T h e Ep i d e m i o l o g y o f A c u t e

R e s p i r a t o r y D i s t re s s
S y n d ro m e B e f o re a n d A f t e r
C o ro n a v i r u s D i s e a s e 2 0 1 9
Kathryn W. Hendrickson, MDa,b, Ithan D. Peltan, a,c
MD, MSc ,
Samuel M. Brown, MD, MSa,b,*

KEYWORDS
 ARDS  Epidemiology  Incidence  Subtypes  Mortality  COVID-19

KEY POINTS
 Acute respiratory distress syndrome (ARDS) is heterogeneous.
 ARDS has high incidence among intensive care unit patients.
 ARDS has high morbidity and mortality.
 Improved supportive care has decreased ARDS incidence and mortality.
 Coronavirus Disease 2019–associated ARDS is a syndrome within the known ARDS
spectrum.

INTRODUCTION

Acute respiratory distress syndrome (ARDS) occurs when a diverse array of triggers
cause acute, bilateral pulmonary inflammation and increased pulmonary capillary
permeability leading to acute hypoxemic respiratory failure. Pulmonary biopsy (or au-
topsy) classically demonstrates diffuse alveolar damage (DAD).1 Recognizing that
ARDS is a syndrome and that research and benchmarking require reproducible defi-
nitions, a 2011 consensus conference in Berlin proposed a practical, updated defini-
tion (the “Berlin Definition”),2 In summary, this requires,

a
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of
Utah School of Medicine, 26 North 1900 East, Salt Lake City, UT 84112, USA; b Division of
Pulmonary and Critical Care Medicine, Department of Medicine, Intermountain Medical Cen-
ter; c Pulmonary Division, Department of Medicine, Intermountain Medical Center, 5121 South
Cottonwood Street, Murray, UT 84107, USA
* Corresponding author. Pulmonary Division, Department of Medicine, Intermountain Medical
Center, 5121 South Cottonwood Street, Murray, UT 84107.
E-mail address: [email protected]

Crit Care Clin 37 (2021) 703–716

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704 Hendrickson et al

1. An acute process developing within 1 week of a known clinical insult or new or

worsening respiratory symptoms;
2. Radiographic images showing bilateral opacities not fully explained by effusions,
lobar or lung collapse, or nodules; and
3. Impairment in oxygenation as measured by a PaO2/FiO2 300 mm Hg in the pres-
ence of a positive end-expiratory pressure (PEEP) of at least 5 cm H2O.
Despite many advances in the understanding of ARDS, morbidity and mortality
remain high with few targeted therapies. In this epidemiologic review, we consider
the etiology, subtypes and phenotypes, incidence, mortality, long-term outcomes,
and the relationship(s) between Coronavirus Disease 2019 (COVID-19) and prepan-
demic ARDS.

ETIOLOGY

Admitting that patients would not have survived long enough to be diagnosed with
ARDS before the widespread use of intensive care unit (ICU) ventilators for hypoxemic
respiratory failure, Ashbaugh and colleagues first reported on ARDS as a distinct syn-
drome in a 1967 series of 12 patients.3 Despite suffering from heterogeneous primary
insults, the patients all developed similar patterns of acute-onset respiratory failure
with bilateral infiltrates and decreased pulmonary compliance accompanied by au-
topsy findings of acute inflammation and hyaline membranes.3
This initial report captured the heterogeneity of ARDS that continues to present chal-
lenges in diagnosis and treatment. Pneumonia is the most common trigger for ARDS,
although nonpulmonary sepsis, aspiration pneumonitis, and trauma are also common.
An assortment of less common triggers have been identified including pancreatitis and
blood transfusion. Clinical syndromes compatible with ARDS but with no identifiable
trigger are referred to as acute interstitial pneumonia (AIP) or sometimes Hamman-
Rich syndrome rather than ARDS and may represent a response to an array of some-
times overlapping pulmonary insults.1,4–15 In both ARDS and, presumptively, AIP, an
insult elicits an inflammatory response which leads to increased-permeability pulmo-
nary edema creating the hypoxemia and bilateral opacities on imaging required for
diagnosis.16,17 In its most severe forms, DAD results pathologically.
ARDS resulting from direct pulmonary insult such as pneumonia manifests patho-
logically as alveolar collapse, fibrinous exudate, and edema of the alveolar walls to
a greater degree than ARDS resulting from nonpulmonary causes such as pancrea-
titis.18 This may represent a spectrum of severity or alternative pathophysiological pro-
cesses. What is less clear is why some patients with inciting conditions develop ARDS
while others do not, and whether differences in genotype, phenotype, or therapeutic
context play a role remains unclear.
Chronic conditions including obesity and diabetes have been associated with a
decreased incidence of ARDS. In diabetes, some hypothesize that this observed as-
sociation reflects a decreased inflammatory response among diabetics.19,20 A poten-
tial association with obesity is less clear.21–23 Importantly, collider bias may in fact
account for the observed associations.24
On the contrary, chronic alcohol use has been associated with higher risk of ARDS.
Kaphalia and Calhoun25 found that chronic alcohol use leads to pulmonary immune
dysfunction, epithelial dysfunction, and the inability to handle reactive oxygen species
leading to the high permeability pulmonary edema and hyaline membrane formation
seen in ARDS. Smoking is also associated with higher risks of ARDS. Not only are pa-
tients who smoke more likely to get pneumonia they also have higher rates of ARDS
triggered by nonpulmonary causes.26,27 Cigarette smoking may thus increase the
 The Epidemiology of ARDS Before and After COVID-19 705

risk of the inflammatory cascade that results in ARDS. Interestingly, ozone exposure
(but no other known pollutants) is also associated with increased risk of ARDS.28
Consistently, older age,8 non-white race (likely a surrogate for “social determinants
of disease”),29 and some genetic variants30 have been described as host factors asso-
ciated with risk of developing ARDS.
Although age is a risk factor for developing ARDS, it has not consistently been found
to be associated with increased mortality. The multinational LUNG-SAFE (The Large
Observational Study to Understand the Global Impact of Severe Acute Respiratory Fail-
ure) study showed older age to be a risk factor for mortality31; however, when controlling
for risk, severity, and comorbidity, the independent relationship between age and mor-
tality in ARDS is not consistent.8 The association of race and ethnicity with ARDS mor-
tality was studied in a retrospective cohort study in 2009 using patient data from three
ARDS network randomized control trials. Black race and Hispanic ethnicity were found
to have not only higher rates of ARDS than white individuals but higher mortality as well.
The causes of race- and ethnicity-related differences are not well understood and likely
vary between groups but, in all cases, likely derive substantially from “social determi-
nants of disease” rather than genetic factors. For instance, the fact that higher mortality
in Black patients resolves with adjustment for illness severity suggests barriers that
hinder Black individuals from seeking early care, physician delay in diagnosis, and other
factors worsen the severity mix in these groups.29

SUBTYPES

A defining characteristic of ARDS is its heterogeneity, from Ashbaugh’s initial publica-

tion to the present day.32,33 Traditional categorizations (as, eg, in the Berlin definition)
are based on severity of hypoxemia, which correlates with mortality and the extent of
DAD on pathologic examination.34,35 The effects of some potential ARDS therapies
may also vary with hypoxemia severity. For example, in 2018, Guo and colleagues36
published a systemic review and meta-analysis showing a likely trend toward
improved outcomes in patients receiving a high-PEEP protocol. For patients with a
PaO2/FiO2 (P/F) ratio 200, there was a slightly lower risk of death; however, in patients
with a P/F ratio 201 to 300, there was a possible higher risk of death. Of note this mor-
tality benefit has not been seen in any individual randomized control trials37–39 and re-
mains a controversial topic. Another example is the 2019 study of therapeutic
neuromuscular blockade to improve outcomes in ARDS. Although a previous trial
hinted at decreased mortality in patients with P/F ratio less than 130,40 this larger trial
concluded no mortality benefit.41
ARDS can also be subdivided based on the initial insult, whether pulmonary (pneu-
monia, pulmonary contusion, and aspiration) or extrapulmonary (nonthoracic trauma,
nonpulmonary sepsis, and transfusion).7,42,43 Several pathologic, biologic, and physio-
logic differences have been identified on this basis.18,44–47 However, in practice, it is diffi-
cult to differentiate between the two groups based on substantial overlap.13 These
pathologic, biologic, and physiologic differences are heavily influenced by underlying
lung function and architecture, smoking status, chronic diseases, and other conditions,
which inflate the heterogeneity of ARDS. No mortality difference has been found between
the two groups, likely related to the complexities of the overlap between the two groups.48
More recently, “machine learning”-style techniques have been used to identify
distinct subtypes. Post-hoc analysis (using latent class analysis) of the ARMA (ARDSnet:
Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for
Acute Lung Injury and the Acute Respiratory Distress Syndrome) and ALVEOLI (Assess-
ment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury)
706 Hendrickson et al

trials revealed two phenotypes of ARDS.37,49 Relative to phenotype 1, phenotype 2 was

hyperinflammatory, with higher plasma levels of inflammatory biomarkers, a higher
prevalence of vasopressor use, lower serum bicarbonate, and a higher prevalence of
sepsis found in phenotype 2 than in phenotype 1.50 Critically, in terms of its clinical util-
ity, this hyperinflammatory phenotype was also associated with higher mortality. Pheno-
type may also predict response to therapies: A post-hoc analysis of a randomized
controlled trial of statin therapy for ARDS suggested benefit for hyperinflammatory pa-
tients.51 It will be important with the expanding use of novel statistical techniques for
subtyping to ground them in reality and validate them in both prospective cohorts
and within prespecified subgroups in prospective trials.

INCIDENCE

The incidence of ARDS varies globally by over 400%.52 It is important to acknowledge

in this context that ARDS as a syndrome reflects both patient physiology and clinical
context. For example, where patients with hypoxemic respiratory failure are not
routinely intubated (as may occur in certain institutional settings in USA/Europe or in
low- and middle-income country settings with limited supplies of ventilators and/or re-
sources and personnel for ICU-level care), ARDS incidence may appear lower than it
actually is. Similarly, routine use of high-tidal-volume ventilation among patients at risk
may increase the incidence of ARDS in a given setting. With those caveats in mind,
incidence ranges from 10.1/100,000/y in Brazil in 2014 to 82/100,000/y in the United
States in 2005 (Table 1).5,7,8,10 Between-study differences in case ascertainment and
local context may drive these observed differences.53,54 Some studies, for instance,
relied on clinician diagnosis while others used billing codes, both of which may be
inaccurate. Both methods are likely to undercount ARDS cases, as only 60% of
ARDS cases were appropriately identified by clinicians in one large study.1 Differences
in the prevalence of ARDS risk factors may account for some of the variation as well.
Likely the highest quality evidence on ARDS incidence and management patterns orig-
inates from LUNG-SAFE, a prevalence study conducted during a 4-week period in 459
ICUs in 50 countries. Overall, 10% of all ICU patients and 23% of mechanically ventilated
patients met ARDS criteria, yielding an ICU incidence of 5.5 cases per ICU bed per year.
In 2011, the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network
developed the Lung Injury Prediction Score (LIPS) to help identify patients in the emer-
gency department with high risk of developing ARDS. ARDS predictors included in the
final score both triggers (ie, shock, aspiration, lung contusion) and risk modifiers (ie,
smoking, diabetes mellitus, acidosis). This tool also works in hospitalized patients as
a quick and effective way of identifying high-risk patients.55–57 Hopes that this score
would help enrich enrollment in trials of therapeutics to decrease incidence and death
from ARDS, however, have so far not borne fruit. For instance, the LIPS-A trial, in which
aspirin was tested as a possible intervention in this subgroup of patients, showed no dif-
ference in rates of ARDS and rates of death after receiving aspirin versus placebo.58
Between 2001 and 2008, rates of ARDS fell by half in two ICUs in Rochester, Min-
nesota, in a population-based, retrospective cohort study of the epidemiology of
ARDS patients admitted during that time period. Severity of acute illness, greater num-
ber of comorbidities, and major predisposing conditions in patients with ARDS
increased while mortality stayed the same during this time. Interestingly, the reduction
in incidence occurred exclusively in patients with hospital-acquired ARDS. As noted
by the authors, during this time, a separate hospital-wide program to limit risk factors
for ARDS was undertaken which can explain this reduction in hospital-acquired ARDS.
This indicates that ARDS may, in part, be a preventable hospital-acquired
 The Epidemiology of ARDS Before and After COVID-19 707

Table 1
Main epidemiologic studies on ARDS incidence after AECC definition

Incidence of
Moderate and
Severe ARDS
Incidence of All Categories (per
ARDS 100,000 Person-
Categories (per Years-
100,000 Person- Population-
Years-Population- Based Studies)
Authors, Based Studies) or or
Year of Percentage (%, Percentage (%,
Publication Study Country or Hospitalization- Hospitalization-
[Reference] Period Countries Based Studies) Based Studies)
Sigurdsson 1988–2010 Iceland 3.65–9.63
et al,15 2013
Nolan et al,4 1990–1994 Australia 7.3–9.3
1997
Luhr et al,5 1997 Scandinavia 17.9 13.5
1999 (Sweden,
Denmark, Iceland,
Norway)
Bersten 1999 Australia (South, 34 28
et al,6 2002 Western, and
Tasmania)
Brun-Buisson 1999 Europe 7.1% (of all ICU 6.1% (of all ICU
et al,13 2004 admissions) admissions)
Rubenfeld 1999–2000 King County, WA, 78.9 58.7
et al,7 2005 USA
Manzano et al,8 2001 Granada, Spain 25.5 23
2005
Sakr et al,92 2002 Europe 12.5% (of all ICU 10.6% (of all ICU
2005 admissions), admissions),
19.1% (of all 16.5% (of all
mechanically mechanically
ventilated ventilated
patients) patients)
Li et al,9 2011 2001–2008 Olmsted County, 81 (in 2001),
MN 38.3 (in 2008)
The Irish Critical 2006 Ireland 19%
Care Trials
Group,14 2008
Caser et al,10 2006–2007 Vitoria Region, 10.1 6.3
2014 Brazil
Linko et al,11 2007 Finland 10.6 5
2009
Villar et al,12 2008–2009 Spain 7.2
2011
Bellani et al,1 2014 50 Countries 10.4% of all ICU
2016 admissions, 5.5
cases per ICU bed
per year

ARDS was defined using the Berlin definition nomenclature: All ARDS categories include mild,
moderate, and severe ARDS.
708 Hendrickson et al

complication.9 Multiple additional studies have shown that using LTVV in all visitors to
the hospital and ICU have decreased incidence of ARDS arguing for the use of LTVV in
all patients and not only on those with respiratory failure.59,60

ACUTE RESPIRATORY DISTRESS SYNDROME-ASSOCIATED MORTALITY

Despite improved mortality rates, ARDS continues to be a syndrome of high mortality.

As noted previously, P/F ratio correlates with ARDS outcome, prompting the authors
of the Berlin Criteria to maintain the traditional severity categories in their updated
consensus definition. Mortality in cohorts analyzed by the Berlin Criteria authors
was 34.9% (95% confidence interval [CI]: 24%-30%) in mild ARDS, 40.3% (95% CI:
29%-34%) in moderate ARDS, and 46.1% (95% CI: 29%-34%) in severe ARDS, as
defined by P/F thresholds of 300, 200, and 100.2 The LUNG-SAFE study reported
similar findings, with 28-day mortality of 29.6% (95% CI: 26.2%-33.0%) in mild
ARDS, 35.2% (95% CI: 32.4%-38.1%) in moderate ARDS, and 40.9% (95% CI:
36.8%-45.1%) in severe ARDS using the same P/F thresholds used in the Berlin
definition.1
Reported ARDS mortality has decreased over recent decades. Compared to the
late 1990s, when independent studies reported ARDS mortality of 58% to 59%,4,13
mortality in contemporary studies is much lower (Figs. 1 and 2). ARDS mortality in
2014 in LUNG-SAFE was 10.4%,1 and 28% in the LOTUS-FRUIT U.S. multicenter
study conducted by the PETAL Network in 2019.61 While imperfect,62 death certificate
data also suggest decreasing risk of death for ARDS patients, with annual attributable
mortality in one U.S. death certificate analysis decreasing from 5.01 per 100,000 peo-
ple in 1999 to 2.82 per 100,000 population in 2013.63 While changes in ascertainment
(diagnosing more patients with less-severe ARDS) and decreasing use of mechanical
ventilation for patients near the end of life may contribute to this trend, it appears likely
that increasing the use of LTVV since the publication of the seminal ARMA trial in 2000
is a key factor driving improved outcomes in ARDS.49 In fact, among patients who do

Fig. 1. Estimated overall hospital mortality rates for patients with ARDS of any severity. Hos-
pital mortality reported in the main epidemiologic studies in all ARDS categories (mild,
moderate, and severe). On the X-axis, the studies are chronologically ordered based on
the study period.
 The Epidemiology of ARDS Before and After COVID-19 709

Fig. 2. Estimated mortality rates for patients with moderate-severe ARDS. Hospital mortality
reported in the subgroups of moderate-severe ARDS. Moderate-severe ARDS hospital mor-
tality in the study by Li and colleagues [2011] is reported in two different years of study,
2001 and 2008. On the X-axis, the studies are chronologically ordered based on the study
period.

receive low tidal volume ventilation, there has been no change in mortality.64 It is also
important to note that, in some settings, apparent stability of crude ARDS mortality
may mask changes in case mix (increasing illness severity and comorbidities) and
therefore improving risk-adjusted mortality.9

LONG-TERM OUTCOMES

Despite the significant lung injury experienced during the course of a patient’s illness
with ARDS, postillness pulmonary function tests showed normalization at 5 years after
ICU.65 Despite this normalization in lung function, reported quality-of-life scores and
exercise tolerance, measured by 6-minute walk test, remain lower than average at
5 years. Multiple factors likely contribute to this including persistent weakness and
neuropsychologic impairments. These neuropsychologic issues are heterogeneous
and affect both the patient and their caregivers.65 These patients also accrue larger
health care costs after hospitalization because of increased utilization of the health
care system. ARDS is one of the most common reasons for admission to a long-
term ventilator rehabilitation unit.66

COVID-19

The severe acute respiratory distress syndrome-associated coronavirus-2 was first

identified in December 2019 in Wuhan, Hubei, China, as the agent causing what is
now called COVID-19.67 COVID-19 was officially declared a pandemic by the World
Health Organization on March 11, 2020. As of November 21, 2020, 57,274,018
confirmed cases have been reported with 1,368,000 deaths worldwide.68 While it is
increasingly clear that COVID-19 is a multisystem disease, the primary manifestation
is a viral pneumonia that, in some patients, progresses to ARDS, often complicated by
protracted illness or death.
Mortality estimates for COVID-19-associated ARDS vary widely, ranging from 3.4%
to 88.3% (Table 2).69–74 These estimates are affected by the studied population,
710 Hendrickson et al

Table 2
Twenty-eight-day mortality rate data of patients with ARDS from COVID-19

Authors, Year of
Publication
[Reference] Study Period City, Country Mortality
Yang et al,69 2020 12/24/2019–01/26/2020 Wuhan, China 61.5%
Wang et al,70 2020 01/25/2020–02/25/2020 Shanghai, China 88.3%
Grasselli et al,71 2020 02/20/2020–03/18/2020 Milan, Italy 26%
Ferrando et al,72 2020 03/12/2020–06/01/2020 Spain and Andora 36%
Bhatraju et al,74 2020 02/24/2020–03/09/2020 Seattle, USA 50%*
Gupta et al,73 2020 03/04/2020–04/04/2020 Various cities, USA 6.6%-80.8%
(35.4%)

All patients were admitted to the ICU with ARDS due to COVID-19. All mortalities are 28-d mortality
except the study by *Batraju et al which includes a 14-d mortality.

health system factors (thresholds for hospitalization varied across cohorts substan-
tially), therapeutic context (Early in the pandemic, large numbers of potentially toxic
therapies were administered in cocktails.), institutional context (the degree to which
the studied health care systems were strained by the pandemic surge), and patient-
level risk factors (some sites predominantly cared for patients in nursing homes).
For example, patients admitted to hospitals with fewer ICU beds had higher risk of
death likely because of less training and comfort of caregivers in treating ARDS as
well as limited resources in these settings, particularly in the pandemic context. Crit-
ically, some early mortality studies had insufficient follow-up to provide accurate esti-
mates of morality, excluding patients without a final outcome (discharge or death) and
thereby inflating mortality estimates by excluding patients alive and still in the hospital.
The question of whether and how COVID-19-associated ARDS differs from prior
forms of ARDS has been surprisingly contentious.75 Early anxiety about abrupt
decompensation specific to this condition, the risk of aerosolization and consequent
transmission to caregivers with high-flow nasal cannula oxygen, and lack of effective
therapeutics all played a role, as did clinician perceptions that some patients with
COVID-19 exhibit “happy hypoxemia” and/or higher-than-expected lung compliance
for their degree of hypoxemia.76 The opinion that ARDS resulting from COVID-19
might be exceptional and clinicians’ frustration over the lack of proven treatments
were sometimes associated with calls for application of therapies previously shown
ineffective in general ARDS and even for the use of high-tidal-volume ventilation.
Spring and summer 2020 witnessed a vigorous debate on the issues, with some
thought leaders arguing for novel supportive care, and others arguing that standard
supportive care for ARDS represented the best approach.77,78
While some prognostic factors differ and time from COVID-19 symptom onset to full
ARDS is sometimes slightly longer than with some classic ARDS etiologies,79 most ev-
idence to date suggests that ARDS in COVID-19 lacks important differences from the
syndrome generally. Contradicting the postulated “L-type” (high compliance) and “H-
type” (low compliance) dichotomy advanced by some as unique to COVID-19
ARDS,76,80 the spectrum of lung compliance in COVID-19 ARDS appears similar to
that observed in prior studies of general ARDS.81 Pathologic analysis also shows find-
ings similar to ARDS generally, demonstrating hyaline membrane formation, edema,
and DAD.82 We therefore manage COVID-19 ARDS with the package of evidence-
based care that we apply to ARDS generally, including strict adherence to low-tidal-
volume ventilation,49 consideration of prone positioning,83 and high PEEP for more
 The Epidemiology of ARDS Before and After COVID-19 711

severe ARDS,36 conservative fluid management,84 protocolized spontaneous breath-

ing and awakening trial,85 and early mobilization.86 It is nevertheless plausible that,
given its homogeneous trigger and potentially more homogeneous inflammatory
phenotype, ARDS resulting from COVID-19 could respond to therapies that failed trials
enrolling patients with a heterogeneous array of triggers and endotypes. The apparent
efficacy of steroid therapy in several (imperfect) trials,87,88 a treatment for which trials
in general ARDS population had repeatedly yielded conflicting evidence,89–91 may be
one early example of this phenomenon.

SUMMARY

ARDS remains a common, deadly problem among critically ill patients around the
world. It is a syndrome of significant heterogeneity, with sub-phenotypes requiring
further characterization and tools for prompt clinical identification. COVID-19 has
brought new challenges including a large, and relatively homogeneous, population
of ARDS patients but does not seem to cause a truly unique respiratory failure syn-
drome distinct from ARDS generally nor even engender a truly homogenous subtype
of ARDS. Further advances in ARDS care will likely require improved understanding of
the epidemiology of this syndrome and its subtypes as well as innovative trials of
focused therapeutics. Given the high mortality of the syndrome and its long-term
morbidity, ongoing study into treatment and care of patients with ARDS is paramount.

CLINICS CARE POINTS

 Although acute respiratory distress syndrome (ARDS) has a high incidence among intensive
care unit patients, with high morbidity and mortality, it remains underdiagnosed.
 The Berlin criteria were created to help clearly identify patients with ARDS.
 Supportive measures with low-tidal-volume ventilation, prone positioning, conservative
fluid management strategies, high PEEP for severe disease, protocolized spontaneous
breathing and awakening trials, and early mobilization have lowered the morbidity and
mortality of ARDS and are the cornerstone of therapy.
 COVID-19-associated ARDS is a syndrome on the ARDS spectrum and should therefore be
treated with the same strategies as classic ARDS while we await results of ongoing trials.

DISCLOSURE

K.W. Hendrickson declares no disclosures. I.D. Peltan reports receiving research sup-
port from the National Institutes of Health, Centers for Disease Control, Janssen Phar-
maceuticals, and Immunexpress, Inc. and support to institution from Regeneron and
Asahi Kasei Pharma. S.M. Brown-please see pdf in Other Content tab.

REFERENCES

1. Bellani G, et al. Epidemiology, patterns of care, and mortality for patients with
acute respiratory distress syndrome in intensive care units in 50 countries.
JAMA 2016;315(8):788–800.
2. Force ADT, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA
2012;307(23):2526–33.
3. Ashbaugh DG, et al. Acute respiratory distress in adults. Lancet 1967;2(7511):
319–23.
712 Hendrickson et al

4. Nolan S, et al. Acute respiratory distress syndrome in a community hospital ICU.

Intensive Care Med 1997;23(5):530–8.
5. Luhr OR, et al. Incidence and mortality after acute respiratory failure and acute
respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study
Group. Am J Respir Crit Care Med 1999;159(6):1849–61.
6. Bersten AD, et al. Incidence and mortality of acute lung injury and the acute res-
piratory distress syndrome in three Australian States. Am J Respir Crit Care Med
2002;165(4):443–8.
7. Rubenfeld GD, et al. Incidence and outcomes of acute lung injury. N Engl J Med
2005;353(16):1685–93.
8. Manzano F, et al. Incidence of acute respiratory distress syndrome and its relation
to age. J Crit Care 2005;20(3):274–80.
9. Li G, et al. Eight-year trend of acute respiratory distress syndrome: a population-
based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011;
183(1):59–66.
10. Caser EB, et al. Impact of distinct definitions of acute lung injury on its incidence
and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients*. Crit
Care Med 2014;42(3):574–82.
11. Linko R, et al. Acute respiratory failure in intensive care units. FINNALI: a pro-
spective cohort study. Intensive Care Med 2009;35(8):1352–61.
12. Villar J, et al. The ALIEN study: incidence and outcome of acute respiratory
distress syndrome in the era of lung protective ventilation. Intensive Care Med
2011;37(12):1932–41.
13. Brun-Buisson C, et al. Epidemiology and outcome of acute lung injury in Euro-
pean intensive care units. Results from the ALIVE study. Intensive Care Med
2004;30(1):51–61.
14. Irish Critical Care Trials, G. Acute lung injury and the acute respiratory distress
syndrome in Ireland: a prospective audit of epidemiology and management.
Crit Care 2008;12(1):R30.
15. Sigurdsson MI, et al. Acute respiratory distress syndrome: nationwide changes in
incidence, treatment and mortality over 23 years. Acta Anaesthesiol Scand 2013;
57(1):37–45.
16. Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult
respiratory distress syndrome. Clin Chest Med 1982;3(1):35–56.
17. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syn-
drome. Clin Chest Med 1990;11(4):593–619.
18. Hoelz C, et al. Morphometric differences in pulmonary lesions in primary and sec-
ondary ARDS. A preliminary study in autopsies. Pathol Res Pract 2001;197(8):
521–30.
19. Moss M, et al. Diabetic patients have a decreased incidence of acute respiratory
distress syndrome. Crit Care Med 2000;28(7):2187–92.
20. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury.
Chest 2007;131(2):554–62.
21. Ni YN, et al. Can body mass index predict clinical outcomes for patients with
acute lung injury/acute respiratory distress syndrome? A meta-analysis. Crit
Care 2017;21(1):36.
22. Zhi G, et al. Obesity paradox" in acute respiratory distress syndrome: asyste-
matic review and meta-analysis. PLoS One 2016;11(9):e0163677.
23. McCallister JW, Adkins EJ, O’Brien JM Jr. Obesity and acute lung injury. Clin
Chest Med 2009;30(3):495–508, viii.
 The Epidemiology of ARDS Before and After COVID-19 713

24. Stensrud MJ, Valberg M, Aalen OO. Can collider bias explain paradoxical asso-
ciations? Epidemiology 2017;28(4):e39–40.
25. Kaphalia L, Calhoun WJ. Alcoholic lung injury: metabolic, biochemical and immu-
nological aspects. Toxicol Lett 2013;222(2):171–9.
26. Calfee CS, et al. Cigarette smoke exposure and the acute respiratory distress
syndrome. Crit Care Med 2015;43(9):1790–7.
27. Hsieh SJ, et al. Prevalence and impact of active and passive cigarette smoking in
acute respiratory distress syndrome. Crit Care Med 2014;42(9):2058–68.
28. Ware LB, et al. Long-term ozone exposure increases the risk of developing the
acute respiratory distress syndrome. Am J Respir Crit Care Med 2016;193(10):
1143–50.
29. Erickson SE, et al. Racial and ethnic disparities in mortality from acute lung injury.
Crit Care Med 2009;37(1):1–6.
30. Meyer NJ, Christie JD. Genetic heterogeneity and risk of acute respiratory
distress syndrome. Semin Respir Crit Care Med 2013;34(4):459–74.
31. Laffey JG, et al. Potentially modifiable factors contributing to outcome from acute
respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med 2016;
42(12):1865–76.
32. Calfee CS, et al. Trauma-associated lung injury differs clinically and biologically
from acute lung injury due to other clinical disorders. Crit Care Med 2007;
35(10):2243–50.
33. Tejera P, et al. Distinct and replicable genetic risk factors for acute respiratory
distress syndrome of pulmonary or extrapulmonary origin. J Med Genet 2012;
49(11):671–80.
34. Villar J, et al. A universal definition of ARDS: the PaO2/FiO2 ratio under a stan-
dard ventilatory setting–a prospective, multicenter validation study. Intensive
Care Med 2013;39(4):583–92.
35. Thille AW, et al. Comparison of the Berlin definition for acute respiratory distress
syndrome with autopsy. Am J Respir Crit Care Med 2013;187(7):761–7.
36. Guo L, et al. Higher PEEP improves outcomes in ARDS patients with clinically
objective positive oxygenation response to PEEP: a systematic review and
meta-analysis. BMC Anesthesiol 2018;18(1):172.
37. Brower RG, et al. Higher versus lower positive end-expiratory pressures in pa-
tients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):
327–36.
38. Meade MO, et al. Ventilation strategy using low tidal volumes, recruitment maneu-
vers, and high positive end-expiratory pressure for acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial. JAMA 2008;
299(6):637–45.
39. Mercat A, et al. Positive end-expiratory pressure setting in adults with acute lung
injury and acute respiratory distress syndrome: a randomized controlled trial.
JAMA 2008;299(6):646–55.
40. Papazian L, et al. Neuromuscular blockers in early acute respiratory distress syn-
drome. N Engl J Med 2010;363(12):1107–16.
41. National Heart L, et al. Early neuromuscular blockade in the acute respiratory
distress syndrome. N Engl J Med 2019;380(21):1997–2008.
42. Shaver CM, Bastarache JA. Clinical and biological heterogeneity in acute respi-
ratory distress syndrome: direct versus indirect lung injury. Clin Chest Med 2014;
35(4):639–53.
714 Hendrickson et al

43. Bernard GR, et al. The American-European Consensus Conference on ARDS.

Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am
J Respir Crit Care Med 1994;149(3 Pt 1):818–24.
44. Pelosi P, et al. Pulmonary and extrapulmonary acute respiratory distress syn-
drome are different. Eur Respir J Suppl 2003;42:48s–56s.
45. Gattinoni L, et al. Acute respiratory distress syndrome caused by pulmonary and
extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 1998;
158(1):3–11.
46. Albaiceta GM, et al. Differences in the deflation limb of the pressure-volume
curves in acute respiratory distress syndrome from pulmonary and extrapulmo-
nary origin. Intensive Care Med 2003;29(11):1943–9.
47. Calfee CS, et al. Distinct molecular phenotypes of direct vs indirect ARDS in
single-center and multicenter studies. Chest 2015;147(6):1539–48.
48. Agarwal R, et al. Is the mortality higher in the pulmonary vs the extrapulmonary
ARDS? A meta analysis. Chest 2008;133(6):1463–73.
49. Acute Respiratory Distress Syndrome, N, et al. Ventilation with lower tidal volumes
as compared with traditional tidal volumes for acute lung injury and the acute res-
piratory distress syndrome. N Engl J Med 2000;342(18):1301–8.
50. Calfee CS, et al. Subphenotypes in acute respiratory distress syndrome: latent
class analysis of data from two randomised controlled trials. Lancet Respir
Med 2014;2(8):611–20.
51. Calfee CS, et al. Acute respiratory distress syndrome subphenotypes and differ-
ential response to simvastatin: secondary analysis of a randomised controlled
trial. Lancet Respir Med 2018;6(9):691–8.
52. Pham T, Rubenfeld GD. Fifty years of research in ARDS. The epidemiology of
acute respiratory distress syndrome. A 50th birthday review. Am J Respir Crit
Care Med 2017;195(7):860–70.
53. Ferguson ND, et al. Acute respiratory distress syndrome: underrecognition by cli-
nicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005;
33(10):2228–34.
54. Frohlich S, et al. Acute respiratory distress syndrome: underrecognition by clini-
cians. J Crit Care 2013;28(5):663–8.
55. Gajic O, et al. Early identification of patients at risk of acute lung injury: evaluation
of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care
Med 2011;183(4):462–70.
56. Trillo-Alvarez C, et al. Acute lung injury prediction score: derivation and validation
in a population-based sample. Eur Respir J 2011;37(3):604–9.
57. Soto GJ, et al. Lung injury prediction score in hospitalized patients at risk of acute
respiratory distress syndrome. Crit Care Med 2016;44(12):2182–91.
58. Kor DJ, et al. Effect of aspirin on development of ARDS in at-risk patients present-
ing to the emergency department: the LIPS-A randomized clinical trial. JAMA
2016;315(22):2406–14.
59. Serpa Neto A, et al. Association between use of lung-protective ventilation with
lower tidal volumes and clinical outcomes among patients without acute respira-
tory distress syndrome: a meta-analysis. JAMA 2012;308(16):1651–9.
60. Writing Group for the, P.I, et al. Effect of a low vs intermediate tidal volume strat-
egy on ventilator-free days in intensive care unit patients without ARDS: a ran-
domized clinical trial. JAMA 2018;320(18):1872–80.
61. Lanspa MJ, et al. Prospective assessment of the feasibility of a trial of low-tidal
volume ventilation for patients with acute respiratory failure. Ann Am Thorac
Soc 2019;16(3):356–62.
 The Epidemiology of ARDS Before and After COVID-19 715

62. Falci L, et al. Examination of cause-of-death data quality among New York city
deaths due to cancer, pneumonia, or diabetes from 2010 to 2014. Am J Epide-
miol 2018;187(1):144–52.
63. Cochi SE, et al. Mortality trends of acute respiratory distress syndrome in the
United States from 1999 to 2013. Ann Am Thorac Soc 2016;13(10):1742–51.
64. Walkey AJ, et al. Acute respiratory distress syndrome: epidemiology and man-
agement approaches. Clin Epidemiol 2012;4:159–69.
65. Herridge MS, et al. Functional disability 5 years after acute respiratory distress
syndrome. N Engl J Med 2011;364(14):1293–304.
66. Mamary AJ, et al. Survival in patients receiving prolonged ventilation: factors that
influence outcome. Clin Med Insights Circ Respir Pulm Med 2011;5:17–26.
67. Zhu N, et al. A novel coronavirus from patients with pneumonia in China, 2019.
N Engl J Med 2020;382(8):727–33.
68. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019?
gclid5EAIaIQobChMIoNWJg6m86wIVjcDACh2RZAFnEAAYASAAEgI7APD_BwE.
Accessed August 27, 2020.
69. Yang X, et al. Clinical course and outcomes of critically ill patients with SARS-
CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observa-
tional study. Lancet Respir Med 2020;8(5):475–81.
70. Wang Y, et al. Clinical course and outcomes of 344 intensive care patients with
COVID-19. Am J Respir Crit Care Med 2020;201(11):1430–4.
71. Grasselli G, et al. Baseline characteristics and outcomes of 1591 patients in-
fected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA
2020;323(16):1574–81.
72. Ferrando C, et al. Clinical features, ventilatory management, and outcome of
ARDS caused by COVID-19 are similar to other causes of ARDS. Intensive
Care Med 2020;46(12):2200–11.
73. Gupta S, et al. Factors associated with death in critically ill patients with corona-
virus disease 2019 in the US. JAMA Intern Med 2020;180(11):1436–47.
74. Bhatraju PK, et al. Covid-19 in critically ill patients in the seattle region - case se-
ries. N Engl J Med 2020;382(21):2012–22.
75. Barbeta E, et al. SARS-CoV-2-induced acute respiratory distress syndrome: pul-
monary mechanics and gas-exchange abnormalities. Ann Am Thorac Soc 2020;
17(9):1164–8.
76. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA
2020;323(22):2329–30.
77. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress
syndrome from COVID-19. Lancet Respir Med 2020;8(5):433–4.
78. Wiersinga WJ, et al. Pathophysiology, transmission, diagnosis, and treatment of
coronavirus disease 2019 (COVID-19): a review. JAMA 2020;324(8):782–93.
79. Li X, Ma X. Acute respiratory failure in COVID-19: is it "typical" ARDS? Crit Care
2020;24(1):198.
80. Gattinoni L, et al. COVID-19 pneumonia: different respiratory treatments for
different phenotypes? Intensive Care Med 2020;46(6):1099–102.
81. Panwar R, et al. Compliance phenotypes in early acute respiratory distress syn-
drome before the COVID-19 pandemic. Am J Respir Crit Care Med 2020;202(9):
1244–52.
82. Calabrese F, et al. Pulmonary pathology and COVID-19: lessons from autopsy.
The experience of European Pulmonary Pathologists. Virchows Arch 2020;
477(3):359–72.
716 Hendrickson et al

83. Guerin C, Reignier J, Richard JC. Prone positioning in the acute respiratory
distress syndrome. N Engl J Med 2013;369(10):980–1.
84. National Heart L, et al. Comparison of two fluid-management strategies in acute
lung injury. N Engl J Med 2006;354(24):2564–75.
85. Girard TD, et al. Efficacy and safety of a paired sedation and ventilator weaning
protocol for mechanically ventilated patients in intensive care (Awakening and
Breathing Controlled trial): a randomised controlled trial. Lancet 2008;
371(9607):126–34.
86. Taito S, et al. Early mobilization of mechanically ventilated patients in the intensive
care unit. J Intensive Care 2016;4:50.
87. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hos-
pitalized patients with Covid-19. N Engl J Med 2021;384(8):693–704. https://doi.
org/10.1056/NEJMoa2021436.
88. Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: evidence and Hope
during the pandemic. JAMA 2020;324(13):1292–5.
89. Schein RM, et al. Complement activation and corticosteroid therapy in the devel-
opment of the adult respiratory distress syndrome. Chest 1987;91(6):850–4.
90. Peter JV, et al. Corticosteroids in the prevention and treatment of acute respira-
tory distress syndrome (ARDS) in adults: meta-analysis. BMJ 2008;336(7651):
1006–9.
91. Villar J, et al. Dexamethasone treatment for the acute respiratory distress syn-
drome: a multicentre, randomised controlled trial. Lancet Respir Med 2020;
8(3):267–76.
92. Sakr Y, et al. High tidal volume and positive fluid balance are associated with
worse outcome in acute lung injury. Chest 2005;128(5):3098–108.