Comment

PS reports grants, personal fees, and non-financial support from Roche, 2 Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease
PPM Services, and Boehringer-Ingelheim and reports personal fees from Red X 2019 in China. N Engl J Med 2020; published online Feb 28. DOI:10.1056/
Pharma, Galapagos, and Chiesi, outside of the submitted work. PS reports that his NEJMoa2002032.
wife is an employee of Novartis. SA reports grants and personal fees from Bayer 3 Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized
Healthcare, Aradigm Corporation, Grifols, Chiesi, and INSMED and reports patients with 2019 novel coronavirus-infected pneumonia in Wuhan,
personal fees from AstraZeneca, Basilea, Zambon, Novartis, Raptor, Actavis UK, China. JAMA 2020; 323: 1061–69.
Horizon, outside of the submitted work. TMM reports, industry-academic funding 4 National Institute of Allergy and Infectious Diseases. COVID-19, MERS &
from GlaxoSmithKline to his institution and reports consultancy or speaker fees SARS. 2020 https://www.niaid.nih.gov/diseases-conditions/covid-19
from Apellis, AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, (accessed May 6, 2020).
Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Indalo, Novartis, Pliant, 5 Ooi GC, Khong PL, Müller NL, et al. Severe acute respiratory syndrome:
Respivant, Roche, and Samumed. All other authors report no competing interests. temporal lung changes at thin-section CT in 30 patients. Radiology 2004;
230: 836–44.
*Paolo Spagnolo, Elisabetta Balestro, Stefano Aliberti, 6 Zhang P, Li J, Liu H, et al. Long-term bone and lung consequences
associated with hospital-acquired severe acute respiratory syndrome:
Elisabetta Cocconcelli, Davide Biondini, Giovanni Della Casa, a 15-year follow-up from a prospective cohort study. Bone Res 2020; 8: 8.
Nicola Sverzellati, Toby M Maher 7 Das KM, Lee EY, Singh R, et al. Follow-up chest radiographic findings in
paolo.spagnolo@unipd.it patients with MERS-CoV after recovery. Indian J Radiol Imaging 2017;
27: 342–49.
Respiratory Disease Unit, Department of Cardiac Thoracic, Vascular Sciences and
8 Burnham EL, Janssen WJ, Riches DW, Moss M, Downey GP.
Public Health, University of Padova, Padova 35128, Italy (PS, EB, EC, DB); The fibroproliferative response in acute respiratory distress syndrome:
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Respiratory Unit mechanisms and clinical significance. Eur Respir J 2014; 43: 276–85.
and Cystic Fibrosis Adult Center, Milan, Italy (SA); Department of 9 Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory
Pathophysiology and Transplantation, University of Milan, Milan, Italy (SA); distress syndrome and death in patients with coronavirus disease 2019
Radiology Unit, Azienda Ospedaliera Universitaria Policlinico di Modena, Modena, pneumonia in Wuhan, China. JAMA Intern Med 2020; published online
Italy (GDC); Section of Diagnostic Imaging, Department of Surgery, University of March 13. DOI:10.1001/jamainternmed.2020.0994.
Parma, Parma, Italy (NS); National Institute for Health Research, Respiratory 10 Brown KK, Martinez FJ, Walsh SLF, et al. The natural history of progressive
Clinical Research Facility, Royal Brompton Hospital, London, UK (TMM); National fibrosing interstitial lung diseases. Eur Respir J 2020; published online
Heart and Lung Institute, Imperial College, London, UK (TMM) March 26. DOI:10.1183/13993003.00085-2020.
1 WHO. Coronavirus disease 2019 (COVID-19) situation report. 2020.
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/
events-as-they-happen. (accessed May 6, 2020).

Identification of pathophysiological patterns for triage and

respiratory support in COVID-19
Published Online In the UK, more than 279 392 cases of COVID-19 number of patients, while controlling the number
June 26, 2020
https://doi.org/10.1016/
had been documented by June 3, 2020, and more of critical care admissions and protecting staff,
S2213-2600(20)30279-4 than 39 500 patients had died with the disease, have at times generated adversarial positions at the
according to the COVID-19 web-based dashboard at extremes of the debate. The motivations behind these
Johns Hopkins University.1 Data derived from the UK arguments are undoubtedly positive, but they do not
For more on the ICNARC audit Intensive Care National Audit and Research Centre necessarily help frontline clinicians who are caring for
see https://www.icnarc.org/Our-
Audit/Audits/Cmp/Reports
(ICNARC) Case Mix Programme Database show individuals with COVID-19.
that, for the first 8062 patients admitted to the ICU To design triage systems and pathways of care, it is
across the UK with documented outcomes, by May important to operate cautiously within models that best
29, 2020, about 72% received advanced mechanical reflect evolving understanding of the pathophysiology
ventilation and the mortality rate was around 53%. and natural history of this new disease. COVID-19
This mortality far exceeds that of typical severe acute pneumonia leads to hypoxaemic respiratory failure,
respiratory distress syndrome (ARDS).2 The significant initially due to the coexistence of interstitial oedema
surge in the number of patients requiring ventilatory and altered pulmonary perfusion, in the absence of
support has presented the UK National Health Service a significant loss of lung volume and compliance.4
with unprecedented challenges, including pressures Although, on average, patients present with an
on critical care capacity, resources, and supplies, oxygenation deficit5 similar to that of moderate-to-
concerns about staff protection, as well as ethical severe ARDS (median PaO2/FiO2 of 20 kPa),2 the cause of
issues associated with triage and resource allocation.3 this deficit seems to be unlike that of classic ARDS, and
Debates about the way in which different modalities of the response to positive end-expiratory pressure (PEEP)
ventilatory support should be provided to the largest or continuous positive airway pressure (CPAP) in terms

752 www.thelancet.com/respiratory Vol 8 August 2020

 Comment

of alveolar recruitment is not substantial in patients Irreversible

with COVID-19.6 Compliance
lung fibrosis

Multiple mechanisms of dysregulation in the pulmonary O2

Time
supplement
perfusion exist in COVID-19: the abolition of hypoxic
Indolent HFNC or
pulmonary vasoconstriction, causing an increase in Hyperacute NIV/CPAP

iNO trial ± pulmonary vasodilators

venous admixture; excessive pulmonary vasoconstriction; Biphasic IMV

Immunomodulation
and microthrombosis or macrothrombosis, leading

Hypoxaemia
Respiratory drive

Prone position
Shunt

Dead-space
to increased dead-space.7 Patients with COVID-19
and hypoxaemia predominantly due to shunt have a ECMO
variable work of breathing, might respond to CPAP,
and could be considered for awake prone positioning.8
As dead-space ventilation increases, patients typically Low PEEP Higher PEEP Low PEEP
More liberal VT Low VT Low VT
have greater respiratory drive and work of breathing,
Recruitability
and greater minute ventilation at the expense of higher (response to PEEP)
transpulmonary pressures. These patients are at higher
risk of self-induced lung injury, are prone to further Figure: Pathophysiological trajectory in COVID-19 and proposed implications for respiratory support
deterioration with non-invasive ventilation (NIV), The schematic is based on our observations in a large centre for the management of patients with severe
respiratory failure, part of a UK severe respiratory failure/ECMO network. CPAP=continuous positive airway
which might be associated with worse outcomes,9 and pressure. ECMO=extracorporeal membrane oxygenation. HFNC=high-flow nasal cannula. IMV=invasive
might benefit from prompt invasive ventilation. In mechanical ventilation. iNO=inhaled nitric oxide. NIV=non-invasive ventilation. PEEP=positive end-expiratory
pressure. VT=tidal volume.
patients with COVID-19, increased dead-space can be
due to vasoconstriction or prevalent microthrombosis
or macrothrombosis, so they are likely to benefit from and a biphasic course, in which patients have an initial
pulmonary vasodilators or systemic anticoagulation. indolent course followed—typically after 5–7 days—by an
Furthermore, the hyperinflammatory and hypermetabolic acute deterioration with hyperinflammation, fever, and
state might determine a further significant increase worsening respiratory failure with bilateral infiltrates and
in respiratory drive, and transpulmonary stress and consolidation. It seems logical that triage and ventilatory
strain. The consequent lung oedema, lung weight, and strategies should reflect these factors in addition to
worsening consolidation can contribute to disease resource and ethical considerations. Proposed approaches
progression.10 At this stage, patients with COVID-19 are presented in the accompanying schematic (figure), but
often present with features resembling more typical further studies of the course of COVID-19 will be needed
ARDS—including a variable degree of lung recruitability— to describe and validate phenotypes of the disease.
and might respond to treatments generally used in A one-size-fits-all approach will not lead to improved
this condition. Finally, on the basis of radiological and outcomes in patients with COVID-19. Importantly, we
pathological findings from our institution (unpublished), argue that consideration for extracorporeal support
COVID-19 seems to be associated with early and extensive should be given to patients who become refractory
fibroproliferation. Therefore, patients in the later stages to conventional management strategies—particularly
of severe and progressive disease might lose recruitability those with a hyperacute course—before they develop
as the lung oedema is replaced by dense consolidation overt and diffuse fibrosis. The selection of patients likely
and fibrosis, with failure to respond to conventional to benefit from extracorporeal membrane oxygenation
treatment, prone positioning, or pulmonary vasodilators. (ECMO) is extremely difficult, given the large number
On the basis of our experience, patients can present to of potential candidates, the limited resources available,
hospital with any of these phenotypes, and the clinical and lack of evidence for the effectiveness of ECMO
course tends to follow one of three main patterns: above and beyond conventional strategies.3
a hyperacute course, with severe hypoxaemia and We propose that ventilation strategy should be
breathlessness leading to immediate intubation; an integrated with the observed phases and physiological
indolent course, in which patients have a moderate or patterns of the disease. This might prove to be useful
severe hypoxaemia but only moderate work of breathing; in addressing ongoing controversies about the use

www.thelancet.com/respiratory Vol 8 August 2020 753

 Comment

of NIV versus invasive mechanical ventilation, as well 1 Dong E, Du H, Gardner L. An interactive web-based dashboard to track
COVID-19 in real time. Lancet Infect Dis 2020; 20: 533–34.
as intubation timing and criteria. Future research 2 Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and
should aim to clarify the best ventilation strategy for mortality for patients with acute respiratory distress syndrome in intensive
care units in 50 countries. JAMA 2016; 315: 788–800.
individual patients (eg, phenotypes and response to 3 Phua J, Weng L, Ling L, et al. Intensive care management of coronavirus
PEEP), to describe disease mechanisms associated with disease 2019 (COVID-19): challenges and recommendations.
Lancet Respir Med 2020; 8: 506–17.
the pathophysiological patterns and clinical course of 4 Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different
COVID-19 (eg, early vs late presentation; vascular vs respiratory treatments for different phenotypes? Intensive Care Med 2020;
published online April 14. DOI:10.1007/s00134-020-06033-2.
parenchymal), to identify biomarkers (eg, cytokines, 5 Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and
outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of
ferritin, D-dimer, or procalcitonin) that could help to the Lombardy region, Italy. JAMA 2020; 323: 1574–81.
guide management, and to establish the efficacy and 6 Pan C, Chen L, Lu C, et al. Lung recruitability in COVID-19-associated acute
respiratory distress syndrome: a single-center observational study.
optimum timing of promising therapeutics. In the Am J Respir Crit Care Med 2020; 201: 1294–97.
meantime, in an era of big data and large databases, 7 McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune
mechanisms of pulmonary intravascular coagulopathy in COVID-19
it would be worth using machine learning and other pneumonia. Lancet Rheumatol 2020; published online May 7.
https://doi.org/10.1016/S2665-9913(20)30121-1.
approaches to try to identify the link between observed
8 Elharrar X, Trigui Y, Dols AM, et al. Use of prone positioning in
patterns of physiology, interventions, and outcomes nonintubated patients with COVID-19 and hypoxemic acute respiratory
failure. JAMA 2020; published online May 15. DOI:10.1001/
before clinical trials have been completed. jama.2020.8255.
We declare no competing interests. 9 Bellani G, Laffey JG, Pham T, et al. Noninvasive ventilation of patients with
acute respiratory distress syndrome. Insights from the LUNG SAFE study.
*Luigi Camporota, Francesco Vasques, Barnaby Sanderson, Am J Respir Crit Care Med 2017; 195: 67–77.
Nicholas A Barrett, Luciano Gattinoni 10 Tonelli R, Fantini R, Tabbi L, et al. Inspiratory effort assessment by
esophageal manometry early predicts noninvasive ventilation outcome in
luigi.camporota@gstt.nhs.uk de novo respiratory failure: a pilot study. Am J Respir Crit Care Med 2020;
St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK (LC, FV, BS, published online April 23. DOI:10.1164/rccm.201912-2512OC.
NAB); Department of Adult Critical Care, Guy’s and St Thomas’ NHS Foundation
Trust, Health Centre for Human and Applied Physiological Sciences, King’s
College London, London, UK (LC, FV, BS, NAB); and Department of
Anaesthesiology, Emergency and Intensive Care Medicine, University of
Göttingen, Göttingen, Germany (LG)

Use of aerosolised medications at home for COVID-19

Respiratory viruses are the most common trigger Patients with pulmonary diseases are considered
for pulmonary disease exacerbations and infection to have an increased risk of having COVID-19.
Colin Cuthbert/Science Photo Library

can result in deterioration in patient symptoms. However, the prevalence of COVID-19 is lower in
Although inhaled medications are commonly used, this patient population than in populations of other
many clinicians have questioned whether inhaled chronic illnesses, and treatments used in pulmonary
corticosteroids (ICS) affect acute respiratory infection diseases might reduce the risk of infection and the
and disease progression caused by severe acute development of disease symptoms.1 Although ICS are
Published Online respiratory syndrome coronavirus 2 (SARS-CoV-2). associated with an increased risk of upper respiratory
June 22, 2020
https://doi.org/10.1016/
Because ICS are considered immuno­suppressive, some infections2 and pneumonia,3 these medications might
S2213-2600(20)30270-8 clinicians are unsure about using these medications have beneficial effects in viral infections,4 and might
during the COVID-19 pandemic. Patients also hesitate reduce the severity of COVID-19 by blocking SARS-
For more on the guidelines from to use inhaled medications that are seen as a potential CoV-2 RNA replication.5 Guidelines from the Global
the Global Initiative for Chronic
Obstructive Lung Disease see
source of viral transmission and immunosuppression. Initiative for Chronic Obstructive Lung Disease and
http://www.goldcopd.org Despite many discussions on COVID-19 having taken the Global Initiative for Asthma recommend the use
For more on the guidelines place, little attention has been brought to patients with of prescribed ICS in pulmonary diseases to prevent the
from the Global Initiative for
Asthma see https://ginasthma. pulmonary diseases treated at home. There is an urgent worsening of pulmonary disease severity during the
org/recommendations-for- need for guidance on treating such patients (with and pandemic. Increasing the dose of ICS at the beginning of
inhaled-asthma-controller-
medications/ without COVID-19) to minimise the use of hospitals exacerbation might prevent disease progression and the
under pressure with admissions. need for oral corticosteroids; however, patients should

754 www.thelancet.com/respiratory Vol 8 August 2020