was the sheer number of trials testing similar interventions. For example, a search of
https://clinicaltrials.gov on 29 March 2021 revealed 272 trials on this registry alone with
the search terms “hydroxychloroquine” and “COVID19”. Globally, most of these trials
have small sample sizes and are therefore unlikely to deliver definitive answers to the
questions of efficacy and safety. Many trials initiated in early 2020 have either not been
completed or have been terminated early due to poor recruitment. This often does not
reflect a lack of cases but rather a lack of research coordination leading to multiple
competing trials.
In March 2020, the UK’s NIHR established a national portal for prioritising funding and
support for urgent COVID-19 research [44]. Studies receiving the Urgent Public Health
Research (UPH) designation were eligible for support from local Clinical Research
Networks and were prioritised by hospitals across the UK as a result. This initiative had the
effect of centralising decision-making around which studies would be given priority across
the UK, resulting in a small number of trials recruiting large numbers of participants,
rather than those participants being spread across a much larger number of individual
trials. Approvals and set-up timelines were also accelerated for UPH studies. This process
particularly benefited large platform trials such as RECOVERY (Randomised evaluation of
COVID-19 therapy) [13, 17], REMAP-CAP [32, 45] and PRINCIPLE (Platform
randomised trial of treatments in the community for epidemic and pandemic illnesses)
[46], and vaccine trials [47].
Adaptive platform trials
Conventional randomised trials have historically followed a similar pattern of testing single
interventions in carefully selected patient populations using samples sizes that are designed
as a balance between clinical relevance and financial and feasibility considerations.
Regulators regard relevant end-points as those that impact how a patient “feels, functions
or survives” [48], but many randomised studies utilise surrogate end-points; for example,
forced expiratory volume in 1 s (FEV1) or exacerbations in COPD [49] and FVC decline in
pulmonary fibrosis [50] are considered meaningful by practitioners but are in many ways
surrogates for breathlessness, healthcare resource utilisation and survival. Conventional
randomised studies also attempt to minimise bias through careful patient selection, an
https://doi.org/10.1183/2312508X.10005521 217
approach that has been criticised for generating unrepresentative populations in some cases
[51, 52]. Blinding of drug trial interventions has also historically been considered essential
to guard against placebo effects among participants and different approaches to treatment
by clinicians when they are aware of subjects’ treatment allocation.
The concept of pragmatic adaptive trials is not new, and several such trials existed
pre-pandemic, but the way in which this approach has been rapidly embraced and accepted
has subsequently informed clinical practice globally, resulting in one of the major paradigm
shifts in clinical research arising from the pandemic [53, 54].
Broadly, when we talk about adaptive platform trials, we are discussing trials that are the
antithesis of the description of conventional trials above (table 1). These trials test multiple
interventions and use broad patient populations with little selection. They use large sample
sizes that are often not determined by pretrial sample size calculation but rather are
affected by a continuous analysis of incoming results. They use end-points such as
mortality that are not surrogates. They are typically nonblinded and the “success” of the
intervention is monitored in real time, allowing modification of interventions, variable
target patient selection and discontinuation of ineffective therapies. This is in contrast to
predetermined sample sizes, patient characteristics and outcome measures of a conventional
trial. The term pragmatic is typically used to describe these studies, which can broadly be
defined as “actions based on practical rather than theoretical considerations”. In the context
Table 1. Key differences in the design of conventional versus adaptive trials
Design feature Conventional trials Pragmatic and adaptive trials
Inclusion/ Often highly selective; exclusions Sparse; includes a broad

exclusion are based on comorbidity, representative population with
criteria comedications and other factors exclusions often only based
on safety
Interventions Single intervention Multiple interventions, either parallel
or sequential to multiple domains
Choice of New or repurposed therapies Largely used for repurposed
treatments therapies to date
Blinding Typically double blind and placebo Typically open label
controlled but can be any design
Sample size Variable depending on design but Often determined by interim analyses
often fixed at start of trial and either frequentist or Bayesian
stopping rules
Data collection Often detailed with multiple patient Sparse, with only the data required to
visits and a high number of answer the direct research
data points questions being asked; methods to
minimise manual data collection
(e.g. record linkage) may be utilised
End-points Variable, but many trials utilise Simple and clinically relevant,
surrogate end-points e.g. mortality, clinical recovery
Statistical Typically frequentist Examples of frequentist and Bayesian
approaches approaches used to date
Regulation Typically highly regulated/monitored Streamlined governance approvals,
with a high administrative burden monitoring approaches and
for sites reduced administrative burden
for sites
218 https://doi.org/10.1183/2312508X.10005521
of the COVID-19 pandemic, this means accepting some limitations in terms of patient
selection, trial conduct, the data collected and potential bias in view of the practical
challenges of delivering a trial under pandemic conditions.
Examples of adaptive platform trials are the international SOLIDARITY (WHO Public
Health Emergency “Solidarity” Clinical Trial for COVID-19 Treatments) [55] and
REMAP-CAP [45] trials, and the UK primary care (PRINCIPLE [46]) and secondary care
(RECOVERY [13]) platform trials, which have all reported results during the current
pandemic. Table 2 outlines some of the numerous adaptive platform trials that are taking
place internationally during the pandemic.
The RECOVERY trial is an example of a platform trial that has made a major contribution
to international COVID-19 guidelines. The key underlying feature of the RECOVERY trial
design was simplicity. The eligibility was simple: hospitalised patients with COVID-19,
including patients with suspected COVID-19 not confirmed by PCR. The primary outcome
was important and objective: mortality at 28 days. Emphasis was placed on simplifying the
process of enrolment. Any UK site that had the treatments could join the trial. Any
suitable healthcare professional who completed the online training could enrol patients.
Paperwork typically associated with the set-up of RCTs in the UK, such as delegation logs,
was not required. The patient information and consent form are contained in a single
five-page document that is printed on demand from the trial website to ensure that the
latest version is used, a necessity given the frequency of changes in such a trial.
Digitalising the randomisation process allowed it to be both rapid and convenient with the
ability to do so on a ward-based computer. Follow-up reporting was equally simplified,
utilising the prepared one-page reporting form that was linked with NHS datasets; this later
linkage reduced redundant data input, thereby adding to its overall efficiency by design.
The RECOVERY trial began as a simple randomisation to one of four treatment arms or
standard care (control). It then evolved into a factorial design with multiple
randomisations. Such a fundamental structural change would be difficult to implement in a
more conventional trial, but the “online” nature of this trial allowed this transition at a very
busy time for all trial sites. This inherent flexibility of the adaptive platform trials allowed
treatments to be added or removed according to real-time data analysis. This is a key
distinguishing feature when compared with conventional trials.
While the RECOVERY trial evolved into a factorial design where two or more treatments
can be given simultaneously, this design was inherent in the REMAP-CAP trial, which had
a multifactorial statistical model comparing multiple interventions across multiple patient
subgroups [31]. This multifactorial design mirrors the nature of community-acquired
pneumonia management in the ICU, where multiple simultaneous therapies are
implemented to combat the microbe and support vital organs.
Of the adaptive trials, the design of REMAP-CAP is perhaps the most complex but also the
most innovative. It is, in fact, the only example of a trial that was present before and adapted to
the pandemic. Indeed, it was designed to persist beyond the pandemic as a perpetual platform
trial infrastructure from its PERPARE consortium origins. The generic study protocol and
Bayesian statistical analysis allowed the active trial to be influenced by simulation algorithms
(Monte Carlo simulations), a technique incorporated from other industries that recognises the
need for many responses to a changing situation. This structure was pandemic ready, and the
advent of COVID-19 prompted the addition of new treatment domains in the trial.
https://doi.org/10.1183/2312508X.10005521 219
220

Table 2. Adaptive RCTs conducted during the COVID-19 pandemic
Trial Design Setting Sites Interventions Comparator Primary outcome
RECOVERY Randomised adaptive Hospital, 177, UK Hydroxychloroquine, SoC Mortality within 28 days
[13, 17, 42, 56]# multi-arm, and adult and dexamethasone,
multistage, then paediatric lopinavir-ritonavir, azithromycin,
multifactorial convalescent plasma,
tocilizumab, colchicine, aspirin,
baricitinib, REGEN-COV2
REMAP-CAP Randomised ICU >200, Antiviral domain, antibiotic ICU (organ support)-free days
[32, 45]¶ multifactorial adaptive international domain, macrolide domain, up to day 21: superiority,
platform trial corticosteroid domain, immune inferiority and equivalence
modulatory domain, ventilation
domain
PRINCIPLE [46] Adaptive platform RCT Primary >100, UK Azithromycin, doxycycline, SoC Hospital admission or mortality
care inhaled budesonide (28 days)
ATTACC+ Pragmatic, Bayesian Hospital 58, LMWH, UFH; both at SoC Mortality and days free of organ
adaptive RCT international therapeutic dose support (time frame: 21 days)
§
ACTIV-4 Adaptive, randomised Hospital 60, USA and Prophylactic dose: LMWH, UFH; 21-day organ support
controlled platform trial Spain treatment dose: LMWH, UFH (respiratory or
±P2Y12 inhibitor vasopressor)-free days
SOLIDARITYƒ Adaptive, open-label Hospital 50, Remdesivir, hydroxychloroquine, SoC Clinical status (7-point ordinal
RCT international lopinavir and IFN-β1a scale) at day 15
https://doi.org/10.1183/2312508X.10005521
DISCOVERY [57] Adaptive, open-label, Hospital 52, Western Remdesivir, hydroxychloroquine, SoC Clinical status (7-point ordinal
phase 3 RCT Europe lopinavir and IFN-β1a scale) at day 15
ACTT-1 [58] Adaptive, double-blind, Hospital >100, Remdesivir Placebo Time to recovery on ordinal
placebo-controlled RCT international scale (1–29 days)
ACTT-2 [59] Adaptive, double-blind, Hospital >100, Remdesivir, baricitinib Placebo Time to recovery on ordinal
placebo-controlled RCT international +remdesivir scale (1–29 days)
ACTT-3## Adaptive, double-blind, Hospital >100, Remdesivir, IFN-β1a+remdesivir Placebo Time to recovery on ordinal
placebo-controlled RCT international scale (1–29 days)
TACTIC-R [60] Randomised, Hospital Multisite, UK Ravulizumab, baricitinib SoC Time to incidence of the
parallel-arm, (pre-ICU) composite end-point of: death,
open-label platform mechanical ventilation, ECMO,
trial cardiovascular organ support or
renal failure (time frame: up to
day 14)
Continued
https://doi.org/10.1183/2312508X.10005521
Table 2. Continued
Trial Design Setting Sites Interventions Comparator Primary outcome
TACTIC-E [61] Randomised, Hospital Multisite, UK EDP1815, dapagliflozin SoC Time to incidence of the
parallel-arm, (pre-ICU) +ambrisentan, composite end-point of: death,
open-label platform mechanical ventilation, ECMO,
trial cardiovascular organ support or
renal failure (time frame: up to
day 14)
ACCORD [62] Adaptive, open-label, Hospital Multisite, UK Bemcentinib, MEDI3506, SoC Time to clinical improvement on
RCT platform trial acalabrutinib, zilucoplan and WHO scale (29 days)
nebulised heparin
CATALYST [63] Open-label, Bayesian, Hospital Multisite, UK Namilumab, infliximab SoC CRP concentration
adaptive multifactorial
RCT

CORIMUNO Open-label, Bayesian Hospital Multisite, Tocilizumab, sarilumab, anakinra SoC WHO Clinical Progression Scale
[64, 65] RCT France and eculizumab
RECOVERY: Randomised evaluation of COVID-19 therapy trial; REMAP-CAP: Randomized embedded multifactorial adaptive platform for
community-acquired pneumonia; PRINCIPLE: Platform randomised trial of treatments in the community for epidemic and pandemic illnesses;
ATTACC: Antithrombotic therapy to ameliorate complications of COVID-19 trial; ACTIV-4: Anti-thrombotics for adults hospitalized with COVID-19;
SOLIDARITY: WHO Public Health Emergency “Solidarity” Clinical Trial for COVID-19 Treatments; DISCOVERY: Multi-centre, adaptive, randomized trial
of the safety and efficacy of treatments of COVID-19 in hospitalized adults; ACTT: Adaptive COVID-19 treatment trial; TACTIC-R: Multi-arm therapeutic
study in pre-ICU patients admitted with Covid-19 – repurposed drugs; TACTIC-E: Multi-arm therapeutic study in pre-ICU patients admitted with
Covid-19 – experimental drugs and mechanisms; ACCORD: A multicentre, seamless, phase 2 adaptive randomisation platform study to assess the
efficacy and safety of multiple candidate agents for the treatment of COVID 19 in hospitalised patients; CATALYST: A randomised phase II proof of
principle multi-arm multi-stage trial designed to guide the selection of interventions for phase III trials in hospitalised patients with COVID-19
infection; CORIMUNO: Cohort multiple randomized controlled trials open-label of immune modulatory drugs and other treatments; REGEN-COV2:
casirivimab and imdevimab; SoC: standard of care; UFH: unfractionated heparin; ECMO: extracorporeal membrane oxygenation. #: Clinicaltrials.gov
identifier NCT04381936; ¶: Clinicaltrials.gov identifier NCT02735707; +: Clinicaltrials.gov identifier NCT04372589; §: Clinicaltrials.gov identifier
NCT04505774; ƒ: Clinicaltrials.gov identifier NCT04647669; ##: Clinicaltrials.gov identifier NCT04492475.
221
The embedded nature of REMAP-CAP allowed all new severe COVID-19 pneumonia
patients to be enrolled into the trial on admission to the ICU (clinical “point of care”).
Probabilities from the Bayesian inference model allowed treatments to be randomly
assigned to patients according to what appeared most favourable at that time point. It also
collaborated with two other international trials, ATTACC (Antithrombotic therapy to
ameliorate complications of COVID-19, ClinicalTrials.gov identifier NCT04372589) and
ACTIV-4 (Anti-thrombotics for adults hospitalized with COVID-19, ClinicalTrials.gov
identifier NCT04505774), investing the effects of anticoagulation by harmonising key
aspects of the protocol design and statistical analysis. The combined interim analysis of the
anticoagulation domain of REMAP-CAP and the two embedded trials were released in a
preliminary form in December 2020 and suggested divergent results in the severe (futile
with high probability of inferiority/harm) versus moderate (superiority) states. These data
have not yet been peer reviewed but demonstrate the potential for combining data from
multiple trials prospectively to increase power [66].
Steroids are now used as standard practice since the reporting of the dexamethasone arm
results in RECOVERY [13]. Results from the steroid domain in REMAP-CAP later
supported this finding, as have smaller trials [32, 67, 68]. In addition to the consistent
results for corticosteroid use, both trials also suggested a treatment benefit for the use of
IL-6 receptor antagonists in severe COVID-19 [45, 69]. The RECOVERY trial most
recently reported that the monoclonal antibody combination of casirivimab and
imdevimab (REGEN-COV) reduced 28-day mortality among patients who were
seronegative at baseline [70].
The CORIMUNO (Cohort multiple randomized controlled trials open-label of immune

modulatory drugs and other treatments) consortium was set up in France at the
beginning of its COVID-19 epidemic. Resulting CORIMUNO platform trials have several
design features that distinguish them from other platform trials. A large cohort was
consented to potentially participate in any one of multiple RCTs that were testing
immunomodulation therapies in COVID-19 (they would then re-consent for the specific
trial after random selection). This design facilitated the rapid testing of several
immunomodulating therapies, and each trial had a target sample size in contrast to other
large Bayesian adaptive trials. It also had outcomes more similar to phase 2 trials because
the stated objective of CORIMUNO trials was to advance “successful” drugs into larger
trials that would more robustly test their efficacy. In the CORIMUNO-TOC trial,
tocilizumab did not reduce the WHO 10-point Clinical Progression Scale scores lower
than 5 at day 4 [71], but a post-hoc analysis selecting patients with higher CRP did show
a mortality benefit in keeping with the results from RECOVERY and REMAP-CAP [64].
The CORIMUNO-ANA-1 trial reported a lack of benefit for anakinra in patients with
mild-to-moderate COVID-19 pneumonia [65]. Results of the other trials from the
CORIMUNO consortium are awaiting publication.
The third large adaptive trial initially prioritised by NIHR, and the only RCT investigating
treatments in a primary care setting in the UK, is the PRINCIPLE trial [46]. The story so
far with this trial has been one of excluding ineffective therapies, something that platform
trials will tend to do at a high cost, as we shall discuss. Recruiting patients for
azithromycin and doxycycline was stopped in January 2021 after an interim analysis
concluded clinically meaningful benefit from either treatment. This trial recently reported
that inhaled budesonide did not reduce the risk of hospitalisation but may have increased
the rate of recovery.
222 https://doi.org/10.1183/2312508X.10005521
The SOLIDARITY trial was the largest multinational adaptive platform trial that was
conducted in the hospital setting. This was an open-label adaptive RCT that recruited
patients at 50 sites internationally. The trial published its interim results in February 2021,
concluding that all of the interventions studied (remdesivir, hydroxychloroquine, lopinavir
and IFN-β1a) had little or no effect on hospitalised patients with COVID-19 [55].
ACTT-1 (Adaptive COVID-19 treatment trial) is an example of an adaptive phase 2 RCT

that otherwise had a more traditional design, being placebo controlled and double blind. This
trial compared remdesivir with placebo in a 1/1 allocation and met both its primary and
main secondary outcomes, suggesting that remdesivir shortens time to recovery and improves
clinical status on day 15 in hospitalised patients with COVID-19 [58]. The conflicting
evidence on the efficacy of remdesivir that this trial has created with respect to SOLIDARITY
has generated a legitimate difference of opinion regarding its use in hospitalised COVID-19
patients, and the recent European Respiratory Society (ERS) guidance has refrained from
making a positive or negative recommendation regarding its use [39].
Do conventional trial designs still have a role?
We refer to nonplatform/nonadaptive clinical trials performed during the pandemic as

conventional, a choice of nomenclature influenced by the innovative and novel design
aspects of an adaptive platform trial.
Despite the disruption to normal life caused by the pandemic, the last 12 months have seen
a massive increase in the number of registered clinical trials globally. Most of these trials
have conventional designs, testing a single drug in an open-label or blinded fashion, often
with surrogate end-points, although many utilise the WHO ordinal scale as a primary
end-point [68, 71–73].
By design, platform trial protocols are purposefully generic and are ready to test any therapy
(table 1). However, the limited safety monitoring restricts the large platform trials to
investigating repurposed drugs that have a known safety and tolerability profile. This limitation
results in a paradox that is not initially obvious when considering the apparent efficiency of
these trial designs, namely that the platform trials are liable to trial many ineffective
treatments at the cost of spending valuable resources and time during the pandemic.
Indeed, of all the repurposed treatments trialled on thousands of patients, we currently only
have two therapies recommended in the current ERS COVID-19 guidelines [39].
Considering the overlap in therapies studied in the platform trial, this represents multiple
large investments with diminishing returns.
Overall, clinical trials will mostly exclude ineffective therapies, but small-scale, conventional
or pragmatic trials may be a less costly and more effective method of doing this [74]. A
novel agent investigated in a conventional phase 2 clinical trial will undergo robust safety
monitoring, with a clinical trial team on site offering more standardised patient follow-up.
Large pragmatic platform trials are not designed to evaluate the efficacy and safety of novel
agents, which is the role of phase 1 and phase 2 trials. Such trials typically include smaller
numbers of patients with detailed capture of safety data, close monitoring, and biosampling
to look at pharmacokinetics, pharmacodynamics and effects on target pathways of interest.
https://doi.org/10.1183/2312508X.10005521 223
Phase 2 trials are needed to progress a therapy to be investigated in a larger conventional

phase 3 trial, and in a similar way, conventional phase 2 trials can prioritise therapies for
the adaptive platform trials [62, 63, 74]. Again, in the field of phase 2 trials, we have seen
innovation during the COVID-19 pandemic with phase 2 platform trials that are very
different in design to studies such as RECOVERY but nevertheless utilise the concept of
streamlining designs and efficient use of trial subjects. The ACCORD (Accelerating
COVID-19 research and development) platform [62] in the UK is one example of a
phase 2 platform for hospitalised patients with COVID-19. This novel design evaluated
multiple agents simultaneously (bemcentinib, MEDI3506, acalabrutinib, zilucoplan and
nebulised heparin) against a single standard-of-care control arm. By not requiring each
drug to have an equally sized standard-of-care arm, more patients can receive active
treatment and trials reach results more quickly. A two-stage process of testing was used
with an initial 60 patients in stage 1, with drugs progressing to a second stage if they
showed evidence of efficacy and acceptable safety, with a larger sample size used in stage
2. Other platforms that could similarly add and remove drugs when shown to be ineffective
have been launched and illustrate innovation in trial designs even where it is not possible
to have the same level of pragmatism as was demonstrated for trials like RECOVERY.
Most drugs entering large platforms such as RECOVERY and SOLIDARITY are
repurposed therapies or therapies that were already widely used in different parts of the
world “off label”. There was therefore no requirement to carefully evaluate the safety, and
pragmatic designs were appropriate. As fewer drugs become available that are
“repurposable”, it is likely that phase 2 trials will become increasingly important, with
drugs specifically designed to combat COVID-19 becoming available [75]. As we hope
vaccination reduces the prevalence of the disease globally, it will be more and more
important to carefully select which medications go forward into large platform trials.
Establishing the safety of novel interventions before they are given to large populations is a
key role of phase 2 trials and therefore most new drugs moving into platforms in the future
are likely to have had their safety established in phase 2 trials.
The counterargument to the insistence of conducting a phase 2 trial first is that smaller
conventional trials are at greater risk of either a type 1 (identifying a treatment effect that
does not exist) or type 2 (missing a treatment effect that is present) error. An example of
this type 2 error handicap was evident with the conventional studies that investigated the
IL-6 antagonist tocilizumab during the pandemic [45, 71–73, 76, 77]. Smaller studies
provided inconsistent results regarding the efficacy of tocilizumab. In contrast, RECOVERY
and REMAP-CAP were consistent in reporting a benefit with regard to survival and
organ-support-free days, respectively. It is indeed plausible that tocilizumab would have
been disregarded if decisions were based on some small RCTs [45, 78].
How the evidence has been conveyed
The COVID-19 pandemic is unique as the first global pandemic of the modern internet age.
It became the practice of governments to conduct daily televised briefings alongside senior
medical and science advisers. Every element of society was affected, and the demand for
information was persistent. This heightened demand could not be supplied by the prolonged
process of a peer-reviewed publication. In this way, the COVID-19 pandemic accelerated a
change in how clinical trials are reported. For good or bad, the change in the way science is
reported has major implications. Major trials would first report their results as a press
224 https://doi.org/10.1183/2312508X.10005521
release that would predominantly be consumed with little scrutiny by the lay general public.
Press releases are usually followed by non-peer-reviewed publications referred to as preprints.
Prior to COVID-19 accelerating this change in reporting, clinical practice would usually be
influenced en masse after a peer-reviewed publication. During the pandemic, clinical
practice undoubtedly changed in response to press releases and preprints, and in some cases
unscrutinised publicity through various media platforms impacted practice.
The practice-changing result of dexamethasone reducing mortality (RECOVERY) was first

reported through the RECOVERY trial website and then by the British prime minister and
his senior scientific and medical advisers. After the results were reported, an immediate
recommendation was given to implement its results. The subsequent peer-reviewed
publication emerged several months later, by which time dexamethasone was already
standard practice for oxygen-dependent patients [13].
This new process of trial reporting could in some instances become problematic, especially
for trial instigators eager to publish their positive results to a public desperate for good
news. The COLCORONA (Colchicine coronavirus SARS-CoV2 trial, ClinicalTrials.gov
identifier NCT04322682) trial investigated colchicine use in prehospitalised COVID-19
patients and reported via a press release on 23 January 2021 that “colchicine reduces the
risk of COVID-19-related complications” [79]. This positive news circulated rapidly, as
expected, through social media networks. The press release was followed by the preprint
version of their paper, which was published 4 days later [80]. The preprint revealed that
this trial was in fact stopped early (75% of planned enrolment) due to the perceived need
by the investigators to rapidly disseminate a positive signal from the study. The primary
end-point of death or hospitalisation occurred less in the colchicine group, but this effect
did not reach statistical significance (OR 0.79; 95.1% CI 0.61–1.03; p=0.08). Most
commentators interpreted this as an equivocal result that was required to be replicated in a
future trial. In a hospitalised population, the RECOVERY trial closed its colchicine arm on
5 March 2021 after reporting no benefit with respect to mortality in an analysis that
included more than double the number of patients as the COLCORONA trial. It has
previously been reported that clinical trials stopped early for benefit typically overestimate
the beneficial effects of treatments and lead to further trials needing to be performed that
often do not confirm benefit [81]. COLCORONA appears to be an example of this, with
the added complexity that clear benefit had been reported via a press release. There is as
yet no evidence of whether this influenced prescribing decisions.
The RECOVERY and COLCORONA examples represent good case studies of the benefits
and risks of rapid dissemination of data. Implementing the RECOVERY findings prior to
publication undoubtedly saved lives, while implementing COLCORONA results into
clinical practice would have been inappropriate.
Figure 1 shows a simplified model that summarises pre- and post-pandemic research
structure in terms of both the selection of treatments moving into large-scale randomised
trials and the dissemination of these results.
Unique challenges and ethical considerations
The pandemic disrupted normal life for patients and clinical trial teams alike. Infection risk
to clinical staff was increased, even with an adequate PPE supply [82–84]. The nature of
https://doi.org/10.1183/2312508X.10005521 225
Pre-pandemic research Pandemic research
Preclinical/phase 1 Preclinical/phase 1 Theoretical Phase 2
Phase 2
Adapted phase 3 platform
Phase 3 DBPCT
Dissemination in Preprint
peer-reviewed journal dissemination
Guidelines and
implementation into
clinical practice
Figure 1. Pre- and post-pandemic research structure. DBPCT: double-blind placebo-controlled trial.
the exponential infection rate and its rapid decrease after lockdown measures took effect
created a limited window of opportunity in which treatments could be trialled [72]. Indeed,
many trials were only able to conclude their enrolment after a second wave of infection.
There was little time to train new staff, and trained staff were often needed on the front line
in routine clinical work as the pressure on health services intensified. This sometimes
resulted in the default reliance on “free workers” or clinical staff who also undertook the
extra unpaid role as clinical trialists. Platform trials such as RECOVERY allowed clinicians
with no previous experience of research to incorporate clinical trial conduct into their daily
work by simplifying and pragmatising the training, consent process and data entry.
Patients are the focus of clinical trials, and the patient’s perspective raises further ethical
considerations [85]. Patients were asked to consent to an experimental treatment to combat a
disease that was not completely understood. Informed consent is challenging in acutely
unwell individuals and is made even more challenging when wearing full PPE in highly
controlled environments. Many patients were simply too unwell to consent in the first place,
thereby transferring the burden of decision onto their relatives. In open-label studies, patients
were given standard of care when many would have wanted to receive a trial therapy.
The normally prolonged process of grant application and trial funding had to be
accelerated. This urgent process required government resources, and the funding allocation
was managed centrally in many European countries as part of their emergency public
health response. Rapid funding and regulatory approval of trials needs to be balanced by
maintaining the same standards of oversight and ensuring the safety of participants. A key
challenge when there are so many possible therapies to test is who decides which
medications will be tested in platform trials. At the individual hospital level, how does an
individual hospital or healthcare provider decide which of thousands of potential trials
should be offered to their patients? Many healthcare systems established expert panels to
prioritise treatments, while individual hospitals also established groups to decide which
226 https://doi.org/10.1183/2312508X.10005521
trials should be prioritised locally. The major platform trials relied on the collaboration of
thousands of healthcare workers and the participation of tens of thousands of patients who,
although fundamental in implementing the trials, had no influence on which treatments
were selected for investigation in these adaptive platforms.
It should also be noted that lockdown restrictions globally and the redeployment of
research resources towards the pandemic is likely to have had a disruptive impact on
non-COVID-19-related research for years to come [86, 87]. Many trials were suspended or
terminated, and research programmes were severely impacted. Research into conditions
other than COVID-19 remains important, and in future it will be very important to achieve
a balance between COVID-19- and non-COVID-19-related research.
A “new normal” for clinical trials
COVID-19 has tested our current research models and practices. The innovation of the
adaptive platform trials has disrupted an otherwise slowly changing clinical trial
framework. With the massive, coordinated clinical trial effort over the past year, we are
now at a vantage point from which to reflect on which trial features worked best to more
efficiently and effectively achieve reliable clinical evidence.
There is no reason why the advantages provided by large-scale pragmatic trial designs would
disappear when the pandemic ends where COVID-19 may become endemic. A pipeline of
treatments going forward will be required. In much the same way as a transport
infrastructure requires small roads to feed into medium roads and then into motorways, we
may need small studies to prove concepts that are tested for indications of efficacy in
medium-sized trials that are then validated in “mega-trials” recruiting thousands of patients.
The therapeutic breakthroughs of the platform trials must not distract us from the
importance of smaller-scale studies that guide selection of drugs for human trials. The
experience of hydroxychloroquine has recently been highlighted when XU and CAO [88]
pointed out that preclinical data that arose during the pandemic would have clearly
predicted the absence of benefit, but trials had already been initiated before such preclinical
data was available. The higher level of research collaboration seen over the past year must
also be carried forward as we move towards a more productive research infrastructure.
Many trials allowed for co-enrolment in other trials, thus offering patients multiple
potential treatment options. Some trials harmonised their trial structure and statistical
analysis plan to increase the power of their results [89]. There is still much room for
improvement, and the degree of overlap in treatments trialled could have been avoided with
a more collaborated approach.
REMAP-CAP was set up as a “perpetual” trial and is essentially a platform in which

clinical practice is monitored and outcomes are analysed to inform better practice. The
question we should ask is why interventions for other heterogeneous diseases should not be
assessed in a similar fashion.
To illustrate this concept, we could take the example of bronchiectasis, a complex

heterogeneous chronic disease [90, 91]. Bronchiectasis patients are treated with multimodal
therapies in the real world, despite none having been proved efficacious to the standards
required for licensing. Nevertheless, therapies have gone through trials and at all phases
https://doi.org/10.1183/2312508X.10005521 227
have passed the reassuring milestones in safety and efficacy for them to be recommended
in international guidance [92]. An adaptive platform trial investigating all these therapies in
current clinical practice could provide us with the necessary evidence required for licensing.
Similar approaches could be taken for any drug X in any disease Y, and in such a way the
experience of the COVID-19 era platform trial innovation could become embedded into
our current research framework. Although there are many strengths to the adaptive trial
designs, regulatory standards and approval criteria are most centred around the results of
conventional phase 3 trials, and it remains to be seen how regulators will interpret results
from adaptive design trials.
Notwithstanding the extraordinary challenges, the past year in clinical trials has saved
thousands of lives. We are encouraged by the collaboration witnessed during this pandemic
but also see an urgent need for this collaboration to be fortified within individual countries
and expanded to encompass countries that do not currently have a mature pandemic
preparedness platform. If we continue to collaborate, modernise and refine the way we
conduct research, we are set to convert what has been a painful recent past into a much
brighter future for our patients.
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Disclosures: H. Abo-Leyah has nothing to declare. J.D. Chalmers reports receiving the following, outside the
submitted work: grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis,
Insmed and Grifols; personal fees from Chiesi, Janssen and Zambon; and grants from Gilead Sciences.
https://doi.org/10.1183/2312508X.10005521 231
| Chapter 14
Economic, physical and social
determinants of health during
lockdown: a call for renewed
societal responses
Leanna M.W. Lui1,2, Yena Lee1,2 and Roger S. McIntyre1,2,3,4,5
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 [https://doi.org/10.1183/2312508X.
10024720].
@ERSpublications
SARS-CoV-2, the cause of the COVID-19 pandemic, is a socially transmitted virus that
should be approached from an economic, biological and social perspective https://bit.ly/
3sYBXEZ
T he COVID-19 pandemic is an unprecedented global public health crisis across high-,

middle- and low-income countries. Government and public health responses to reduce
virus transmission have resulted in global lockdown policies of varying stringency (e.g.
physical distancing measures, school and daycare closures, travel/stay-at-home warnings) [1].
1
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada. 2Institute of Medical Science, University
of Toronto, Toronto, ON, Canada. 3Dept of Psychiatry, University of Toronto, Toronto, ON, Canada. 4Dept of Pharmacology, University
of Toronto, Toronto, ON, Canada. 5Brain and Cognition Discovery Foundation, Toronto, ON, Canada.
Correspondence: Roger McIntyre (roger.mcintyre@uhn.ca)
232 https://doi.org/10.1183/2312508X.10024720
SOCIETAL RESPONSE | L.M.W. LUI ET AL.
While early and population-wide lockdown policies may be effective at limiting the spread
of the virus during the early inception of transmission, prolonged quarantine measures
have been reported to result in compounding multiplicative consequences, leading to the
deterioration of economic, physical and mental health [1]. Taken together, the COVID-19
pandemic should be conceptualised as a syndemic with respect to its impact as an
economic, population health and mental health crisis [2].
Economic crisis
Global economic impact of the pandemic
In October 2020, the International Monetary Fund projected an ∼4% contraction of gross
domestic product (GDP) across high-, middle- and low-income countries. The World Bank
projected a 7% decrease in per capita income for high-income countries, and a 2.5%
contraction for low- and middle-income countries [3]. More specifically, the World Bank
reported a decrease of −2.7% in GDP for South Asia, −2.8% for sub-Saharan Africa, −4.2%
for the Middle East and North Africa, −4.7% for Europe and Central Asia and −7.2% for
Latin America, and 0.5% growth for East Asia and the Pacific [3].
As a result of international lockdown regulations, disruptions in global trade and supply

linkages have significantly affected the production, consumption and trade of goods and
services [4]. For example, the World Trade Organization forecasted a 9.2% decrease in
global merchandise trade for 2020 [5], and in October 2020, the International Finance
Corporation reported a decrease in merchandise imports and exports for all regions in 2020
[4]. Net export reductions result in decreased foreign exchange availability and further debt
service pressures [4]. Conversely, net import reductions may reduce the availability of
important, life-sustaining goods [4]. Hitherto, downward pressures on trade have created
considerable challenges for managing economic health.
Gendered effect in the economy
Previous recessions impacted sectors that were cyclical in nature, which had a pronounced
effect on male unemployment [6]. However, the current crisis is unique insofar as it has
differentially affected the manufacturing and service sector, which comprises a greater
proportion of female employees [6]. Accordingly, females in these economies are less likely
to be employed in occupations that offer remote working options and are more likely to
retain positions lower on the production ladder [7]. Consequently, the aggregate effects of
destabilised global supply chains and lower consumer confidence, as well as vulnerabilities
related to the informal employment sector, have increased unemployment risk especially
for females during this time of economic contraction [7]. For example, 80% of the
garment production workforce in Bangladesh is represented by female employees [8].
Restrictions in global supply chains resulted in a 45.8% decrease in production during the
first quarter of 2020 [8].
Female migrants or females in developing economies are also less likely to have access to
technology and information technology skills necessary for teleworking and e-commerce
opportunities, which have become critical assets for the current employment landscape [7].
Additionally, those who have not obtained a formal education are likely to be predisposed
to poor working conditions and affected by low social protections (e.g. lack of
https://doi.org/10.1183/2312508X.10024720 233
unemployment and healthcare insurance) [9]. For example, a study surveying paid
domestic workers (PDWs) in Peru reported an 86% decline in employment, but only 5% of
this population reported receiving government salary support [10]. While the government
implemented two subsidy programmes to supplement lost income for vulnerable workers,
this programme did not include PDWs. Additionally, the legal rights of PDWs were
ignored due to lack of legal protections.
Females who own or manage a business tend to own firms that are categorised as micro-,
small- and medium-sized enterprises [7]. The effects of limited financial resources available
for these types of enterprise and economic shocks as a result of the pandemic are likely to
be significant drivers of unemployment and bankruptcy [7].
The pandemic has also reinforced the role of females in the “care economy” (e.g. childcare,
provision of the elderly) [11]. Prior to the pandemic, females were responsible for a greater
share of domestic labour compared with males (4.1 versus 1.7 h·day−1, respectively) [11].
However, the onset of the pandemic combined with the subsequent shutdown of schools,
as well as closure and/or reduction of childcare services and support for the elderly, have
increased the burden of unpaid care work for females [11].
To that effect, the combination of added familial responsibility and workplace obligations
have had a negative and measurable impact on female participation in the paid economy
[11]. For example, a study in the USA reporting on the impact of gender inequality during
the pandemic suggested a relationship between decreased occupational flexibility and rising
female unemployment [11]. Accordingly, the conflicting responsibilities of the care
economy and paid economy may cause difficulties in maintaining their employment status
and/or result in furloughing of promotions.
A broad range of financial measures have been enforced to support individuals and
businesses, albeit not all provisions are gender specific [7]. For example, select countries
have enforced regulations to prohibit layoffs during complete and/or partial lockdowns,
which have included industries with a high rate of female employment [7]. Additionally,
some governments have offered stimulus packages in export-related industries [7].
However, in addition to these general measures, gender-sensitive policies targeting fiscal

recovery as well as female participation in economic activity across and within high-, middle-
and low-income countries should be established [7]. For example, implementing a cash transfer
programme, providing food vouchers and paid sick leave as well as childcare subsidies, and
creating opportunities for digital technology education and teleworking may lead to long-term
gender-inclusive growth [7]. Restoring and building female participation in the economy during
the post-pandemic era through economic, legal and social reforms is key to reducing barriers to
entry into the workforce, as well as building resilience in the recovery period [7].
During the current pandemic, an increase in domestic violence prevalence and/or severity
has been emphasised as a public health concern [12]. A recent study reported on evidence
related to a change in domestic violence risk classification [13]. For example, an exploratory
analysis of police referrals (n=2292) related to domestic abuse of adult women before and
during lockdown in South Wales, UK, reported an increased proportion of high-risk cases
among domestic abuse referrals [13]. In this study, researchers did not identify a significant
increase in the number of police referrals; however, they indicated a notable increase in the
prevalence of high-risk cases from ∼33% prior to lockdown (December 2019–February 2020)
234 https://doi.org/10.1183/2312508X.10024720
to an increase of ∼50% classification during lockdown, where this level remained above
baseline during the pandemic observation period (March 2020–July 2020) [13]. However,
data reporting on the prevalence of domestic abuse are complicated by several factors
including, but not limited to, decreased opportunity to utilise support services and
helplines, which may serve as proxies for domestic abuse data [13].
In an online cross-sectional study of Iranian women (n=203) between May and June 2020,
researchers reported an increase in domestic violence [14]. Prior to the COVID-19
pandemic, domestic abuse against females in Iran was a significant public health concern
[15]. Consequently, quarantine measures enacted during the lockdown have aggravated this
concern (e.g. increased marital conflicts and disagreements). Data reporting on domestic
violence against females are limited for several reasons, which include, but are not limited
to, cultural values, distrust of health officials and financial dependence on their spouses.
Risk factors identified for domestic abuse in this study align with previously reported
literature (e.g. unemployment, life stress, lower education) [14].
Taken together, the COVID-19 pandemic has aggravated the social and economic
vulnerabilities of females. There is a need for governments to adopt broad protection initiatives
such as formal education opportunities, digital literacy programmes, legal rights, income
support and business subsidies to promote financial independence and economic recovery.
Mental health crisis
Increase in suicide
Financial security is a key mediator of mental health during economic downturn. Notably,
macroeconomic indicators (e.g. employment status) are important indicators of suicide risk
[16, 17]. For example, a projection analysis of suicide mortality in Canada reported a
significant relationship between unemployment and excess suicide, wherein a percentage
point increase in unemployment was associated with a 1.0% increase in suicide [17].
Unexpected and abrupt changes in economic insecurity diminish timely utilisation of
quality healthcare services (e.g. loss of health benefits, less disposable income for healthcare
services) [18–20].
A recent cross-sectional study evaluating suicide mortality in Canada during the pandemic
reported a decrease in suicide rates during the first post-pandemic interval (March 2020–
February 2021) [21]. It is hypothesised that this decrease is related to government support
measures (e.g. financial subsidies, increased emergency childcare funding) [21]. However,
the data used to report the foregoing results are provisional and may not accurately capture
true suicide mortality data [21].
A study reporting on suicide mortality data during the pandemic in Japan presages the
potential effect of time and government provisions on trends in suicide rates [22].
Researchers reported an increase in suicide in Japan during the second wave ( July–October
2020) of the pandemic, which followed an initial decline (14%) during the first wave of the
pandemic (February–June 2020) [22]. Several potential mechanisms may belie the initial
decline in suicide rates during the first wave of the pandemic, which include government
subsidies to individuals and businesses, and reduced working hours (high working hours
have historically been known as risk factors for suicide in Japan) [22].
https://doi.org/10.1183/2312508X.10024720 235
Moreover, researchers indicated that the effects of the pandemic on suicide rates were more
pronounced in select populations, and the current observations do not align with previous
suicide data. For example, female suicide rates were five times greater than male suicide
rates during the second wave of the pandemic, which was accompanied by the observation
of a specific increase among housewives [22]. Taken together, the compounding effects of
financial insecurity and unpaid work, as well as an increased incidence of domestic
violence, are key factors mediating the risk of suicide among females (and working
mothers) during the pandemic [22–25].
Loneliness epidemic magnified by the pandemic
Prolonged quarantine and lockdown measures have worsened the loneliness epidemic [26].
For example, social distancing and isolation policies have probably had nuanced effects on
physical and mental health [27]. While these measures have been implemented to reduce
virus transmission, they have also resulted in a maladaptive stress response leading to
increased anxiety, depression and loneliness [28, 29].
Loneliness during the pandemic has pronounced effects on students and older adults in
long-term care (LTC) facilities [30–32]. For example, school closures and the transition to
virtual learning have decreased the amount of social interaction among students, and
have increased emotional stress and loneliness, which are contributing factors to
increased suicide risk [32]. Moreover, individuals in LTC facilities have accounted for a
majority of COVID-19 deaths [33]. In addition to their heightened vulnerability of
infection, they are at risk for adverse mental health outcomes [31]. The direct risks related
to concerns about contraction of and mortality from the virus, as well as indirect risks of
adverse mental health outcomes (e.g. loneliness, depression, anxiety and cognitive decline),
have been identified as risk factors exacerbating the mental well-being of individuals in
LTC facilities [31].
To reduce and/or mitigate the effects of loneliness and psychological distress among
individuals in LTC facilities, LTC staff should increase social engagement through virtual
community befriending volunteer programmes and video calls with family members and
friends, as well as integrating self-guided psychological therapies [34]. However, critical to
the implementation of these programmes are the funds to purchase and integrate digital
technologies in LTC facilities, education of practice guidelines for telepsychology,
improvement of digital literacy of LTC residents and staff, and cooperation of LTC staff to
ensure safe monitoring, as well as respect of privacy and autonomy, of digital
communication strategies [34].
Intersection between depression and COVID-19 infection
Available evidence indicates that individuals with mental illness are at greater risk of
infection and severe virus-related outcomes [35]. For example, they may have difficulty
complying and incorporating preventative behaviours into their daily routines [36].
In addition, their living environment may not allow them to practice physical distancing
and protective behaviours (e.g. crowded hospitals, residences) [37]. Furthermore, individuals
with serious mental illness are often socioeconomically disadvantaged [35]. This result may
cause them to work in unsafe environments or create unstable housing situations, as well as
severely reduce their access to health professionals.
236 https://doi.org/10.1183/2312508X.10024720
The literature indicates an overlapping biological phenomenon between COVID-19 and

depression [37, 38]. Psychiatric consequences of infection are hypothesised to be the result
of an immune response to the virus and/or the trigger of psychological stressors [37].
COVID-19 induces an immune response with local and systemic production of
inflammatory biomarkers (a “cytokine storm”) [37]. Specifically, COVID-19 in patients
triggers cytokine dysregulation, notably of IL-1β, IL-6, IL-10, IFN-γ and TNF-α, as well as
transforming growth factor-β, all of which are associated with the presence of psychiatric
disorders [37]. To date, the literature suggests that neuroinflammation caused by the
infection, as well as stress-associated inflammation, triggers the onset of mental illness [37].
In a 1-month follow-up study investigating 402 adults who survived COVID-19,
researchers found that a significant proportion of survivors were diagnosed with a mental
illness (28% for PTSD, 31% for depression, 42% for anxiety, 20% for obsessive compulsive
symptoms and 40% for insomnia) [37].
There are several factors that may contribute to this phenomenon. Individuals with severe
mental illness are likely to be immunocompromised as a result of medical comorbidities
(e.g. cardiovascular disease, obesity, diabetes) [36]. Consequently, they are also more likely
to experience a severe illness trajectory. For example, an analysis of 61 million adult patient
electronic health records in the USA reported that individuals with depression (adjusted
OR 7.64, 95% CI 7.45–7.83; p<0.001) or schizophrenia (adjusted OR 7.34, 95% CI 6.65–
8.10; p<0.001) had the greatest risk for infection [35]. In addition, individuals with a mood
disorder who were diagnosed with COVID-19 have a higher hospitalisation rate than
COVID-19 patients without a mood disorder [35]. Indeed, mood disorders may be
conceptualised as an underlying risk factor for COVID-19 hospitalisation, as well as death,
for several reasons, which include, but are not limited to, immune dysregulation, comorbid
substance use disorder (SUD), nonconcordance with recommended public health
guidelines and poor social determinants of health (e.g. low health literacy) [39].
Aggravating the addiction epidemic
The pandemic has worsened the ongoing public health SUD crisis [40]. Since the start of
the pandemic, there has been an increase in the number of fatal overdoses and harm from
substances (e.g. opioids, methamphetamine, cocaine) [41]. For example, the number of
opioid-related deaths in British Columbia, Canada, which became the epicentre of the
opioid epidemic in 2016, reported the highest number of opioid-related deaths in June
2020 (183 deaths) [40]. Taken together, physical distancing regulations and lockdown
measures have severely reduced access to critical health services (e.g. supervised
consumption facilities, harm-reduction services) [40]. Limiting the availability of these
programmes has disrupted treatment programmes and increased the risk of withdrawal and
overdose fatalities [40].
The behavioural, socioeconomic and healthcare delivery challenges presented by the

pandemic have increased the risk of infection, as well as exacerbated current addiction
disorders, among individuals with SUD [35]. Individuals with SUD face food, housing and
economic insecurities, which are significant risk factors for contraction of the virus [36, 42].
For example, individuals may not be able to adhere to stay-at-home measures as they rely
on food banks [36]. Moreover, persons with SUD in shelters may be unable to follow
physical distancing and protective measures due to crowded conditions, and have limited
availability of sanitiser, water and soap [35].
https://doi.org/10.1183/2312508X.10024720 237
Additionally, individuals with SUD are predisposed to contraction of the virus due to
frequent hand-to-mouth behaviours (e.g. sharing of smoking paraphernalia and
vapourisers) [43]. Personal hygiene may also be neglected during the procurement and use
of these products (e.g. frequent contact with individuals, travel to different environments,
hesitancy to use alcohol-based sanitisers due to their flammable nature) [43].
Substance use decreases barriers to infection by suppressing immune defence pathways

[44]. Substance use also complicates the illness trajectory for those infected with the virus
as a result of interference with neural, endocrine and immune circuitry pathways [44]. For
example, individuals with SUD are reported to have a predisposition for and/or a diagnosis
for multiple chronic physical comorbidities (e.g. cardiovascular disease, lung disease),
which are severe risk factors for increased COVID-19 severity and mortality [45].
In addition, limited access to quality health services is likely to be a contributing

factor delaying the diagnosis of SUD and treatment for withdrawal from addictive
substances, and the treatment and supervision of COVID-19, increasing the risk of
morbidity to themselves and infection for others [46, 47]. Persistent stigma and
discrimination of this population in general and healthcare environments may also prevent
health-seeking behaviour [48, 49].
While telehealth has been a popular avenue of care during the pandemic, there are
few equity considerations integrated with this digital delivery of health. For example,
telehealth does not accommodate the socioeconomic vulnerabilities of individuals with
SUD (e.g. lack of or no smartphone, internet availability) [43]. Additionally, in-person
substance use treatment programmes have been severely limited [50]. Taken together,
there is a need to expand remote health services to this population in primary care and
community settings.
A social virus
The rapid transition to digital living has highlighted the digital inequities that have been
pervasive during the pandemic. There is a significant association between digital exclusion,
social exclusion, poverty and health inequities [51]. Exclusion may be grouped into three
categories: 1) inaccessibility to digital technologies and services, 2) the cost of obtaining a
device and maintaining internet fees, and 3) barriers to digital literacy and incorporation of
digital technology into daily living [51].
Moreover, clinicians have also reported limitations with respect to the adoption of
telehealth. For example, physical examinations and diagnostics cannot be performed
virtually [52]. Additionally, the limited training and guidelines available to inform safe and
effective use of this digital platform have acted as a barrier to use [52]. Available literature
indicates that clinicians may be unwilling to adopt telehealth, as it is perceived to be
disruptive and complex [53, 54].
In addition, the lack of available funding has decreased the implementation of telehealth,
especially for individuals in rural and remote areas [52, 55, 56], and individual clinicians
have limited ability to implement and expand their practice to telehealth [52]. There must
be appropriate technology infrastructure to ensure that there are effective management
strategies to limit disruptions in the telehealth experience [52].
238 https://doi.org/10.1183/2312508X.10024720
The immediate pathways to acquiring infection have been augmented during the pandemic
[57]. Increased transmission of the virus, and disease outbreaks in general, have been
characterised as socially transmitted conditions reflecting the pervasive social and
environmental inequalities (e.g. overcrowding, hazardous working conditions, unemployment)
[57]. For example, ethnic minorities, the elderly and individuals of low socioeconomic
status are more vulnerable to COVID-19 as a result of adverse working conditions and
reduced access to quality healthcare and nutrition, as well as housing insecurity [58]. In
addition, these vulnerable populations are more likely to acquire respiratory diseases (e.g.
asthma due to overcrowding) or noncommunicable diseases, and to experience acute injury,
all of which contribute to and/or worsen transmission of the virus and the severity of the
infection [57]. Taken together, public health policies should target upstream factors (e.g.
health systems, education, labour market) that underlie the determinants of ill health.
Allocation of scarce medical resources
Increased demands by public health units, healthcare workers and health systems have
created an imbalance between the demand and supply of PPE, medical supplies and
healthcare personnel. In response to the increasing scarcity of resources, as well as rising
infection rates, medical equipment and personnel have been rationed. In light of these
events, the WHO released a report documenting the importance of fair allocation of scarce
resources, which must be transparent, inclusive, consistent and accountable [59].
Previous proposals regarding the allocation of scarce medical resources converged on four
fundamental values: 1) maximising benefits (i.e. saving the most lives or most life-years),
2) equal treatment (e.g. by lottery or on a first-come, first-served basis), 3) promoting and
rewarding instrumental value (e.g. contribution to the pandemic, such as frontline healthcare
workers), and 4) prioritising the worst off [60–64]. For example, in Saskatchewan, Canada,
health authorities developed a framework that aims to prioritise individuals who would
derive and have the greatest survival benefit by admission to the hospital, as well as
individuals who have not had the opportunity to live through stages of life (e.g. career
development, having children) and individuals who have made significant contributions to
the pandemic efforts (e.g. healthcare workers) [65]. Special populations (e.g. older adults,
pregnant women, individuals with disabilities) are given specific consideration [65].
Similarly, in New South Wales, Australia, health authorities have adopted a similar
approach wherein individuals who would benefit the most from hospital resources (i.e. who
would recover and benefit long-term) would be given priority [66]. However, this
understanding is determined on a case-by-case basis [66]. Generally, individuals who are
unlikely to recover without intensive care, are suffering from fatal diseases or who choose
not to be admitted would not receive treatment [66].
The limitations of medical resources and personnel are not limited to COVID-19 patients,
and instead are prevalent for individuals who suffer from other acute and chronic
conditions [67]. Elective and interventional care have been postponed, and patient volumes
for care have deteriorated to accommodate the increasing volume of COVID-19 patients
[67]. For example, surgical oncology cases have been deferred to face the rising number of
COVID-19 cases, which has potentially delayed cancer diagnosis or treatment.
Considerations regarding the triaging of non-COVID-19 medical care must consider the
availability of PPE, other equipment, inpatient and surgical spaces, as well as the number of
https://doi.org/10.1183/2312508X.10024720 239
Table 1. Summary points
The COVID-19 pandemic is a syndemic of biological, economic and population health threats
resulting in an unprecedented global economic, population health and mental health crisis
across high-, low- and middle-income countries
There has been a differential impact on females with respect to disruptions in the manufacturing
and service sector, as well as an increase of burden from the “care economy”
The rise in unemployment has led to an increase in suicide risk
The loneliness epidemic has been exacerbated by the current pandemic with effects particularly
pronounced among students and the elderly
Individuals with depression and/or substance use disorders are particularly vulnerable to COVID-19
The pandemic may be characterised as being caused by a socially transmitted virus with respect to
the exacerbation of social inequalities (e.g. poverty, food insecurity, economic insecurity)
Rising case counts have worsened the scarcity of medical resources and created significant
disruptions in other areas of healthcare
There is a need to combat the social, environmental and biological determinants of ill health
evidenced by the pandemic, and implement a holistic approach to augment resilience
personnel allowed to adhere to local and national public health guidelines [68–70].
Hitherto, the pandemic has created significant limitations that necessitate delays in the
delivery of other essential health services.
COVID-19 across low-, middle- and high-income countries
The COVID-19 pandemic should be characterised as a syndemic, given the significant

interaction between biological and social determinants of health [2]. The heterogeneous effects
of this syndemic across low-, middle- and high-income countries have emphasised pre-existing
disparities among regions, as well as exacerbated related pervasive inequities [71].
For example, a study comparing stringency index (i.e. containment measures during
COVID-19) and compliance with the enforced regulations across four high-income countries
(Germany, Sweden, Italy and South Korea), two middle-income countries (Mexico and
Columbia) and three low-income countries (India, Nigeria and Nepal) has highlighted the
entrenched vulnerabilities of lower-income countries along the infection curve [71]. While
high-income countries that enforced containment measures were successful in managing
infection rates, low- and middle-income countries did not demonstrate similar efficacy.
It is hypothesised that factors related to poor health infrastructure (e.g. weak regulation of
systematic testing, lack of PPE and hygiene practices), as well inadequate social supports (e.g.
unemployment provisions) have contributed to difficulties complying with lockdown measures
and unsuccessful management of the infection rate [71]. However, containment measures in
resource-constrained settings may not be the most effective course of action to protect these
populations, given the diversity of health and social infrastructure. Accordingly, the
conceptualisation of COVID-19 as a syndemic is appropriate, given the significant influence of
social determinants on infection rates beyond its management through clinical medicine.
Conclusion
The COVID-19 syndemic has augmented social and economic determinants of health that
forecast risk for poor mental and physical outcomes (table 1). Based on the current economic
240 https://doi.org/10.1183/2312508X.10024720
climate with respect to fragmented global trade and supply linkages, and the increased need
for fiscal and monetary support, deep global recessions are predicted to occur over the next
few decades. Furthermore, the entrenched social disparities and inequities driving virus
transmission have highlighted the need to engage with experts outside medicine to
implement appropriate social and welfare protections, and to consult with individuals and
groups among high-, middle- and low-income countries. International collaboration is critical
for understanding the diversity in phenomena of the consequences of the current pandemic.
Thus, there is a need to invite a larger, more encompassing and holistic approach to treat the
root causes of this syndemic. Taken together, there is a need to pivot towards the “three Es”
(economic stability, education and equality) to address upstream factors affecting health
outcomes, as well as implement measures related to improved environmental measures and
fiscal growth to combat the consequences of the pandemic and augment resilience.
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Disclosures: L.M.W. Lui has received: personal fees from Braxia Scientific Corp and honoraria Medscape.
Y. Lee is the Chief Research Officer of Braxia Scientific Corp. Y. Lee has received: salary support from the
Global Alliance for Chronic Diseases, the Canadian Institutes of Health Research (CIHR), the National Natural
Science Foundation of China’s Mental Health Team and the CIHR Frederick Banting and Charles Best Canada
Graduate Scholarship; and personal fees from Braxia Scientific Corp. R.S. McIntyre has received research
grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation
fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo
Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. R.S. McIntyre is a CEO of
Braxia Scientific Corp.
https://doi.org/10.1183/2312508X.10024720 243
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The story of COVID-19 now seems so familiar: from the first

This book is one in a series of ERS Monographs. Each individual issue

ERS Monographs are available online at books.ersjournals.com and print

Managing Editor: Rachel Gozzard

Published by European Respiratory Society ©2021

Guest Editors iii

1. Respiratory failure: a patient’s perspective and clinical cases 1

2. Epidemiology: global spread, risk factors for disease incidence, 14

3. Historical perspective: other human coronavirus infectious diseases, 28

4. Drug repurposing and other strategies for rapid antiviral 39

5. Can the immune system be targeted to treat COVID-19? 69

7. Clinical features and acute management in adults 101

8. Management in the ICU 124

9. Clinical features and acute management in children 144

11. Post-COVID-19 sequelae 180

12. Post-COVID-19 rehabilitation 197

15. Vaccines: immunology regulation and clinical management 244

Even though SARS-CoV-2 can theoretically infect a variety of

Adaptive mutations of the SARS-CoV-2 genome alter its

Nevertheless, at the time of writing in December 2021, 2 years

Disclosures: A.T. Dinh-Xuan's institution is supported by a research grant

Aurelie Fabre is a Consultant Histopathologist and Full Clinical

Aurelie was Chair of the European Respiratory Society (ERS)

John R. Hurst is Professor of Respiratory Medicine at University

Sheila Ramjug is a Consultant Pulmonologist with a specialist

She obtained her first consultant position at the start of the

Sheila is part of the ERS Monograph editorial board as the

In March 2020, Sheila distinctly remembers sitting in a hospital lecture theatre in

Correspondence: Sheila Ramjug (sheilaramjug@hotmail.com)

ACE angiotensin-converting enzyme

Correspondence: Stefano Aliberti (stefano.aliberti@hunimed.eu)

Case 1: criteria and time to intubation and the role of prone

Day in FIO2, RR ABG pre-PP RR ABG post-PP

4 50 24 7.47 39 136 1.0 272 20 7.51 34 200 0.9 400

PATIENT PERSPECTIVE AND CLINICAL CASES | F. AMATI ET AL.

Case 2: pulse steroid treatment as rescue therapy to prevent

admission, he was treated with clarithromycin with no clinical improvement. He then

Case 3: is pneumomediastinum in a COVID-19 patient treated with

Disclosures: None declared.

Correspondence: Joan B. Soriano ( jbsoriano2@gmail.com)

SARS-CoV-2 belongs to the broad coronavirus family. It is a positive-sense single-stranded

The natural history of SARS-CoV-2

Case definitions of COVID-19

Case definitions of COVID-19 surveillance – suspected, probable, confirmed [12] – need to

The severity of COVID-19

Epidemiology estimators and determinants

Peak before or within the first 5 days

Peak 1–2 days after onset Peak in second week

Table 1. Case definitions for COVID-19 surveillance

The percentage use of ICU

This is the proportion of ICU beds occupied by COVID-19 patients. It is considered a

ERS MONOGRAPH | COVID-19

A patient with severe acute respiratory illness: (SARI: acute

Table 2. Severity staging of COVID-19

Category Definition Clinical criteria

Asymptomatic No symptoms An individual with an ongoing (within 20 days

The basic reproductive number

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