CYIR

Clinical Year in Review

2023
[Link] Washington, DC | May 19-24
 2023

Clinical Year in Review

Bibliography
MODERATORS
Rupal J. Shah, MD, MSCE
University of California, San Francisco
Department of Medicine
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
San Francisco, CA

Juliana C. Ferreira, MD, PhD, ATSF

University of Sao Paulo
Pulmonary Division
Sao Paulo, Brazil

Sara Auld, MD, MSc

Emory University
Division of Pulmonary and Critical Care Medicine
Atlanta, GA

TABLE OF CONTENTS
A1
• ARDS ............................................................................................................. 4
• Pulmonary Vascular Disease................................................................ 9
• COPD............................................................................................................ 16
• Interstitial Lung Disease...................................................................... 21
This session and the International Conference are supported by
independent medical educational grants from Actelion Pharmaceuticals
US, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson,
AstraZeneca LP, Boehringer Ingelheim Pharmaceuticals, Inc., and Merck
& Co.
B1
• Lung Cancer ............................................................................................ 26
• COVID-19 ................................................................................................... 31
• Palliative Care..........................................................................................36
• Critical Care.............................................................................................. 42
This session and the International Conference are supported by an
independentmedical educational grant from Merck & Co.

Table of contents continued on next page

1SECTION Table of Contents
 2023

Clinical Year in Review

Bibliography

TABLE OF CONTENTS CONTINUED

C1
• Asthma...................................................................................................... 48
• Sarcoidosis............................................................................................... 52
• Sepsis.......................................................................................................... 57
• Sleep........................................................................................................... 63
This session and the International Conference are supported by an
independentmedical educational grant from Boehringer Ingelheim
Pharmaceuticals, Inc.

D1
• Lung Transplant...................................................................................... 70
• Medical Education................................................................................. 76
• Health Equity............................................................................................ 81
• CF/non-CF Bronchiectasis................................................................... 87
This session and the International Conference are supported by an
independent medical educational grant from Insmed Incorporated,
Vertex Pharmaceuticals, and Zambon.

2
SECTION Table of Contents
 Clinical Year in Review

ARDS
Derek W. Russell, MD
University of Alabama at Birmingham
Department of Medicine; Division of Pulmonary, Allergy and Critical Care Medicine
Birmingham, Alabama

IMPACT ON LONG-TERM PATIENT-CENTERED OUTCOMES and cognitive domains, and these symptoms were
OF CRITICAL ILLNESS DUE TO COVID-19 often disabling, with 58% of patients reporting
problems returning to work.
Heesakkers H, van der Hoeven JG, Corsten S, Janssen I, 2. The same group also recently demonstrated that
Ewalds E, Simons KS, Westerhof B, Rettig TCD, Jacobs C, obesity is a significant risk factor for development
van Santen S, Slooter AJC, van der Woude MCE, van den of new, persistent physical, emotional, and
Boogaard M, Zegers M. Clinical Outcomes Among cognitive impairments among survivors of critical
Patients With 1-Year Survival Following Intensive Care illness due to COVID-19 (Kooistra E, Heesakkers H,
Unit Treatment for COVID-19. JAMA 2022; 327: 559-565. Pickkers P, Zegers M, van den Boogaard M. Long-
Term Impairments Are Most Pronounced in Critically
Summary Ill Patients with COVID-19 with Severe Obesity. Am J
In this multicenter, prospective cohort study conducted Respir Crit Care Med 2022; 206: 1037-1039.).
in the Netherlands, the outcomes and symptom burden 3. The long-term sequelae of COVID-19 itself are likely
of 246 survivors of critical illness due to COVID-19 who to be inextricably intertwined with the sequelae of
completed questionnaires one year after their ICU critical illness, as significant long-term sequelae of
treatment are described. This study adds to a large COVID-19 has also been reported in other cohorts
body of evidence that the critical illness experience (as comprised of COVID-19 patients who were less
well as COVID-19 itself) are associated with physical, acutely ill on average during their index
emotional, and cognitive impairments persisting long hospitalization (Admon AJ, Iwashyna TJ, Kamphuis
beyond the nominal recovery and hospital discharge in LA, Gundel SJ, Sahetya SK, Peltan ID, Chang SY, Han
a great number of ICU survivors. Given the magnitude JH, Vranas KC, Mayer KP, Hope AA, Jolley SE, Caldwell
and scope of the ongoing pandemic, these findings E, Monahan ML, Hauschildt K, Brown SM, Aggarwal
suggest an enormous societal burden of such NR, Thompson BT, Hough CL, National Heart L, Blood
symptoms that are likely largely attributable to the ICU Institute PN. Assessment of Symptom, Disability,
experience. Bedside practitioners, researchers, and and Financial Trajectories in Patients Hospitalized
healthcare policy-makers must urgently pursue means for COVID-19 at 6 Months. JAMA Netw Open 2023; 6:
of mitigating this reality. Furthermore, clinicians must e2255795.).
be cognizant of the important downstream sequelae of 4. Supporting the notion that the sequelae of COVID-
COVID-19, ARDS and other critical illnesses as these may 19 itself and those of critical illness per se may be
inform not only our bedside compassion and clinical additive, the prevalence of problems returning to
judgement, but also our prognostication and work in this cohort was 58%, compared to 42% in a
discussions of therapeutic goals with patients, families similar Dutch study conducted prior to COVID-19
and other healthcare surrogates. Lastly, this report (Geense WW, Zegers M, Peters MAA, Ewalds E,
underscores the importance of strategies (e.g., Simons KS, Vermeulen H, van der Hoeven JG, van
protocols to avoid benzodiazepines and unnecessary den Boogaard M. New Physical, Mental, and
analgo-sedation in general, robust ventilator liberation Cognitive Problems 1 Year after ICU Admission: A
protocols, and physical rehabilitation) designed to Prospective Multicenter Study. Am J Respir Crit Care
reduce the long-term sequelae of critical illness. Med 2021; 203: 1512-1521.).
5. A high burden of persistent mental health
Comments symptoms has also been described in family
1. In this report, almost 3/4 of ICU survivors had members of critical illness due to COVID-19
physical impairment persisting 1 year after the (Heesakkers H, van der Hoeven JG, Corsten S,
index illness, and 10.5% of ICU survivors had Janssen I, Ewalds E, Burgers-Bonthuis D, Rettig TCD,
concurrent impairments in the physical, emotional, Jacobs C, van Santen S, Slooter AJC, van der Woude

ARDS 4
 Clinical Year in Review

MCE, Zegers M, van den Boogaard M. Mental health PILOT and other recent studies of this question
symptoms in family members of COVID-19 ICU have not excluded such differences.
survivors 3 and 12 months after ICU admission: a 4. The point estimates of ventilator-free days between
multicentre prospective cohort study. Intensive Care oxygen target assignments in the subset of patients
Med 2022; 48: 322-331.). who had ARDS (N=190) suggest that targeting a
higher oxygen saturation of 98% (96-100 range) is
OPTIMIZING OXYGEN SATURATION TARGET RANGE unlikely to be harmful in ARDS patients relative to
targeting an oxygen saturation of 94% or lower.
Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays MA, 5. An ongoing, international study of oxygen targets
Stollings JL, Buell KG, Brems JH, Qian ET, Seitz KP, Wang (Mega-ROX) in the critically ill will be powered
L, Lindsell CJ, Freundlich RE, Wanderer JP, Han JH, (N=40,000) to detect smaller but likely clinically
Bernard GR, Self WH, Rice TW, Investigators P, the relevant differences in patient outcomes between
Pragmatic Critical Care Research G. Oxygen-Saturation lower and higher oxygen target ranges.
Targets for Critically Ill Adults Receiving Mechanical
Ventilation. N Engl J Med 2022; 387: 1759-1769. STEPS TOWARD PERSONALIZED CARE IN ARDS

Summary Chen H, Yu Q, Xie J, Liu S, Pan C, Liu L, Huang Y, Guo F,

Continuous monitoring of arterial oxygen saturation is a Qiu H, Yang Y. Longitudinal phenotypes in patients with
fundamental aspect of care of patients with ARDS and acute respiratory distress syndrome: a multi-database
other forms of hypoxemic respiratory failure receiving study. Crit Care 2022; 26: 340.
invasive mechanical ventilation. There exist multiple
mechanisms by which both low and high levels of Summary
oxygen in the lung, blood, and/or tissues may cause ARDS is characterized by varying pathophysiology; this
harm in the critically ill. Multiple recent studies have heterogeneity presents a barrier to finding and testing
suggested that targeting lower and higher oxygen levels ARDS treatments. Using latent class analysis (LCA), prior
may lead to similar patient outcomes. PILOT is the first work by Carolyn Calfee’s group has demonstrated two
large, randomized trial to compare outcomes with use major sub-phenotypes of disease among ARDS patients
of an intermediate oxygen target range to lower and (hyper- and hypo-inflammatory). These are
higher oxygen targets. This pragmatic, cluster- distinguished by inflammatory biomarker levels and
randomized, cluster-crossover trial enrolled 2,541 clinical parameters, are associated with different
patients receiving invasive ventilation at single center outcomes and appear to have differential responses to
in the US. 22 clusters were randomized to pulse therapies. In this retrospective, multi-database study of
oximetry readings of either low (between 88-92%), ARDS patients (derived from the Chinese Database in
intermediate (92-96%) or high (96-100%) target ranges. Intensive Care and validated in cohorts from four prior
No significant difference in the primary outcome of randomized ARDS trials), LCA was performed using
ventilator-free days was seen between any of these these and additional parameters (including chest
groups. This provides reassurance that there is unlikely imaging variables and change in respiratory mechanics
to be a large difference in ventilator-free days between over time). Using this approach, they reported the best
lower, intermediate, and higher oxygen saturation fit to be with not two, but three ARDS sub-phenotypes
targets. with divergent characteristics, outcomes and treatment
effects. Due to the added complexity and longitudinal
Comments nature of the classification system used by Chen and
1. The incidence of significant hyperoxemia in the high colleagues, it is likely further from translation into
saturation target range group was low, so this trial research or practice than the cross-sectional
does not speak to the safety of supraphysiological hyper/hypo-inflammatory ARDS sub-phenotype
partial pressures of oxygen relative to normal or dichotomy. However, this paradigm may distinguish
lower values. between biologically diverse groups identifiable with
2. In the context of this and other recent studies longitudinal data, and, after further validation, could
comparing low and high oxygenation targets, it is potentially be incorporated into the design of eventual
likely that any difference in outcomes between response-adaptive ARDS trials.
oxygenation target ranges is small.
3. Given the frequency with which peripheral arterial
oxygen saturation monitoring is used, a small
difference between outcomes may be important;

ARDS 5
 Clinical Year in Review

Comments Summary
1. One of the ultimate goals of ARDS patient Multiple reports have now described a subset of ARDS
classification by latent class analysis is to derive a patients who exhibit a paradoxical improvement in
set of patients predicted to respond in similar ways driving pressure, plateau pressure, and compliance in
to a given therapeutic strategy (e.g., personalized response to various maneuvers that entail application
medicine and trials using predictive enrichment). of extrinsic compression to the respiratory system.
2. Research exploring the biological underpinnings of These simple bedside techniques include firm manual
ARDS sub-phenotypes and development of ARDS abdominal compression and postural changes. A
sub-phenotype experimental models are needed counter-intuitive response to increased external
for sub-phenotype descriptions such as this article pressure on the respiratory system is thought to be the
to translate into “treatable traits” that can be result of hyperinflated alveolar units. As such, these
exploited at the bedside with agents effective for a maneuvers may be useful techniques for detecting end-
given patient’s pathophysiology. tidal hyperinflation in ARDS patients to inform
3. Development of techniques and technologies to ventilator management and optimization of PEEP
rapidly sub-phenotype patients is another critical settings. This phenomenon garnered attention recently
area for the translation of ARDS sub-phenotype after a report by Kummer and colleagues (2021, Chest)
research, and ongoing work to that end likely hold of a series of late-phase ARDS patients with COVID-19
the key to advancement of disease-modifying who displayed hyperinflation associated with
therapies in ARDS (e.g., PHIND NCT04009330 and I- paradoxical improvements of compliance upon manual
SPY COVID (I-SPY COVID Consortium. Clinical trial abdominal compression at bedside; a number of case
design during and beyond the pandemic: the I-SPY series have now been published demonstrating similar
COVID trial. Nat Med 2022; 28: 9-11.). findings with other techniques that constrain chest wall
4. There may sometimes be a tradeoff between the expansion. This interpretive review article, which
descriptive power of a sub-phenotype classification includes helpful illustrations, summarizes the
system and its clinical utility or simplicity; work physiology of chest wall interactions with the
exploring both ends of this spectrum ultimately are respiratory system, applies them to these recently
needed to advance our treatment, and published observations, and articulates the remaining
understanding, of ARDS. questions concerning the potential utility of such
5. Another recent example of the tradeoff between maneuvers in clinical practice.
biological accuracy and simplicity may be seen can
be found in work by Sathe and colleagues, who Comments
observed minimal overlap between classifications 1. As published reports thus far have been
of patients on the basis of the inflammatory profile observational in nature and relatively recent, the
in plasma relative to that of their bronchoalveolar physiological significance of improvements in
lavage fluid, suggesting that biomarkers of respiratory mechanics with extrinsic compression
inflammation in the alveolar compartment may on the respiratory system remain somewhat
contribute additional sub-phenotype classification speculative, but the interpretations proposed in this
power relative to plasma biomarkers alone (Sathe article may explain them.
NA, Morrell ED, Bhatraju PK, Fessler MB, Stapleton 2. Much remains to be understood about this
RD, Wurfel MM, Mikacenic C. Alveolar Biomarker phenomenon, including its incidence, natural
Profiles in Subphenotypes of the Acute Respiratory history, correlation with altered ARDS and ventilator
Distress Syndrome. Crit Care Med 2023; 51: e13-e18.). management strategies.
3. The extent to which the extrinsic compression
maneuvers discussed in this article add new
VENTILATOR MANAGEMENT IN ARDS: NOVEL BEDSIDE information to other readily available techniques
TECHNIQUES FOR DETECTION OF HYPERINFLATION (e.g. ventilator waveform analysis, driving pressure
dynamics in response to PEEP changes, etc.)
Selickman J, Marini JJ. Chest wall loading in the ICU: regarding the presence or absence of hyperinflation
pushes, weights, and positions. Ann Intensive Care. 2022 is unknown.
Nov 8;12(1):103. doi: 10.1186/s13613-022-01076-8. PMID: 4. Nonetheless, published associations between the
36346532; PMCID: PMC9640797. presence of this phenomenon, alveolar
hyperinflation and improved respiratory mechanics
after PEEP reductions, along with the ease and low

ARDS 6
 Clinical Year in Review

cost of maneuvers to elicit them, suggest potential BEST PRACTICES IN TRACHEAL INTUBATION: FLUID BOLUS
for clinical utility. FOR PREVENTION OF POST-INTUBATION
5. Awareness of this phenomenon at bedside may aid CARDIOVASCULAR COLLAPSE
providers in maintaining vigilance for otherwise
unrecognized hyperinflation in invasively ventilated Russell DW, Casey JD, Gibbs KW, Ghamande S, Dargin JM,
ARDS patients. Vonderhaar DJ, Joffe AM, Khan A, Prekker ME, Brewer JM,
Dutta S, Landsperger JS, White HD, Robison SW, Wozniak
JM, Stempek S, Barnes CR, Krol OF, Arroliga AC, Lat T,
EARLY VENTILATORY RATIO TRAJECTORY IS ASSOCIATED Gandotra S, Gulati S, Bentov I, Walters AM, Dischert KM,
WITH MORTALITY IN ARDS PATIENTS Nonas S, Driver BE, Wang L, Lindsell CJ, Self WH, Rice TW,
Janz DR, Semler MW, Investigators PI, the Pragmatic
Monteiro ACC, Vangala S, Wick KD, Delucchi KL, Siegel ER, Critical Care Research G. Effect of Fluid Bolus
Thompson BT, Liu KD, Sapru A, Sinha P, Matthay MA; Administration on Cardiovascular Collapse Among
NHLBI PETAL Network. The prognostic value of early Critically Ill Patients Undergoing Tracheal Intubation: A
measures of the ventilatory ratio in the ARDS ROSE trial. Randomized Clinical Trial. JAMA 2022; 328: 270-279.
Crit Care. 2022 Sep 29;26(1):297.
Summary
Summary Tracheal intubation (a procedure almost universally
The ratio of dead space to tidal volume has previously applied to ARDS patients) is associated with high rates
been strongly associated with adverse outcome in of severe hypotension and cardiac arrest in intensive
ARDS, with a higher predictive value than many care settings. Routine use of a 500 mL fluid bolus is a
commonly used prognostic factors such as oxygenation commonly-used, guideline-recommended intervention
index, but it is cumbersome to perform and requires meant to prevent such complications during intubation.
specialized equipment. Ventilatory ratio (VR, [minute In 2019, the PrePARE trial found that fluid bolus was
ventilation × PaCO2]/[predicted body weight × 100 × 37.5) ineffective overall, but some subgroups (namely,
may serve as a useful surrogate for the ratio of dead patients treated with positive pressure ventilation in
space to tidal volume as it is derived entirely from the course of tracheal intubation) appeared to benefit
readily-available clinical data. In this retrospective from fluid bolus. In the 1,065-patient PREPARE II trial, a
analysis of the ROSE trial (neuromuscular blockade predictive enrichment strategy was used, in which
versus usual care with light sedation in US patients with patients undergoing positive pressure ventilation
moderate-severe ARDS), baseline VR and VR trajectory during tracheal intubation were enrolled. PREPARE II
over time were found to be significantly associated with found that the routine use of a 500 mL fluid bolus was
mortality. VR is a promising method for prognostic not effective in preventing cardiovascular collapse.
enrichment for organ failure due to ARDS. Given these results as well as other studies (e.g., the
PrePARE trial and a recent secondary analysis of the
Comments INTUBE study), routine use of a 500 mL fluid bolus
1. The association between VR and mortality was should no longer be recommended. Other aspects of
strongest among patients with lower APACHE III this complex, high-risk, and typically urgent procedure
scores, perhaps due to mortality being driven should instead be emphasized. Further research is
increasingly by extra-pulmonary organ failure in needed to identify whether other strategies (e.g., use of
patients as APACHE III score increases. prophylactic vasopressors and/or alternative anesthetic
2. Female patients were much more likely to have an induction agents) are effective for preventing
elevated VR than males, but the biology of this hemodynamic sequelae of tracheal intubation.
finding is unknown.
Comments
1. This study does not address the question of
whether personalized fluid resuscitation is effective.
2. These findings also do not apply to other
indications for fluid bolus, such as resuscitation in
sepsis, hemorrhage, and pancreatitis.
3. Although they have been independently associated
with mortality in multiple studies, it is doubtful
whether the composite primary outcome used in
PREPARE II (cardiovascular collapse) or the most

ARDS 7
 Clinical Year in Review

common component of this endpoint (new or

increased vasopressors during tracheal intubation) Massart N, Guervilly C, Mansour A, Porto A, Flecher E,
are meaningful to patients per se. Esvan M, Fougerou C, Fillatre P, Duburcq T, Lebreton G,
Para M, Stephan F, Hraiech S, Ross JT, Schmidt M,
Vincentelli A, Nesseler N, Extracorporeal Membrane
Oxygenation for Respiratory Failure and/or Heart
OTHER ARTICLES OF INTEREST failure related to Severe Acute Respiratory Syndrome
Coronavirus I. Impact of Prone Position in COVID-19
Kooistra E, Heesakkers H, Pickkers P, Zegers M, van den Patients on Extracorporeal Membrane Oxygenation. Crit
Boogaard M. Long-Term Impairments Are Most Care Med 2023; 51: 36-46.
Pronounced in Critically Ill Patients with COVID-19 with
Severe Obesity. Am J Respir Crit Care Med. 2022 Oct Hernandez G, Paredes I, Moran F, Buj M, Colinas L,
15;206(8):1037-1039. doi: 10.1164/rccm.202202-0376LE. Rodriguez ML, Velasco A, Rodriguez P, Perez-Pedrero MJ,
PMID: 35696647; PMCID: PMC9801993. Suarez-Sipmann F, Canabal A, Cuena R, Blanch L, Roca
O. Effect of postextubation noninvasive ventilation with
Giani M, Rezoagli E, Guervilly C, Rilinger J, Duburcq T, active humidification vs high-flow nasal cannula on
Petit M, Textoris L, Garcia B, Wengenmayer T, Bellani G, reintubation in patients at very high risk for extubation
Grasselli G, Pesenti A, Combes A, Foti G, Schmidt M, failure: a randomized trial. Intensive Care Med 2022; 48:
European Prone positioning During Extracorporeal 1751-1759.
Membrane Oxygenation I. Timing of Prone Positioning
During Venovenous Extracorporeal Membrane El-Solh AA, Aquilina A, Pineda L, Dhanvantri V, Grant B,
Oxygenation for Acute Respiratory Distress Syndrome. Bouquin P. Noninvasive ventilation for prevention of
Crit Care Med 2023; 51: 25-35. post-extubation respiratory failure in obese patients.
Eur Respir J 2006; 28: 588-595.

Heesakkers H, van der Hoeven JG, Corsten S, Janssen I,

Ewalds E, Burgers-Bonthuis D, Rettig TCD, Jacobs C, van
Santen S, Slooter AJC, van der Woude MCE, Zegers M, van
den Boogaard M. Mental health symptoms in family
members of COVID-19 ICU survivors 3 and 12 months
after ICU admission: a multicentre prospective cohort
study. Intensive Care Med 2022; 48: 322-331

ARDS 8
 Clinical Year in Review

Pulmonary Vascular Disease

Gustavo A. Heresi, MD, MS
Cleveland Clinic
Pulmonary Medicine
Cleveland, Ohio

2022 ESC/ERS PULMONARY HYPERTENSION GUIDELINES now endorsed. “Severe PH” in the context of left heart
Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger or lung disease is now defined as a PVR > 5 Wood units.
RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P,
Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely
DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke- Comments
Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, 1. The new definition of PH is meant to lead to early
Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, recognition of pulmonary vascular disease with a
Delcroix M, Rosenkranz S; ESC/ERS Scientific Document goal of implementing preventive measures when
Group. 2022 ESC/ERS Guidelines for the diagnosis and feasible, and not necessarily a recommendation to
treatment of pulmonary hypertension. Eur Respir J. 2023 treat with PH-targeted therapies.
Jan 6;61(1):2200879. doi: 10.1183/13993003.00879-2022. 2. It remains to be determined the impact of these
PMID: 36028254. updated hemodynamic thresholds on the burden of
PH, proper use of PH-targeted therapies, and the
Summary socio-economic impact on patients and health care
systems.
The 2022 ESC/ERS Pulmonary Hypertension (PH)
3. Patients at intermediate-high risk using the 4-strata
Guidelines represent the most comprehensive
risk assessment during follow up are viewed as
document containing current knowledge and updated
high-risk patients in need of escalation of therapy
evidence-based recommendations for the diagnosis
or referral to lung transplantation.
and treatment of all forms of PH. An overarching theme
4. Patients with group 1 PH and multiple comorbidities
of these guidelines is an emphasis on early diagnosis
should be treated initially with oral monotherapy.
and a multidisciplinary approach to the management of
5. A PVR > 5 Wood units is associated with worse
PH with early referral to expert centers. One of the most
outcomes, defines “severe PH” associated with left
consequential recommendations is the new
heart or lung disease, and requires an
hemodynamic definition of PH, lowering the threshold
individualized treatment approach, which can
for mean pulmonary artery pressure to > 20 mmHg, and
include inhaled treprostinil for PH associated with
for precapillary PH lowering the pulmonary vascular
interstitial lung disease.
resistance (PVR) cutoff to > 2 Wood units. Upfront
combination therapy for pulmonary arterial
hypertension (PAH) based on a 3-strata risk assessment PHENOTYPING OF IDIOPATHIC PULMONARY ARTERIAL
scheme continues to be recommended, but now a 4- HYPERTENSION
strata risk assessment approach during follow up is Hoeper MM, Dwivedi K, Pausch C, Lewis RA, Olsson KM,
endorsed, breaking down the intermediate risk stratum Huscher D, Pittrow D, Grünig E, Staehler G, Vizza CD, Gall
into intermediate-low and intermediate-high. H, Distler O, Opitz C, Gibbs JSR, Delcroix M, Park DH,
Escalation of therapy with an infused prostacyclin Ghofrani HA, Ewert R, Kaemmerer H, Kabitz HJ, Skowasch
analogue or referral to lung transplantation is now D, Behr J, Milger K, Lange TJ, Wilkens H, Seyfarth HJ, Held
recommended for both intermediate- risk and high-risk M, Dumitrescu D, Tsangaris I, Vonk-Noordegraaf A, Ulrich
patients during follow up. Notably, for PAH patients S, Klose H, Claussen M, Eisenmann S, Schmidt KH, Swift
with multiple comorbidities, initial oral monotherapy is AJ, Thompson AAR, Elliot CA, Rosenkranz S, Condliffe R,

Pulmonary Vascular Disease 9

 Clinical Year in Review

Kiely DG, Halank M. Phenotyping of idiopathic with preserved ejection fraction showing similarly
pulmonary arterial hypertension: a registry analysis. blunted response to PH-targeted therapy, have
Lancet Respir Med. 2022 Oct;10(10):937-948. doi: shaped the ERS 2022 guideline recommendation to
10.1016/S2213-2600(22)00097-2. Epub 2022 Jun 28. try monotherapy first in PAH patients with
cardiopulmonary comorbidities.
5. These IPAH comorbid phenotypes represent a larger
Summary proportion of patients seen in practice and
This study reports data from 2 large European registries, reported in registries, and warrant further study to
COMPERA and ASPIRE, comparing 3 groups of patients: delineate the diagnostic and therapeutic
(1) classic idiopathic pulmonary arterial hypertension implications.
(IPAH), defined as absence of risk factors for left heart
disease and a diffusion capacity for carbon monoxide
(DLCO) ≥ 45% predicted; (2) IPAH with a lung phenotype, PULMONARY VASCULAR DISEASE PHENOMICS
defined as having a smoking history and a DLCO < 45%; (PVDOMICs)
and (3) PH due to chronic obstructive or interstitial lung Hemnes AR, Leopold JA, Radeva MK, Beck GJ, Abidov A,
disease (group 3 PH) defined by their physicians. Lung Aldred MA, Barnard J, Rosenzweig EB, Borlaug BA, Chung
phenotype IPAH had normal or near normal spirometry WK, Comhair SAA, Desai AA, Dubrock HM, Erzurum SC,
and no or mild lung parenchymal abnormalities on CT Finet JE, Frantz RP, Garcia JGN, Geraci MW, Gray MP,
chest. Lung phenotype IPAH and PH due to lung disease Grunig G, Hassoun PM, Highland KB, Hill NS, Hu B, Kwon
patients were older and less female-predominant DH, Jacob MS, Jellis CL, Larive AB, Lempel JK, Maron BA,
compared to classic IPAH. Response to PAH therapy, Mathai SC, McCarthy K, Mehra R, Nawabit R, Newman JH,
measured as improvements in functional class, 6- Olman MA, Park MM, Ramos JA, Renapurkar RD, Rischard
minute walk distance and N-terminal pro B-type FP, Sherer SG, Tang WHW, Thomas JD, Vanderpool RR,
natriuretic peptide levels, was significantly more Waxman AB, Wilcox JD, Yuan JX, Horn EM; PVDOMICS
frequent in classic IPAH, and similarly poor in lung Study Group. Clinical Characteristics and Transplant-
phenotype IPAH and PH due to lung disease. Survival at Free Survival Across the Spectrum of Pulmonary
1 and 5 years was similar in lung phenotype IPAH and Vascular Disease. J Am Coll Cardiol. 2022 Aug
PH due to lung disease, and worse than classic IPAH. 16;80(7):697-718. doi: 10.1016/[Link].2022.05.038. PMID:
35953136; PMCID: PMC9897285.
Comments
1. Emerging data suggest that IPAH is a heterogeneous Summary
disorder, and that the presence of comorbidities PVDOMICS (Pulmonary Vascular Disease Phenomics) is a
influences response to therapy and survival. prospective multicenter study using deep clinical and
2. This study confirms that many patients meeting omics phenotyping across the spectrum of pulmonary
current criteria for IPAH have a distinct phenotype vascular disease. PVDOMICS enrolled patients with all 5
characterized by a history of smoking, older age, World Symposium of Pulmonary Hypertension (WSPH)
less female predominance, severely decreased DLCO, groups (group 1=353, group 2=136, group 3=172, group
limited response to PH-targeted therapies and poor 4=57, group 5=32), as well as disease comparators
survival. (subjects with no or mild PH and cardiopulmonary risk
3. In spite of having normal or near normal spirometry factors for the respective group of PH), and healthy
and no evidence of significant parenchymal lung controls who underwent all non-invasive testing. This
disease on CT chest, IPAH patients with this lung article reports the baseline clinical characteristics and
phenotype have clinical characteristics and survival of the PVDOMICS cohort. Almost 40% of
behavior aligned with PH due to lung disease. patients had mixed etiology PH, i.e., more than one
4. These data, in the context of previous data from WSPH group contributing to PH, most commonly lung
patients with several risk factors for heart failure disease in group 1 and 2 PH. Parenchymal lung

Pulmonary Vascular Disease 10

 Clinical Year in Review

abnormalities on CT chest were common in group 1 PH, Mar 6. doi: 10.1056/NEJMoa2213558. Epub ahead of print.
particularly ground glass opacities observed in 50% of PMID: 36877098.
patients compared to 13.7% in comparators. DLCO was
reduced to similar levels in groups 1 (median 58% Summary
predicted), 2 (53%), and 3 (60%) PH. Right atrial volume Sotatercept is a fusion protein that by “trapping” pro-
index was significantly elevated in groups 1-4 PH and to proliferative activins and growth differentiation factors
a higher degree than right ventricular end diastolic might counteract the reduced anti-proliferative bone
dimension compared to comparators. Among morphogenetic protein receptor type 2 (BMPR2)-
comparators and PH, group 3 subjects had the worse mediated signaling in pulmonary vascular cells. The
transplant-free survival. STELLAR trial randomized 163 PAH patients to
subcutaneous sotatercept every 3 weeks and 160 to
placebo. PAH patients had a pulmonary vascular
Comments resistance (PVR) ≥ 400 dynes while on background PAH-
1. PVDOMICS documents a high prevalence (almost targeted therapy (61% triple therapy, 40% infused
40%) of mixed etiology PH, showcasing the prostacyclin). Enrolled subjects were relatively young
limitations of the current clinical classification of (mean age 48), mostly female (79%) and white (89%),
PH and emphasizing the potential of PVDOMICS to and had predominantly idiopathic (58%) and heritable
redefine PH classification in the future. disease (18%). The median change in the 6-minute walk
2. Low DLCO and disproportionate right atrial distance at week 24, the primary endpoint, was 34.4
enlargement emerge as important markers of meters in the sotatercept group and 1 meter in the
pulmonary vascular disease in patients with placebo group. Improvements in all but 1 secondary
cardiopulmonary comorbidities, but they are not endpoints were observed, including a multicomponent
specific to any particular WSPH group. improvement endpoint, PVR, N-terminal pro B-type
3. Half of group 1 PH patients have pulmonary ground natriuretic peptide levels (NT-proBNP), functional class,
glass opacities, a novel observation that might be a time to clinical worsening, low French risk criteria, and
marker of disease severity or an effect of some measures of quality of life. Severe adverse events
prostacyclin therapy. were more frequent in the placebo arm. Adverse events
4. Patients with group 3 risk factors and group 3 PH more frequent in the sotatercept arm included bleeding
have the worst survival, and group 4 comparators (mostly epistaxis and gingival), telangiectasia, increased
(patients with chronic pulmonary embolism with no hemoglobin, dizziness and thrombocytopenia.
or mild PH) have 100% transplant-free survival over
36 months. Comments
5. Incident group 1 PH and WSPH groups 4 and 5 are 1. Sotatercept is a first-in-class drug that for the first
underrepresented in PVDOMICS. time shows efficacy in a phase 3 trial modulating a
biological pathway highly relevant to PAH not
targeted by currently available PAH therapies, and
SOTATERCEPT FOR PULMONARY ARTERIAL importantly, in a heavily pre-treated PAH
HYPERTENSION population.
2. Consistent with effects observed in the phase 2
Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR,
trial, sotatercet reduced PVR by decreasing
Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza
pulmonary artery pressure without changing the
R, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM,
cardiac output, suggesting that regression of
Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J,
pulmonary vascular remodeling might be the
de Oliveira Pena J, Humbert M; STELLAR Trial
underlying mechanism behind its clinical benefits,
Investigators. Phase 3 Trial of Sotatercept for Treatment
but this and other potential mechanisms warrant
of Pulmonary Arterial Hypertension. N Engl J Med. 2023
further study.

Pulmonary Vascular Disease 11

 Clinical Year in Review

3. Ongoing and future studies should determine if the followed with a standardized evaluation at discharge, 3,
clinical benefits are also observed in other PH 12, and 24 months. 70% of patients had intermediate-
populations such us children, newly diagnosed PAH, risk PE. The 2-year cumulative incidence of CTEPH was
high-risk or unstable PAH, and combined pre- and 2.3%. Median time to CTEPH diagnosis was 129 days. The
post-capillary PH due to heart failure with 2-year cumulative incidence of PPEI was 16%. PPEI was
preserved ejection fraction. more frequent in older individuals and in those with
4. Further study is warranted to determine the clinical intermediate risk PE compared to low risk PE. All but 1
benefits of sotatercept in PAH populations not well patient (15/16) with CTEPH also fulfilled criteria for PPEI.
represented in the STELLAR trial, such as connective Patients with PPEI had a higher incidence of death and
tissue disease, older age, and non-white re-hospitalization for any cause, as well as lower
individuals. generic and disease-specific quality of life.
5. While sotatercept appears to be well tolerated,
vascular side effects, particularly bleeding and Comments
telangiectasia, need to be monitored in longer-term 1. The FOCUS study confirms that the incidence of
studies. CTEPH after acute PE is in the low single digit
percent range, but cardiopulmonary limitation after
PE is much more frequent.
FOLLOW UP AFTER ACUTE PULMONARY EMBOLISM 2. In FOCUS, a detailed follow up evaluation allowed
(FOCUS) for the detection of CTEPH after a median of ~4
Valerio L, Mavromanoli AC, Barco S, Abele C, Becker D, months, much earlier than the previously
Bruch L, Ewert R, Faehling M, Fistera D, Gerhardt F, documented delay in diagnosis of more than a year.
Ghofrani HA, Grgic A, Grünig E, Halank M, Held M, 3. Right ventricular dysfunction during index PE was
Hobohm L, Hoeper MM, Klok FA, Lankeit M, Leuchte HH, observed in 81% of CTEPH patients compared to
Martin N, Mayer E, Meyer FJ, Neurohr C, Opitz C, Schmidt only 38% of others, emphasizing the importance of
KH, Seyfarth HJ, Wachter R, Wilkens H, Wild PS, documenting resolution of RV dysfunction during
Konstantinides SV, Rosenkranz S; FOCUS Investigators. follow up.
Chronic thromboembolic pulmonary hypertension and 4. PPEI emerges as a syndrome defined by
impairment after pulmonary embolism: the FOCUS echocardiographic and clinical, functional and
study. Eur Heart J. 2022 Sep 21;43(36):3387-3398. doi: laboratory abnormalities, and could be used to
10.1093/eurheartj/ehac206. PMID: 35484821; PMCID: enrich a population where further testing for CTEPH
PMC9492241. is necessary.
5. PPEI, as defined by FOCUS but not
Summary echocardiographic abnormalities alone, is
FOCUS is a multicenter prospective observational study associated with lower quality of life, and increased
conducted in Germany that aimed to investigate the rates of hospitalization and death, and may warrant
incidence of chronic thromboembolic PH (CTEPH) and interventions to improve quality of life, functional
post-pulmonary embolism impairment (PPEI) after limitation and risk factor mitigation.
acute PE. PPEI was defined as at least 1
echocardiographic criterion of PH plus at least 1 clinical,
functional or laboratory criterion out of persistent
symptoms, signs of right heart failure, syncope, WHO
functional class III or IV, 6-minute walk distance < 300
meters, elevated BNP or NT-proBNP, and low peak O2
uptake or systolic blood pressure on cardiopulmonary
exercise testing. CTEPH was defined via imaging and
right heart catheterization. A total of 1017 patients were

Pulmonary Vascular Disease 12

 Clinical Year in Review

PULMONARY ANGIOPLASTY OR RIOCIGUAT FOR subsegmental arteries considered inoperable, while

INOPERABLE CHRONIC THROMBOEMBOLIC PULMONARY medical therapy with riociguat targets the
HYPERTENSION concomitant microscopic vasculopathy of CTEPH.
Jaïs X, Brenot P, Bouvaist H, Jevnikar M, Canuet M, 2. First-line BPA was more effective than first line
Chabanne C, Chaouat A, Cottin V, De Groote P, Favrolt N, riociguat in decreasing PVR and improving
Horeau-Langlard D, Magro P, Savale L, Prévot G, Renard symptoms and NT-proBNP levels, at the expense of
S, Sitbon O, Parent F, Trésorier R, Tromeur C, Piedvache a higher incidence of serious adverse events.
C, Grimaldi L, Fadel E, Montani D, Humbert M, 3. Patients pre-treated with riociguat followed by BPA
Simonneau G. Balloon pulmonary angioplasty versus experienced a similar decrease in PVR from
riociguat for the treatment of inoperable chronic baseline than patients treated with first line BPA
thromboembolic pulmonary hypertension (RACE): a followed by riociguat, but with a better safety
multicentre, phase 3, open-label, randomised profile.
controlled trial and ancillary follow-up study. Lancet 4. Mean pulmonary artery pressure higher than 45
Respir Med. 2022 Oct;10(10):961-971. doi: 10.1016/S2213- mmHg and first-line BPA were predictors of BPA-
2600(22)00214-4. Epub 2022 Aug 1. PMID: 35926542. related adverse events
5. These data support the use of a combination
Summary management strategy of medical therapy followed
by BPA for patients with inoperable CTEPH,
The soluble guanylate cyclase stimulator riociguat was
particularly those with severe PH, carefully
approved for the treatment of inoperable CTEPH in 2013.
evaluated by expert CTEPH centers.
Around the same time, experience with balloon
pulmonary angioplasty (BPA) was growing across the
world. RACE is a multicenter, open-label randomized
Other Articles of Interest
trial conducted in France that compared riociguat
(n=53) versus BPA (n=52) in inoperable CTEPH patients PH Hemodynamic Assessment
with a PVR > 4 Wood units. The primary endpoint was Zeder K, Banfi C, Steinrisser-Allex G, Maron BA, Humbert
PVR at 26 weeks, which was lower in the BPA group M, Lewis GD, Berghold A, Olschewski H, Kovacs G.
(ratio of geometric means 0.60). Secondary endpoints Diagnostic, prognostic and differential-diagnostic
functional class and NT-proBNP also favored BPA, while relevance of pulmonary haemodynamic parameters
6-minute walk distance was similar between groups. during exercise: a systematic review. Eur Respir J. 2022
Treatment-related serious adverse events were more Oct 13;60(4):2103181. Doi: 10.1183/13993003.03181-2021.
frequent in the BPA group: 22 (42%)/52 patients versus PMID: 35332069; PMCID: PMC9556812.
5(9%)/53, most frequently lung injury and hemoptysis.
After week 26, patients who remained functional class II Khirfan G, Melillo CA, Al Abdi S, Lane JE, Dweik RA,
or higher with a PVR > 4 Wood units were offered Chatburn RL, Hatipoğlu U, Tonelli AR. Impact of
riociguat if there were originally assigned to BPA (n=18) Esophageal Pressure Measurement on Pulmonary
and BPA if they initially received riociguat (n=36). At Hypertension Diagnosis in Patients With Obesity. Chest.
week 52, PVR was similarly reduced in both the first-line 2022 Sep;162(3):684-692. Doi: 10.1016/[Link].2022.04.002.
BPA versus first-line riociguat intention-to-treat Epub 2022 Apr 9. PMID: 35405108; PMCID: PMC9808718.
populations (ratio of geometric mean 0.91). BPA-related
serious adverse events were lower in patients pre-
treated with riociguat (5[14%]/36) versus patients
treated with BPA first (22[42%]/52).

Comments
1. BPA has emerged as a mechanical treatment option
for thrombo-fibrotic lesions in distal segmental and

Pulmonary Vascular Disease 13

 Clinical Year in Review

PAH Risk Assessment Goh ZM, Balasubramanian N, Alabed S, Dwivedi K,

Hoeper MM, Pausch C, Olsson KM, Huscher D, Pittrow D, Shahin Y, Rothman AMK, Garg P, Lawrie A, Capener D,
Grünig E, Staehler G, Vizza CD, Gall H, Distler O, Opitz C, Thompson AAR, Alandejani F, Wild JM, Johns CS, Lewis
Gibbs JSR, Delcroix M, Ghofrani HA, Park DH, Ewert R, RA, Gosling R, Sharkey M, Condliffe R, Kiely DG, Swift AJ.
Kaemmerer H, Kabitz HJ, Skowasch D, Behr J, Milger K, Right ventricular remodelling in pulmonary arterial
Halank M, Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, hypertension predicts treatment response. Heart. 2022
Tsangaris I, Vonk-Noordegraaf A, Ulrich S, Klose H, Aug 11;108(17):1392-1400. Doi: 10.1136/heartjnl-2021-
Claussen M, Lange TJ, Rosenkranz S. COMPERA 2.0: a 320733. PMID: 35512982; PMCID: PMC9380507.
refined four-stratum risk assessment model for
pulmonary arterial hypertension. Eur Respir J. 2022 Jul PAH outcomes
7;60(1):2102311. Doi: 10.1183/13993003.02311-2021. PMID: Hoeper MM, Pausch C, Grünig E, Staehler G, Huscher D,
34737226; PMCID: PMC9260123. Pittrow D, Olsson KM, Vizza CD, Gall H, Distler O, Opitz C,
Gibbs JSR, Delcroix M, Ghofrani HA, Rosenkranz S, Park
Boucly A, Weatherald J, Savale L, de Groote P, Cottin V, DH, Ewert R, Kaemmerer H, Lange TJ, Kabitz HJ, Skowasch
Prévot G, Chaouat A, Picard F, Horeau-Langlard D, D, Skride A, Claussen M, Behr J, Milger K, Halank M,
Bourdin A, Jutant EM, Beurnier A, Jevnikar M, Jaïs X, Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, Tsangaris
Simonneau G, Montani D, Sitbon O, Humbert M. External I, Vonk-Noordegraaf A, Ulrich S, Klose H. Temporal
validation of a refined four-stratum risk assessment trends in pulmonary arterial hypertension: results from
score from the French pulmonary hypertension registry. the COMPERA registry. Eur Respir J. 2022 Jun
Eur Respir J. 2022 Jun 30;59(6):2102419. Doi: 2;59(6):2102024. Doi: 10.1183/13993003.02024-2021. PMID:
10.1183/13993003.02419-2021. PMID: 34737227; PMCID: 34675047; PMCID: PMC9160392.
PMC9245192.
Chang KY, Duval S, Badesch DB, Bull TM, Chakinala MM,
Hoeper MM, Pausch C, Olsson KM, Huscher D, Pittrow D, De Marco T, Frantz RP, Hemnes A, Mathai SC, Rosenzweig
Grünig E, Staehler G, Vizza CD, Gall H, Distler O, Opitz C, EB, Ryan JJ, Thenappan T; PHAR Investigators. Mortality
Gibbs JSR, Delcroix M, Ghofrani HA, Ewert R, Kaemmerer in Pulmonary Arterial Hypertension in the Modern Era:
H, Kabitz HJ, Skowasch D, Behr J, Milger K, Halank M, Early Insights From the Pulmonary Hypertension
Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, Tsangaris Association Registry. J Am Heart Assoc. 2022 May
I, Vonk-Noordegraaf A, Ulrich S, Klose H, Claussen M, 3;11(9):e024969. Doi: 10.1161/JAHA.121.024969. Epub 2022
Eisenmann S, Schmidt KH, Rosenkranz S, Lange TJ. Apr 27. PMID: 35475351; PMCID: PMC9238604.
Prognostic value of improvement endpoints in
pulmonary arterial hypertension trials: A COMPERA PH in COPD
analysis. J Heart Lung Transplant. 2022 Jul;41(7):971-981. Kovacs G, Avian A, Bachmaier G, Troester N, Tornyos A,
Doi: 10.1016/[Link].2022.03.011. Epub 2022 Mar 22. Douschan P, Foris V, Sassmann T, Zeder K, Lindenmann
PMID: 35430147. J, Brcic L, Fuchsjaeger M, Agusti A, Olschewski H. Severe
Pulmonary Hypertension in COPD: Impact on Survival
PAH Treatment and Diagnostic Approach. Chest. 2022 Jul;162(1):202-212.
Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland Doi: 10.1016/[Link].2022.01.031. Epub 2022 Jan 31. PMID:
M, Hoeper MM, Preston IR, Souza R, Waxman AB, 35092746.
Ghofrani HA, Escribano Subias P, Feldman J, Meyer G,
Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, Cook DP, Xu M, Martucci VL, Annis JS, Aldrich MC,
Badesch DB. Sotatercept for the treatment of Hemnes AR, Brittain EL. Clinical insights into pulmonary
pulmonary arterial hypertension: PULSAR open-label hypertension in chronic obstructive pulmonary disease.
extension. Eur Respir J. 2023 Jan 6;61(1):2201347. Doi: Pulm Circ. 2022 Jan 3;12(1):e12006. Doi:
10.1183/13993003.01347-2022. PMID: 36041750; PMCID: 10.1002/pul2.12006. PMID: 35506103; PMCID: PMC9052979.
PMC9816418.

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 Clinical Year in Review

COVID-19 and PH
Montani D, Certain MC, Weatherald J, Jaïs X, Bulifon S, Boon GJAM, Ende-Verhaar YM, Beenen LFM, Coolen J,
Noel-Savina E, Nieves A, Renard S, Traclet J, Bouvaist H, Delcroix M, Golebiowski M, Huisman MV, Mairuhu ATA,
Riou M, de Groote P, Moceri P, Bertoletti L, Favrolt N, Meijboom LJ, Middeldorp S, Pruszczyk P, van Rooden CJ,
Guillaumot A, Jutant EM, Beurnier A, Boucly A, Ebstein N, Vonk Noordegraaf A, Kroft LJM, Klok FA. Prediction of
Jevnikar M, Pichon J, Keddache S, Preda M, Roche A, chronic thromboembolic pulmonary hypertension with
Solinas S, Seferian A, Reynaud-Gaubert M, Cottin V, tandardized evaluation of initial computed tomography
Savale L, Humbert M, Sitbon O; French PH Network pulmonary angiography performed for suspected acute
PULMOTENSION Investigators. COVID-19 in Patients with pulmonary embolism. Eur Radiol. 2022 Apr;32(4):2178-
Pulmonary Hypertension: A National Prospective Cohort 2187. Doi: 10.1007/s00330-021-08364-0. Epub 2021 Dec 2.
Study. Am J Respir Crit Care Med. 2022 Sep 1;206(5):573- PMID: 34854928; PMCID: PMC8921171.
583. Doi: 10.1164/rccm.202112-2761OC. PMID: 35549842;
PMCID: PMC9716894. Klok FA, Ageno W, Ay C, Bäck M, Barco S, Bertoletti L,
Becattini C, Carlsen J, Delcroix M, van Es N, Huisman MV,
PE Treatment and Follow Up Jara-Palomares L, Konstantinides S, Lang I, Meyer G, Ní
Pruszczyk P, Klok FA, Kucher N, Roik M, Meneveau N, Áinle F, Rosenkranz S, Pruszczyk P. Optimal follow-up
Sharp ASP, Nielsen-Kudsk JE, Obradović S, Barco S, after acute pulmonary embolism: a position paper of
Giannini F, Stefanini G, Tarantini G, Konstantinides S, the European Society of Cardiology Working Group on
Dudek D. Percutaneous treatment options for acute Pulmonary Circulation and Right Ventricular Function, in
pulmonary embolism: a clinical consensus statement by collaboration with the European Society of Cardiology
the ESC Working Group on Pulmonary Circulation and Working Group on Atherosclerosis and Vascular Biology,
Right Ventricular Function and the European endorsed by the European Respiratory Society. Eur
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Interventions. EuroIntervention. 2022 Oct 7;18(8):e623- 10.1093/eurheartj/ehab816. PMID: 34875048; PMCID:
e638. Doi: 10.4244/EIJ-D-22-00246. PMID: 36112184. PMC8790766.

Pulmonary Vascular Disease 15

 Clinical Year in Review

COPD
Stephanie A. Christenson, MD, MS
University of California, San Francisco
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine
Department of Medicine
San Francisco, CA
management. Finally, the Commission advocates for
greater access to care as well as earlier access to
IDENTIFYING AND ADDRESSING FACTORS CONTRIBUTING provide future opportunities for curative or
TO COPD BURDEN regenerative management.
Stolz D, Mkorombindo T, Schumann DM, Agusti A, Ash SY,
Bafadhel M, Bai C, Chalmers JD, Criner GJ, Dharmage SC, Comments
Franssen FME, Frey U, Han M, Hansel NH, Hawkins NM, 1. The objective of the Commission is not to provide
Kalhan R, Konigshoff M, Ko FW, Parekh TM, Powell P, guidelines for management, but to present a
Rutten-van Mölken M, Jodie Simpson J, Sin DD, Song Y, framework for future research, public health, and
Suki B, Troosters T, Washko GR, Welte T, Dransfield MT. clinical efforts to decrease COPD disease burden.
Towards the elimination of chronic obstructive 2. The focus on risk factors beyond tobacco smoke
pulmonary disease: a Lancet Commission. Lancet. 2022 follows a recent shift in understanding COPD as a
Sep 17;400(10356):921-972. complex heterogeneous disease due to an
accumulation of factors over the life course.
Summary 3. Emphases on additional risk factors and identifying
The Lancet Commission convened global COPD experts earlier disease states open possibilities for early
to consider the factors contributing to increasing COPD intervention and prevention of progression.
burden, and to provide recommendations on disruptive 4. While the proposed disease etiotypes subgroup
approaches to set the course for disease elimination. COPD by predominant cause, major pathologic
This extensive review highlights several areas for future disease drivers and treatable traits (e.g., symptoms,
intervention. While they strongly recommend limiting exacerbations) could be shared across etiotypes;
tobacco and environmental exposures, the subgrouping based on treatment response is
predominant COPD risk factors, they also advocate needed as well.
greater focus on additional risk factors. Consequently, 5. COPD exacerbation severity classification may be
they endorse classifying COPD based on “etiotypes” in better standardized using objective measurements,
which tobacco smoke, other environmental exposures, as proposed herein, rather than healthcare
genetics, early-life events, or infections are the utilization which can vary geographically, but some
predominant risk factors that may provide specific of the proposed objective measurements may not
intervention opportunities. They recommend expanding be available in resource limited settings.
diagnostic criteria beyond spirometry to include aspects
such as symptoms, risk factors, imaging, and lung
function testing. They argue that this expanded GUIDELINES FOR COPD MANAGEMENT, DIAGNOSIS, AND
definition could provide an opportunity for earlier PREVENTION
diagnosis and management to prevent disease Global Initiative for Chronic Obstructive Lung Disease.
progression. They also note that exacerbation Global strategy for the diagnosis, management, and
prevention is crucial. They suggest standardizing prevention of chronic obstructive pulmonary disease.
exacerbation definitions and determining exacerbation 2023 report. [Link]
severity based on objective measures of clinical
deterioration as important first steps in prevention and

COPD 16
 Clinical Year in Review

Summary studies showing improved symptoms, lung function,

This is an updated recommendation statement from the exacerbations, and quality of life.
Global Initiative for Chronic Obstructive Lung Disease 4. The new guidelines incorporate data from the
(GOLD) committee from 2023. Although last updated in recent LABA/LAMA/ICS triple therapy studies
2021, the 2023 guidelines include substantial changes. (ETHOS, IMPACT, KRONOS, TRILOGY) suggesting
The definition of COPD has been updated to emphasize benefit over LABA/LAMA in exacerbators for
disease heterogeneity and the contribution of factors exacerbation reduction and potentially, as per post-
beyond tobacco smoke in COPD pathogenesis. The hoc pooled analyses, mortality reduction.
committee aligns with the Lancet Commission, 5. The guidelines incorporate recommendations from
proposing a new taxonomy to consider disease the ROME proposal and Lancet Commission that
etiotypes in which predominant COPD etiologies differ. suggest using objective findings to grade severity of
Revisions in recommended management are also exacerbations instead of healthcare utilization.
considerable. Highlights include an update of the ABCD
assessment tool to an ABE tool in which treatment of
individuals who exacerbate should be similar ASYMPTOMATIC COPD SCREENING
regardless of chronic symptom levels. Dual therapy with US Preventive Services Task Force; Mangione CM, Barry
a long-acting beta agonist (LABA) and long-acting MJ, Nicholson WK, Cabana M, Caughey AB, Chelmow D,
muscarinic antagonist (LAMA) is now recommended for Coker TR, Davis EM, Donahue KE, Jaén CR, Kubik M, Li L,
initial management over LABA or LAMA alone in Ogedegbe G, Pbert L, Ruiz JM, Stevermer J, Tseng C, J
individuals with considerable symptoms or Wong JB. Screening for Chronic Obstructive Pulmonary
exacerbations. Furthermore, inhaled corticosteroids Disease: US Preventive Services Task Force
(ICS) are recommended when concomitant asthma, Reaffirmation Recommendation Statement. JAMA. 2022
exacerbations with elevated eosinophils, or hospitalized May 10;327(18):1806-1811. doi: 10.1001/jama.2022.5692.
exacerbations despite LABA/LAMA therapy are
identified. However triple therapy (ICS, LABA, and LAMA Summary
combination therapy) is recommended in this scenario, The US Preventive Services Task Force (USPSTF)
not ICS alone or ICS/LABA combination therapy. provides an evidence update of their 2016
recommendations, again recommending against
Comments screening for COPD in asymptomatic adults and
1. The new GOLD guidelines, similar to the Lancet treatment of these screened individuals. Their literature
commission, draw increased attention to review addresses three topics: 1) accuracy of screening
environmental and early life factors beyond tests, 2) benefits of early detection and treatment, and
tobacco exposure as major risk factors, and focus 3) harms of screening and treatment. They found no
on identification of early disease to provide new new evidence on the accuracy of screening tests. They
opportunities for disease prevention and reviewed three new trials (SUMMIT, PINNACLE, UPLIFT) to
modification. assess benefits of treatment, and conclude that inhaled
2. The guidelines reinforce the importance of therapies are associated with exacerbation reduction in
exacerbation prevention as key to improving moderate symptomatic COPD. However, they assert the
outcomes, recommending more intensive therapy findings are difficult to generalize to asymptomatic
for individuals with exacerbations even if their individuals in which no new data exists. They reviewed
chronic symptoms are minimal. 13 studies on non-pharmacologic interventions in mild-
3. As a major change in therapeutic recommendations, to-moderate COPD and, given mixed results, could draw
LABA/LAMA combination therapy is recommended no conclusions regarding benefit. The USPSTF
over monotherapy for individuals with considered eight new studies in their assessment of
exacerbations or substantial symptoms given screening harm. They found no substantial harm of mild
to moderate COPD treatment in the randomized trials.

COPD 17
 Clinical Year in Review

They conclude that an opportunity cost exists given the Comments

additional medical services required after positive 1. While asymptomatic screening is not currently
screening, but that this cost is small. Overall, they recommended, screening for clinically significant
conclude both benefit and harm to screening and COPD is likely important in decreasing morbidity.
management of asymptomatic COPD are minimal. 2. Spirometry is a limited resource, and thus screening
via spirometry may not be realistic for all at-risk
Comments individuals, particularly in low- and middle-income
1. While asymptomatic screening is not yet considered countries.
useful per the USPSTF, COPD experts are 3. The CAPTURE tool, which combines a questionnaire
increasingly endorsing earlier diagnosis in an effort and peak flow measurements, may be a more
to deliver earlier management that may, upon pragmatic way to screen for COPD than spirometry
further study, be found to be disease modifying. given the overall burden of disease.
2. Further research will be needed to identify the 4. The CAPTURE tool is quite specific, suggesting that
subgroups of asymptomatic individuals most at risk diagnostic studies needed after screening positive
for COPD progression and thus most likely to will be limited to a group likely to benefit from
benefit from earlier screening and intervention. further testing.
3. The harms of early screening and treatment appear 5. Further studies are needed to understand how the
to be minimal. low sensitivity of the CAPTURE tool may be
improved with repeated testing.

SYMPTOMATIC COPD SCREENING

Martinez FJ, Han MK, Lopez C, Murray S, Mannino D,
Anderson S, Brown R, Dolor R, Elder N, Joo M, Khan I, THERAPIES IN UNOBSTRUCTED TOBACCO-EXPOSED
Knox LM, Meldrum C, Peters E, Spino C, Tapp H, INDIVIDUALS
Thomashow B, Zittleman L, Make B, Yawn BP; CAPTURE Han MK, Ye W, Wang D, White E, Arjomandi M,
Study Group. Discriminative Accuracy of the CAPTURE Barjaktarevic IZ, Brown SA, Buhr RG, Comellas AP,
Tool for Identifying Chronic Obstructive Pulmonary Cooper CB, Criner GJ, Dransfield MT, Drescher F, Folz RJ,
Disease in US Primary Care Settings. JAMA. 2023 Feb Hansel NN, Kalhan R, Kaner RJ, Kanner RE, Krishnan JA,
14;329(6):490-501. doi: 10.1001/jama.2023.0128. Lazarus SC, Maddipati V, Martinez FJ, Mathews A,
Meldrum C, McEvoy C, Nyunoya T, Rogers L, Stringer WW,
Summary Wendt CH, Wise RA, Wisniewski SR, Sciurba FC, Woodruff
n this cross-sectional multi-center study, 4325 US PG; RETHINC Study Group. Bronchodilators in Tobacco-
primary care patients were screened for clinically Exposed Persons with Symptoms and Preserved Lung
significant COPD using the CAPTURE tool comprised of Function. N Engl J Med. 2022 Sep 29;387(13):1173-1184.
five questions and select use of peak expiratory flow doi: 10.1056/NEJMoa2204752.
rate. A patient was considered to have clinically
significant COPD if they had: 1) a post-bronchodilator Summary
FEV1/FVC ratio of <0.7 and 2) an FEV1 <60% predicted or It was previously shown that a substantial portion of
self-reported acute respiratory illness in the last 12 individuals with a tobacco smoking history but without
months. 12.3% of participants had a positive screening airway obstruction have clinically significant respiratory
test and 2.5% had clinically significant COPD. A positive symptoms. Many of these individuals are treated with
screening result was only 48.2% sensitive but was 88.6% COPD therapies even though they do not meet
specific for clinically significant COPD. diagnostic criteria for COPD. This was a multi-center
randomized controlled trial of individuals with ≥10 pack
year smoking history and substantial respiratory
symptoms (defined as a score ≥10 on the COPD

COPD 18
 Clinical Year in Review

Assessment Tool (CAT)) but preserved lung function. 471 Eosinophils and Chronic Obstructive Pulmonary
participants analyzed in a modified intention-to-treat Disease: A Global Initiative for Chronic Obstructive Lung
analysis were randomized to placebo or indacaterol, a Disease Science Committee 2022 Review. Am J Respir
long-acting beta agonist (LABA), and glycopyrrolate, a Crit Care Med. 2022 Jul 1;206(1):17-24. doi:
long-acting muscarinic antagonist (LAMA). They found 10.1164/rccm.202201-0209PP.
no significant difference in the primary outcome,
improvement in respiratory symptoms by St. George’s Lacasse Y, Casaburi R, Sliwinski P, Chaouat A, Fletcher E,
Respiratory Questionnaire (SGRQ), between treatment Haidl P, Maltais F. Home oxygen for moderate
and placebo arms. They also found no significant hypoxaemia in chronic obstructive pulmonary disease:
treatment effect in terms of lung function measures or a systematic review and meta-analysis. Lancet Respir
CAT score. Med. 2022 Nov;10(11):1029-1037. doi: 10.1016/S2213-
2600(22)00179-5.

Comments GLOBAL BURDEN OF DISEASE

1. Current and former smokers with respiratory Safiri S, Carson-Chahhoud K, Noori M, Nejadghaderi SA,
symptoms but without airway obstruction often get Sullman MJM, Ahmadian Heris J, Ansarin K, Mansournia
treated with inhalers, similar to individuals with MA, Collins GS, Kolahi AA, Kaufman JS. Burden of chronic
COPD, but without any evidence that these obstructive pulmonary disease and its attributable risk
therapies are useful. factors in 204 countries and territories, 1990-2019:
2. This is the first trial in this large subgroup of results from the Global Burden of Disease Study 2019.
symptomatic smokers, and the lack of benefit of BMJ. 2022 Jul 27;378:e069679. doi: 10.1136/bmj-2021-
bronchodilators here suggests that it is important 069679.
to have objective evidence of COPD via spirometry
prior to initiating bronchodilator therapy. DISPARITIES IN ACCESS TO CARE
3. These symptomatic tobacco exposed individuals are Stolbrink M, Thomson H, Hadfield RM, Ozoh OB,
likely heterogeneous, just like COPD, and thus more Nantanda R, Jayasooriya S, Allwood B, Halpin DMG, Salvi
research is needed to determine if there are S, de Oca MM, Mortimer K, Rylance S. The availability,
subgroups that exhibit beneficial responses to cost, and affordability of essential medicines for
bronchodilators. asthma and COPD in low-income and middle-income
countries: a systematic review. Lancet Glob Health. 2022
Oct;10(10):e1423-e1442. doi: 10.1016/S2214-
OTHER ARTICLES OF INTEREST: 109X(22)00330-8.

REVIEWS
ADVERSE EFFECTS ASSOCIATED WITH COPD THERAPIES
Christenson SA, Smith BM, Bafadhel M, Putcha N.
Yang M, Li Y, Jiang Y, Guo S, He JQ, Sin DD. Combination
Chronic obstructive pulmonary disease. Lancet. 2022 Jun
therapy with long-acting bronchodilators and the risk of
11;399(10342):2227-2242. doi: 10.1016/S0140-
major adverse cardiovascular events in patients with
6736(22)00470-6.
COPD: a systematic review and meta-analysis. Eur
Respir J. 2023 Feb 9;61(2):2200302. doi:
Yang IA, Jenkins CR, Salvi SS. Chronic obstructive
10.1183/13993003.00302-2022.
pulmonary disease in never-smokers: risk factors,
pathogenesis, and implications for prevention and
Chen H, Deng ZX, Sun J, Huang Q, Huang L, He YH, Ma C,
treatment. Lancet Respir Med. 2022 May;10(5):497-511.
Wang K. Association of Inhaled Corticosteroids With All-
doi: 10.1016/S2213-2600(21)00506-3.
Cause Mortality Risk in Patients With COPD: A Meta-
analysis of 60 Randomized Controlled Trials. Chest. 2023
Singh D, Agusti A, Martinez FJ, Papi A, Pavord ID,
Jan;163(1):100-114. doi: 10.1016/[Link].2022.07.015.
Wedzicha JA, Vogelmeier CF, Halpin DMG. Blood

COPD 19
 Clinical Year in Review

EXACERBATIONS AND OUTCOMES OBSTRUCTIVE SLEEP APNEA AND COPD

Dransfield MT, Criner GJ, Halpin DMG, Han MK, Hartley B, Sterling KL, Pépin JL, Linde-Zwirble W, Chen J, Benjafield
Kalhan R, Lange P, Lipson DA, Martinez FJ, Midwinter D, AV, Cistulli PA, Cole KV, Emami H, Woodford C,
Singh D, Wise R, Kunisaki KM. Time-Dependent Risk of Armitstead JP, Nunez CM, Wedzicha JA, Malhotra A.
Cardiovascular Events Following an Exacerbation in Impact of Positive Airway Pressure Therapy Adherence
Patients With Chronic Obstructive Pulmonary Disease: on Outcomes in Patients with Obstructive Sleep Apnea
Post Hoc Analysis From the IMPACT Trial. J Am Heart and Chronic Obstructive Pulmonary Disease. Am J Respir
Assoc. 2022 Sep 20;11(18):e024350. doi: Crit Care Med. 2022 Jul 15;206(2):197-205. doi:
10.1161/JAHA.121.024350. 10.1164/rccm.202109-2035OC.

COPD 20
 Clinical Year in Review

INTERSTITIAL LUNG DISEASE

Rachel Putman, MD, MPH
Brigham & Women’s Hospital
Pulmonary and Critical Care Medicine
Boston, MA

CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE

Solomon JJ, Danoff SK, Woodhead FA, Hurwitz S, Maurer Comments
R, Glaspole I, Dellaripa PF, Gooptu B, Vassallo R, Cox PG, 1. This study evaluated the safety and efficacy of
Flaherty KR, Adamali HI, Gibbons MA, Troy L, Forrest IA, the anti-fibrotic medication, pirfenidone in
Lasky JA, Spencer LG, Golden J, Scholand MB, Chaudhuri treating patients with rheumatoid arthritis-
N, Perrella MA, Lynch DA, Chambers DC, Kolb M, Spino C, associated interstitial lung disease (RA-ILD).
Raghu G, Goldberg HJ, Rosas IO, for the TRAIL1 Network 2. Pirfenidone was safe and fairly well tolerated in
Investigators. Safety, tolerability, and efficacy of patients with RA-ILD, similar side effect profile
pirfenidone in patients with rheumatoid arthritis- to what has been seen in patients with
associated interstitial lung disease: a randomized, idiopathic pulmonary fibrosis.
double-blind, placebo-controlled, phase 2 study. Lancet 3. There was no difference in the primary outcome
Respir Med. 2023;11:87-96. between the pirfenidone and placebo groups.
4. There was a difference in one of the secondary
Summary endpoints, specifically a difference in absolute
This study evaluated the efficacy of the anti-fibrotic FVC decline, with the pirfenidone group having
treatment, pirfenidone in patients with rheumatoid a slower rate of decline than the placebo group.
arthritis-associated interstitial lung disease (RA-ILD).
The trial included 123 patients across four countries CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE
(the UK, the US, Australia, and Canada), 63 were Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher
randomized to the pirfenidone group and 60 to the SV, Denton CP, Hoyles RK, Parfrey H, Renzoni EA, Kokosi
placebo group, over 52 weeks. The primary end point M, Wells AU, Ashby D, Szigeti M, Molyneaux PL, on behalf
was a composite of death and a 10% or more decline in of the RECITAL Investigators. Rituximab versus
baseline forced vital capacity (FVC). The study was intravenous cyclophosphamide in patients with
stopped early due to slow recruitment and the COVID-19 connective tissue disease-associated interstitial lung
pandemic. There was no difference between the disease in the UK (RECITAL): a double-blind, double-
pirfenidone and placebo groups in reaching the primary dummy, randomized, controlled, phase 2b trial. Lancet
end point, with 7 patients (11%) in the pirfenidone group Respir Med. 2023;11:45-54.
and 9 patients (15%) in the placebo group. A difference
was seen in absolute FVC decline. The pirfenidone
group had a slower decline in absolute FVC over the Summary
study period, losing 66mL (1.02% predicted) in the This study evaluated whether rituximab was superior to
pirfenidone group compared to 142mL (3.21% predicted) intravenous cyclophosphamide as a treatment for
in the placebo group. Pirfenidone was not associated severe or progressive connective tissue disease-
with any increase in treatment related adverse events. associated ILD (CTD-ILD), specifically in ILD related to
The study was terminated early and is under powered, scleroderma, idiopathic inflammatory myositis, or
the results must be interpreted with caution, but mixed connective tissue disease. One-hundred-one
pirfenidone was associated with a decreased rate of patients were recruited from 11 centers across the
lung function decline in patients with RA-ILD. United Kingdom and were randomized 1:1 to receive

Interstitial Lung Disease 21

 Clinical Year in Review

either rituximab or IV cyclophosphamide for twenty- CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE
four weeks. The primary outcome was change in forced Richeldi L, Azuma A, Cottin V, Hesslinger C, Stowasser S,
vital capacity (FVC) from baseline at 24 weeks. There Valenzuela C, Wijsenbeek MS, Zoz DF, Voss F, Maher TM,
were multiple secondary end points including FVC for the 1305-0013 Trial Investigators. Trial of a
change from baseline at 48 weeks, change in six-minute Preferential Phosphodiesterase 4B Inhibitor for
walk distance, change in DLCO, quality of life metrics, Idiopathic Pulmonary Fibrosis. N Engl J Med.
physician measures of disease activity, survival, 2022;386:2178-87.
progression-free survival, and steroid dose (added
post-hoc). The study showed no difference in the Summary
rituximab and cyclophosphamide groups across any of
Inhibition of phosphodiesterase 4 (PDE 4) has been
the pre-specified end points, all patients had an
associated with anti-inflammatory and anti-fibrotic
increase in FVC and improvement in patient-reported
effects, which makes it an attractive target for the
quality of life scores. The main differences were seen in
treatment of pulmonary fibrosis. In this trial from
the cumulative steroid dose over 48 weeks in the
Boehringer Ingelheim, a new selective
rituximab group, and there were fewer reported adverse
phosphodiesterase 4B inhibitor was trialed for the
events in the rituximab group compared to the
treatment of idiopathic pulmonary fibrosis. In this
cyclophosphamide group. Leading the authors to
phase 2 trial, patients were randomized 2:1 to treatment
conclude that rituximab is an alternative to
with BI 101550 (the selective PDE 4B inhibitor) or
cyclophosphamide in patients with CTD-ILD requiring
placebo. The primary end point of the trial was forced
intravenous therapy.
vital capacity (FVC) at 12 weeks. Importantly this trial
allowed patients to be on background anti-fibrotic
Comments
therapy with either pirfenidone or nintedanib, the data
1. In patients with progressive or severe CTD-ILD were analyzed in two groups, those on background anti-
related to scleroderma, idiopathic myositis, or fibrotic therapy and those were not on any other anti-
mixed connective tissue disease, both rituximab fibrotic treatment. In both groups, the selective PDE 4b
and cyclophosphamide were associated with an inhibitor, was associated with preservation of lung
improvement in lung function and patient function over the 12-week study period, with a greater
reported quality of life. magnitude of effect in the group not on background
2. Rituximab was associated with few reported anti-fibrotic therapy. The most frequent adverse event
adverse events compared to cyclophosphamide, was diarrhea, 13 patients discontinued treatment with
which may make it better tolerated by patients. BI 1015550 due to adverse events. This trial
3. Rituximab was associated with a lower overall demonstrated that BI 1015550, a selective PDE 4B
steroid dose during the follow-up period, inhibitor is a promising treatment for idiopathic
suggesting it may allow for tapering of other pulmonary fibrosis, in combination with anti-fibrotic
background immune suppression. therapy and alone.
4. The results of this trial should give providers
confidence in choosing either rituximab or
cyclophosphamide for patients with progressive Comments
and/or severe CTD-ILD, with the decision
1. The very promising results of this trial have led
making including a discussion of potential side
to two phase 3 trials of BI 101550, the
effects.
FIBRONEER IPF and ILD studies that are
currently recruiting at 288 sites worldwide.
2. The initial results from this phase 2 study, show
not just a slower rate of decline but a
stabilization of lung function in the treatment

Interstitial Lung Disease 22

 Clinical Year in Review

group over 12 weeks, regardless of background seen in those with ILA without evidence of
anti-fibrotic therapy or not. suspected ILD.
3. Suspected ILD is associated with poor outcomes
like those seen in ILD, including increased
INTERSTITIAL LUNG DISEASE EPIDEMIOLOGY AND respiratory symptoms, decreased functional
DIAGNOSIS status, supplemental oxygen use, severe
Rose JA, Menon AA, Hino T, Hata A, Nishino M, Lynch DA, respiratory exacerbations, and an increased risk
Rosas IO, El-Chemaly S, Raby BA, Ash SY, Choi B, Washko of death.
GR, Silverman EK, Cho MH, Hatabu H, Putman RK, 4. About half of the participants with ILA had
Hunninghake GM. Suspected Interstitial Lung Disease in evidence of suspected ILD, which was about 5%
COPDGene Study. Am J Respir Crit Care Med. of a cohort of smokers with and without COPD.
2023;207(1):60-68.
INTERSTITIAL LUNG DISEASE EPIDEMIOLOGY AND
Summary DIAGNOSIS
Interstitial lung abnormalities (ILA) are specific Pugashetti JV, Adegusoye A, Wu Z, Lee CT, Srikrishnan A,
radiologic patterns incidentally found on chest CT scans Ghodrati S, Vo V, Renzoni EA, Wells AU, Garcia CK, Chua
in people without interstitial lung disease (ILD), thought F, Newton CA, Molyneaux PL, Oldham JM. Validation of
to represent an early or mild form of pulmonary Proposed Criteria for Progressive Pulmonary Fibrosis.
fibrosis. ILA have been associated with an increased risk Am J Respir Crit Care Med. 2023;207(1): 69-76.
of death and decrements in pulmonary function, in this
study authors attempted to determine whether those Summary
outcomes were driven by a subset of participants with Clinical trials, expert opinion, and a consensus
incident ILD, in the COPDGene cohort. Suspected ILD statement have set forth criteria for the definition of
was defined as ILA accompanied by one of the progressive pulmonary fibrosis (PPF), however outside
following: FVC less than 80% predicted, DLCO less than of forced vital capacity (FVC) decline, it was unclear
70% predicted, or evidence of definite fibrotic disease whether these criteria were associated with adverse
on CT. In COPDGene, 5% (239 of 4361) of participants outcomes. A retrospective cohort analysis, utilizing 1,341
with available data had suspected ILD, and 204 (~5%) patients from three US centers and 1 in the UK, the
had ILA without suspected ILD. Those with suspected authors evaluated whether the criteria for PPF were
ILD, compared to both those with and without ILA, had associated with transplant free survival. Using the US
increased respiratory symptoms, decreased six-minute cohort as the test cohort and the UK as validation, the
walk distance, greater supplemental oxygen use, were authors showed that an FVC decline of ≥10% was
more likely to have a severe respiratory exacerbation, strongly associated with reduced transplant free
and had an increased risk of death. This study provides survival. In addition to this criterion, three other PPF
a framework for thinking about when patients with ILA features were independently associated with decreased
have progressed to have true, ILD which may help transplant free survival; including 5-9% FVC decline, 15%
clinicians risk stratify patients with evidence of early or or greater DLCO decline, and CT progression of fibrosis.
mild ILD seen on chest CT scan. Three additional features required the combination of
physiologic, radiologic, and symptomatic worsening.
Comments Importantly, the authors were able to identify a group
1. This article proposes a set of criteria to use to of patients, those with ≥10% FVC decline, that have
help define when those with interstitial lung outcomes that are the most like IPF, despite the varying
abnormalities have progressed to having underlying ILD diagnoses. This data suggests that ≥10%
interstitial lung disease. FVC decline alone can be used to make a diagnosis of
2. Participants with suspected ILD had an PPF, rather than requiring the addition of worsening
increased risk of poor outcomes, these were not symptoms or radiology.

Interstitial Lung Disease 23

 Clinical Year in Review

chest CT scans at baseline and approximately 4 years

Comments later. Sixteen of 252 subjects developed PrePF during
1. Multiple criteria have been proposed to define the follow-up period, which equates to an annual
PPF, in this study an FVC decline of 10% or more incidence of PrePF of 1,023 per 100,000 person-years,
was most strongly predictive of decreased lung which is about 100-fold higher than the incidence of
transplant free survival. sporadic IPF. In addition, participants with PrePF at the
2. Using the single criteria of an FVC decline of baseline examination, were more likely to report
≥10%, in this study, creates a subset of patients worsening dyspnea and it was associated with
that are most like IPF in terms of survival, decreased survival. PrePF was associated with imaging
despite having a variety of underlying progression as measured by an increase in quantitative
diagnoses. imaging measures of fibrosis, with 32.5% of participants
3. Amongst those with PPF, phenotypic variability having an increase in fibrosis over the follow-up period.
persisted in terms of transplant free survival, Given the significantly increased incidence of PrePF and
outside of those with an FVC decline of ≥10%, its association with poor outcomes, including an
with those with CTD-ILD have the best increased of death, the authors advocate for screening
prognosis. unaffected family members over the age of 50 in
4. Additional standalone criteria associated with families with a history of interstitial pneumonia.
decreased transplant free survival included a 5-
9% FVC decline, ≥15% decline in DLCO, and Comments
radiologic progression of fibrosis. 1. While the incidence of PrePF in this study is at
5. This study brings into question, whether the least 100-fold higher than that of sporadic IPF,
diagnosis progressive pulmonary fibrosis it is important to remember that this is an at-
should require a combination of physiologic, risk cohort, where a higher incidence would be
radiologic, and/or symptomatic criteria, or expected.
whether in some circumstances this can be 2. About 1/3 of participants with PrePF at baseline
simplified to a single criterion. had evidence of quantitative fibrosis
progression over the four years follow up
INTERSTITIAL LUNG DISEASE EPIDEMIOLOGY AND period; that there are those with stable and
DIAGNOSIS improved fibrosis suggests that there is
Steele MP, Peljto AL, Mathai SK, Humphries S, Bang TJ, phenotypic variability among those with PrePF.
Oh A, Teague S, Cicchetti G, Sigaskis C, Kropski JA, Loyd 3. The authors advocate for screening in at risk
JE, Blackwell TS, Brown KK, Schwarz MI, Warren RA, populations, but it is still unknown what
Powers J, Walts AD, Markin C, Fingerlin TE, Yang IV, Lynch modalities should be used for screening and
DA, Lee JS, Schwartz DA. Incidence and Progression of the appropriate time intervals for follow up.
Fibrotic Lung Disease in an At-Risk Cohort. Am J Respir 4. As more data is collected on early-stage
Crit Care Med. 2023; 207(5): 587-593. disease and those at risk, we will need to begin
the conversations around treatment and
Summary inclusion in clinical trials to learn how already
approved treatments for pulmonary fibrosis
First degree relatives of patients with idiopathic
work in early-stage disease.
interstitial pneumonia are at increased risk of
developing pulmonary fibrosis, in this work the authors
OTHER ARTICLES OF INTEREST
describe the incidence of asymptomatic pulmonary
fibrosis, which these authors term preclinical Salisbury ML, Markin CR, Wu P, Cogan JD, Mitchell DB, Liu
pulmonary fibrosis (PrePF). Using a cohort of first- Q, Loyd JE, Lancaster LH, Kropski JA, Blackwell TS.
Peripheral Blood Telomere Attrition in Persons at Risk
degree relatives of family members with familial
for Familial Pulmonary Fibrosis. Am J Respir Crit Care
interstitial pneumonia (FIP), family members underwent Med. 2023;207(2):208-211.

Interstitial Lung Disease 24

 Clinical Year in Review

Rose JA, Planchart Ferretto MA, Maeda AH, Perez Garcia are and mortality across racially diverse pulmonary
MF, Carmichael NE, Gulati S, Rice MB, Goldberg HJ, fibrosis cohorts. Nature Communications. 2023;14:1489.
Putman RK, Hatabu H, Raby BA, Rosas IO, Hunninghake
GM. Progressive Interstitial Lung Disease in Relatives of Baker MC, Liu Y, Lu R, Lin J, Melehani J, Robinson WH.
Patients with Pulmonary Fibrosis. Am J Respir Crit Care Incidence of Interstitial Lung Disease in Patients with
Med. 2023;207(2):211-214. Rheumatoid Arthritis Treated with Biologic and Targeted
Synthetic Disease-Modifying Antirheumatic Drugs. JAMA
Khor YH, Bissell B, Ghazipura M, Herman D, Hon SM, Network Open. 2023; 6(3): e233640.
Hossain T, Kheir F, Knight SL, Kreuter M, Macrea M,
Mammen MJ, Molina-Molina M, Selman M, Wijsenbeek M, Jang HJ, Woo A, Kim SY, Yong SH, Park Y, Chung K, Lee SH,
Racghu G, Wilson KC. Antacid Medication and Antireflux Leem AY, Lee SH, Kim EY, Jung JY, Kang YA, Kim YS, Park
Surgery in Patients with Idiopathic Pulmonary Fibrosis. MS. Characteristics and risk factors of mortality in
Ann Am Thorac Soc. 2022;19(5):833-844. patients with systemic sclerosis-associated interstitial
lung disease. Ann of Med. 2023; 55(1):663-671.
Pitre T, Mah J, Helmeczi W, Khalid MF, Cui S, Zhang M,
Husnudinov R, Su J, Banfield L, Guy B, Coyne J, Scallan C, Kim JS, Azarbarzin A, Podolanczuk AJ, Anderson MR, Cade
Kolb MRJ, Jones A, Zeraatkar D. Medical treatments for BE, Kawut SM, Wysoczanski A, Laine AF, Hoffman EA,
idiopathic pulmonary fibrosis: a systematic review and Gottlieb DK, Garcia CK, Barr RG, Redline S. Obstructive
network meta-analysis. Thorax. 2022;77:1243-1250. Sleep Apnea and Longitudinal Changes in Interstitial
Lung Imaging and Lung Function: The MESA Study. Ann
Adegunsoye A, Newton CA, Oldham JM, Ley B, Lee CT, Am Thorac Soc. 2023;
Linderhold AL, Chung H, Garcia N, Zhang D, Vij R, Guzy R,
Jablonski R, Bag R, Voogt RS, Ma SF, Sperline AI, Raghu G,
Martinez FJ, Strek ME, Wolters PJ, Garcia CK, Pierce BL,
Noth I. Telomere length associated with chronological

Interstitial Lung Disease 25

 Clinical Year in Review

Lung Cancer
Anne Melzer, MD MS
University of Minnesota Medical School and the Minneapolis VA Health Care System
Pulmonary and Critical Care
Minneapolis, MN

ENVIRONMENTAL RISK FACTORS FOR LUNG CANCER 2. The authors found evidence of adverse effects of
Cheng I, Yang J, Tseng C, Wu J, Shariff-Marco S, Park SL, traffic-related air pollution on lung cancer risk.
Conroy SM, Inamdar PP, Fruin S, Larson T, Setiawan VW, 3. Exposure to air pollution was greater among those
DeRouen MC, Gomez SL, Wilkens LR, Le Marchand L, residing in neighborhoods with low socioeconomic
Stram DO, Samet J, Ritz B, Wu AH. Traffic-related Air status, which may be a potential contributor to lung
Pollution and Lung Cancer Incidence: The California cancer disparities.
Multiethnic Cohort Study. Am J Respir Crit Care Med. 4. Interventions such as clean air laws may be
2022 Oct 15;206(8):1008-1018. doi: 10.1164/rccm.202107- beneficial for lung cancer prevention.
1770OC.

Summary LUNG CANCER SCREENING

Epidemiologic trends show that lung cancer in non- Silvestri GA, Goldman L, Burleson J, Gould M, Kazerooni
smokers is on the rise. One contributor to this trend EA, Mazzone PJ, Rivera MP, Doria-Rose VP, Rosenthal LS,
may be exposures to non-tobacco-related toxicants Simanowith M, Smith RA. Characteristics of persons
that increase the risk of lung cancer. Previous studies screened for lung cancer in the United States: a cohort
have confirmed a link between work related, traffic and study. Ann Intern Med. 2022 Nov;175(11):1501-5.
environmental pollutants and lung cancer risk, but few doi:10.7326/M22-1325
studies have been adequately powered to examine
these risks across racially, ethnically and Summary
socioeconomically diverse populations. This study Lung cancer screening is endorsed by the US Preventive
followed a prospective cohort of 97,288 individuals Services Task Force (USPSTF). However, uptake has
living in California over an average of 17 years, linking been slower than anticipated. There are also concerns
their lung cancer outcomes with their estimated about fidelity to required components, such as
exposure to traffic-related air pollutants based on eligibility assessment and adherence to subsequent
longitudinal geocoded addresses. In analyses adjusted imaging, that may decrease effectiveness of screening.
for other lung cancer risk factors, higher exposure to In this article, the authors analyzed population
nitrogen oxide and dioxide, fine particulate matter (PM) characteristics and adherence rates among a cohort of
2.5, carbon monoxide and benzene were all associated 1,159,092 patients undergoing low-dose CT for lung
with increased lung cancer incidence, though not all of cancer screening at one of 3625 facilities reporting to
these associations were statistically significant. Toxicant the American College of Radiology Registry.
exposures were higher in low versus high- Characteristics of these individuals were compared to
socioeconomic status neighborhoods. This study adds the likely-eligible population based on data from the
to evidence linking environmental exposure to pollution National Health Interview Survey. Of those screened,
with increased risk of lung cancer. 90.8% were eligible per USPSTF criteria. Compared to
the likely-eligible population, those who were screened
Comments were older (34.7% vs 44.8% aged 65 to 74 years), more
1. Exposure to ambient air pollution is increasingly likely to be female (41.8% vs 48.1%) and more likely to
recognized as risk factor for lung cancer. currently smoke (52.3% vs 61.4%). Only 22.3% had a

Lung Cancer 26
 Clinical Year in Review

repeat annual low-dose CT at a year, and only 34.3% weeks of nicotine patches). Though the intensive arm
within two years. These data suggest disparities in showed increased short-term cessation (14.3% vs 7.9%,
identifying eligible patients, specifically younger, male OR 2.0, 95% CI 1.26-3.18), these differences did not
former smokers. These individuals may have more life- persist to 12 months. When creating a TDT program for
years to gain from screening. It also highlights a lung cancer screening participants, programs must
significant gap in adherence to recommended follow-up consider the adequacy of treatment intensity and
that will limit screening effectiveness. include methods to maintain abstinence over time,
such as chronic disease models of tobacco treatment.
Comments
1. Lung cancer screening implementation has been Comments
challenging and slower than anticipated. 1. Tobacco dependence treatment is a key element of
2. In a national cohort representing over a million a high-quality lung cancer screening program.
individuals, nearly 10% did not meet USPSTF 2. Integrating a relatively low-intensity treatment (8
eligibility criteria. weeks of phone counseling and nicotine patch) into
3. Younger individuals, males and former smokers lung cancer screening did not increase long-term
were less likely to be screened, representing missed abstinence from cigarette smoking.
opportunities and potential disparities in screening 3. As lung cancer screening programs consider
access. integrating tobacco dependence treatments, the
4. Adherence to annual follow-up was very poor at focus should be on connecting to interventions that
less than 25%, below a threshold that would be are adequately intensive to meet the needs of
expected to significantly limit effectiveness. screening participants.

LUNG CANCER SCREENING: TOBACCO DEPENDENCE LUNG CANCER DIAGNOSIS

TREATMENT Kalchiem-Dekel O, Connolly JG, Lin IH, Husta BC,
Taylor KL, Williams RM, Li T, Luta G, Smith L, Davis KM, Adusumilli PS, Beattie JA, Buonocore DJ, Dycoco J,
Stanton CA, Niaura R, Abrams D, Lobo T, Mandelblatt J. A Fuentes P, Jones DR, Lee RP, Park BJ, Rocco G, Chawla M,
randomized trial of telephone-based smoking cessation Bott MJ. Shape-Sensing Robotic-Assisted Bronchoscopy
treatment in the lung cancer screening setting. JNCI.. in the Diagnosis of Pulmonary Parenchymal Lesions.
2022 Oct 6;114(10):1410-9. Chest. 2022 Feb;161(2):572-582. doi:
10.1016/[Link].2021.07.2169. Epub 2021 Aug 9.
Summary
Modeling studies support that integrating effective Summary
tobacco dependence treatment (TDT) into lung cancer Navigational bronchoscopy for the sampling of
screening programs would have a mortality benefit pulmonary lesions has been rapidly implemented over
commensurate with the screening intervention itself. the past 10 years. Robotic-assisted bronchoscopy is a
Lung cancer screening participants who smoke are recent advancement in technology with the goal of
uniformly older, heavy users of tobacco and may providing higher diagnostic yields and the ability to
require intensive treatment to quit successfully (e.g., sample smaller and more distal lesions that were
combined counseling and pharmacotherapy). Screening previously inaccessible. However, there is relatively
programs can serve to connect patients to these little data on the feasibility, yield and safety of these
treatments. In this study, lung cancer screening patients platforms. One such system is the Intuitive Ion platform
who smoke (n=818), regardless of their intention to quit which uses shape-sensing technology to facilitate distal
in the next 30 days, were randomly assigned to one of airway navigation. The authors report outcomes from
two intensities of TDT, a “minimal” program (three 131 robotic-assisted bronchoscopies for diagnosis of
phone sessions and two weeks of free nicotine patch) presumed malignant lesions (n=157) performed using
and an “intensive” program (8 phone sessions and 8 the Ion system. Nearly all (85.5%) procedures also

Lung Cancer 27
 Clinical Year in Review

utilized radial endobronchial ultrasound and one of two thoracic surgery members of the American College of
experienced physicians performed all procedures. The Chest Physicians. Among 453 respondents, 29% were
overall diagnostic yield from 157 individual lesions was unaware that there are guidelines about invasive nodal
81.7%, with increasing size associated with higher yields staging. Of those who were aware of the guidelines
(66% for lesions <1cm, 100% for lesions >3 cm). most (90%) agreed that these guidelines improved their
Complications were rare (3% overall, 1.5% treatment decisions, but 20% felt there was insufficient
pneumothorax). Reported yields were moderately evidence that using these guidelines improved
higher than previously published yields from outcomes. Nearly all physicians reported at least one
electromagnetic navigation bronchoscopy barrier to guideline adherence, including patient
(approximately 65-88%). anxiety (62%), difficulty implementing these guidelines
within routine practice (52%) and delays due to
Comments additional testing (51%). There is a significant
1. Robotic-assisted bronchoscopy is a recent knowledge gap regarding invasive staging guidelines,
advancement developed to increase diagnostic with many reported barriers to adherence.
yields and allow access to smaller and more distal
pulmonary lesions. Comments
2. Using a system (Ion) that employs shape-sensing 1. Pretreatment invasive nodal staging is an important
guidance, overall diagnostic yield for pulmonary part of lung cancer care, and recognized guidelines
lesions in this single-center study of 157 lesions was exist to support treatment decisions.
81.7%. 2. Over a quarter of surveyed pulmonologists and
3. Yield was higher for larger and more central lesions, thoracic surgeons were unaware of guidelines to
with yield from nodules <1 cm at 66%. direct completion of invasive nodal staging.
4. When compared to previous data on 3. Physicians reported many barriers to adherence to
electromagnetic navigation bronchoscopy, these guidelines, including difficulty adhering to
diagnostic yield may be slightly higher. them within routine clinical practice, patient
anxiety, and delays in care.
4. There is a significant knowledge gap in invasive
LUNG CANCER STAGING nodal staging as well as barriers to adherence that
Henderson LM, Farjah F, Detterbeck F, Smith RA, Silvestri need to be addressed to improve lung cancer care.
GA, & Rivera MP. (2022). Pretreatment Invasive Nodal
Staging in Lung Cancer: Knowledge, Attitudes, and
Beliefs Among Academic and Community Physicians. LUNG CANCER TREATMENT
Chest, 161(3), 826-832. Saji H, Okada M, Tsuboi M, Nakajima R, Suzuki K, Aokage
K, Aoki T, Okami J, Yoshino I, Ito H, Okumura N,
Summary Yamaguchi M, Ikeda N, Wakabayashi M, Nakamura K,
Pretreatment invasive nodal staging is an important Fukuda H, Nakamura S, Mitsudomi T, Watanabe SI,
step to ensure patients receive the appropriate Asamura H; West Japan Oncology Group and Japan
therapies for non-small cell lung cancer. Several Clinical Oncology Group. Segmentectomy versus
guidelines exist that recommend when to perform lobectomy in small-sized peripheral non-small-cell
invasive staging, but previous studies suggest that lung cancer (JCOG0802/WJOG4607L): a multicentre,
adherence to recommended staging is poor. One open-label, phase 3, randomised, controlled, non-
potential reason for this finding may be lack of inferiority trial. Lancet. 2022 Apr 23;399(10335):1607-1617.
knowledge or adverse attitudes or beliefs about doi: 10.1016/S0140-6736(21)02333-3.
invasive staging among pulmonologists and thoracic
surgeons. This study reports a web-based survey
distributed to a random sample of pulmonary and

Lung Cancer 28
 Clinical Year in Review

Summary KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J,

Lobectomy is the standard of care for early-stage non- Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet
small-cell lung cancer, but can carry significant CY, Girard N; CheckMate 816 Investigators. Neoadjuvant
morbidity due to the relatively large volume of lung Nivolumab plus Chemotherapy in Resectable Lung
removed. Sublobar resections are an attractive Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. doi:
alternative for small lesions that may offer equivalent 10.1056/NEJMoa2202170. Epub 2022 Apr 11.
survival with less morbidity, if they can offer
comparable cure rates. This study reports the results of Summary
a randomized controlled, noninferiority trial conducted Among the approximately 25% of patients diagnosed
at 70 institutions across Japan which compared with non-small-cell lung cancer (NSCLC) who present
lobectomy to segmentectomy for early-stage lung with resectable disease and undergo surgery, many will
cancer. Participants (n=1106) had lung cancers clinically ultimately have a recurrence and die of lung cancer.
staged at IA (tumor ≤ 2cm, no suspicious lymph nodes Neoadjuvent chemotherapy has been tested as a means
on clinical staging), that were peripherally located to improve recurrence-free survival and has
(outer third), and excluded the right middle lobe. They demonstrated a modest benefit. Nivolumab is an anti-
were randomized to standard lobectomy versus programmed death-1 (PD-1) antibody, with proven
segmentectomy. Procedures in both groups were largely survival benefit for metastatic NSCLC. Immunotherapy
by VATS (80%) with the remainder by thoracotomy. with nivolumab may offer improved eradication of
Groups were similar in their characteristics. At the time micrometastatic disease and lead to better long-term
of operation, 22/552 individuals randomized to survival for early-stage patients as well. In this large
segmentectomy were converted to lobectomy. At a international study (n=505), patients with resectable IB
median of 7.3 years of follow-up, 5-year overall survival to IIIA NSCLC were randomized to conventional
was superior in the segmentectomy arm (94.3% vs 91.1%, platinum-based neoadjuvant therapy vs conventional
p for superiority 0.0082), while 5-year relapse-free therapy + nivolumab. The primary outcomes were
survival was identical. However, local relapse was event-free survival and complete pathologic response
higher in the segmentectomy arm (10.5% vs 5.4%%, in the lymph nodes at the time of surgery. Median
p=0.0018). Complication rates and decline in FEV1 at 1 event-free survival was longer in the nivolumab arm
year were similar between the two arms. (30.6 months vs 20.8 months) with higher complete
pathologic response (24% vs 2.2%). The magnitude of
Comments benefit was greatest in the more advanced (IIIA)
1. In a large (1106 patients) randomized trial patients. This study supports efficacy of nivolumab as
comparing lobectomy to segmentectomy for early- add-on neoadjuvant therapy for resectable patients
stage peripheral lung cancers, segmentectomy was with NSCLC greater than stage 1A. The hazard ratio for
found to have superior 5-year overall survival. overall survival strongly favored nivolumab but did not
2. Local relapse was higher in the segmentectomy arm meet pre-specified significance (HR 0.57, 99.67% CI 0.30-
(10.5% vs 5.4%). 1.07). Safety was similar between the arms.
3. For patients with stage IA lung cancers surgically
resectable via segmentectomy, segmentectomy Comments
appears to offer results that are noninferior and 1. Many patients with resectable non-small-cell lung
likely superior to lobectomy. cancer ultimately die due to recurrence, despite use
of platinum-based neoadjuvant chemotherapy.
2. In this randomized controlled trial of patients with
LUNG CANCER TREATMENT resectable NSCLC, Nivolumab, an anti-PD-1
Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad antibody, was administered as add-on therapy to
MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr standard neoadjuvant therapy.
K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen

Lung Cancer 29
 Clinical Year in Review

3. Event-free survival was higher in the nivolumab arm

(30.6 vs 20.8 months). Potter AL, Rosenstein AL, Kiang MV, Shah SA, Gaissert
4. Complete pathologic response in the lymph nodes HA, Chang DC, Fintelmann FJ, Yang CF. Association of
at the time of surgery was higher in the nivolumab computed tomography screening with lung cancer stage
arm (24% vs 2.2%). shift and survival in the United States: quasi-
5. Nivolumab appears to be a safe and effective add- experimental study. BMJ. 2022 Mar 30;376.
on neoadjuvant therapy for patients with resectable [Link]/10.1136/bmj-2021-069008
stage 1B-IIIA NSCLC. YIR Bibliography=Fira Sans Light

Rivera MP, Durham DD, Long JM, et al. Receipt of

Recommended Follow-up Care After a Positive Lung
OTHER ARTICLES OF INTEREST Cancer Screening Examination. JAMA Netw Open.
Agrawal A, Ho E, Chaddha U, Demirkol B, Bhavani SV, 2022;5(11):e2240403.
Hogarth DK, & Murgu, S. (2022). Factors Associated With doi:10.1001/jamanetworkopen.2022.40403
Diagnostic Accuracy of Robotic Bronchoscopy With 12-
Month Follow-up. The Annals of Thoracic Surgery. Smith HB, Schneider E, Tanner NT. An Evaluation of
Annual Adherence to Lung Cancer Screening in a Large
Farjah F, Monsell SE, Smith-Bindman R, Gould MK, National Cohort. Am J Prev Med. 2022 Mar.
Banegas MP, Ramaprasan A, Schoen K, Buist DS,
Greenlee R. Fleischner Society Guideline Sood R, Alape D, Thakkar D, Shadchehr S, Acash G,
Recommendations for Incidentally Detected Pulmonary Tronic BJ, Lamb CR. Comparison of Sample Adequacy
Nodules and the Probability of Lung Cancer. J Am Coll and Diagnostic Yield of the 21-G and 25-G EBUS TBNA
Radiol, 2022:19(11), 1226-1235. Needles. J Bronchology Interv Pulmonol. 2022 Jan
1;29(1):34-38. doi: 10.1097/LBR.0000000000000753.
Lee EYC, McWilliams AM, Salamonsen MR. Therapeutic
Rigid Bronchoscopy Intervention for Malignant Central Wang J, Zhou C, Yao W, Wang Q, Min X, Chen G, Xu X, Li X,
Airway Obstruction Improves Performance Status to Xu F, Fang Y, Yang R, Yu G, Gong Y, Zhao J, Fan Y, Liu Q,
Allow Systemic Treatment. J Bronchology Interv Cao L, Yao Y, Liu Y, Li X, Wu J, He Z, Lu K, Jiang L, Hu C,
Pulmonol. 29(2):p 93-98, April 2022. DOI: Zhao W, Zhang B, Shi W, Zhang X, Cheng Y; CAPSTONE-1
10.1097/LBR.0000000000000808 Study Group. Adebrelimab or placebo plus carboplatin
and etoposide as first-line treatment for extensive-
Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, stage small-cell lung cancer (CAPSTONE-1): a
Greillier L, Kaplan MA, Talbot T, Monnet I, Hiret S, Baas P, multicentre, randomised, double-blind, placebo-
Nowak AK. First-line nivolumab plus ipilimumab versus controlled, phase 3 trial. Lancet Oncol. 2022
chemotherapy in patients with unresectable malignant Jun;23(6):739-747. doi: 10.1016/S1470-2045(22)00224-8.
pleural mesothelioma: 3-year outcomes from Epub 2022 May 13.
CheckMate 743. Ann Oncol. 2022 May 1;33(5):488-99.

Lung Cancer 30
 Clinical Year in Review

COVID-19
Sarah Jolley, MD, MSc
University of Colorado
Pulmonary and Critical Care Medicine
Aurora, CO

ACUTE MANAGEMENT OF COVID-19 group compared to the control group although no

Alhazzani W, Parhar KKS, Weatherald J, Al Duhailib Z, serious adverse events were reported in either group.
Alshahrani M, Al-Fares A, Buabbas S, Cherian SV, Munshi
L, Fan E, Al-Hameed F, Chalabi J, Rahmatullah AA, Duan
E, Tsang JLY, Lewis K, Lauzier F, Centofanti J, Rochwerg B, Comments
Culgin S, Nelson K, Abdukahil SA, Fiest KM, Stelfox HT, 1. Awake prone positioning for patients with acute
Tlayjeh H, Meade MO, Perri D, Solverson K, Niven DJ, Lim COVID-19 on high flow nasal cannula and/or non-
R, Møller MH, Belley-Cote E, Thabane L, Tamim H, Cook invasive ventilation did not reduce rate of
DJ, Arabi YM; COVI-PRONE Trial Investigators and the intubation or death at 60 days and was not
Saudi Critical Care Trials Group. Effect of Awake Prone associated with reductions in mechanical
Positioning on Endotracheal Intubation in Patients With ventilation, ICU or hospital durations.
COVID-19 and Acute Respiratory Failure: A Randomized 2. Subgroup analysis suggested potential benefit in
Clinical Trial. JAMA. 2022 Jun 7;327(21):2104-2113. patients with less severe hypoxemia/respiratory
failure although this was not a primary endpoint for
Summary the trial.
The COVI-PRONE trial was an unblinded, randomized 3. Awake prone positioning appears safe with no
controlled trial of awake prone positioning for COVID-19 serious adverse events reported although mild
patients across 21 international centers requiring high adverse events were reported more frequently in
flow oxygen or non-invasive ventilation. A total of 400 the prone group compared to the control group.
participants were randomized including 205 to the 4. The short duration of prone positioning in the
awake prone positioning group and 195 to the control intervention group (average 5 hours/day) may have
group. The median duration of prone positioning in the influenced outcomes.
intervention group was 5 hours [IQR 2 to 8 hours] 5. Significant cross-over and refusal of intervention in
compared with 0 hours in the control group [IQR 0 to 0]. the intervention group (10%) may have contributed
The use of prone positioning was associated with to lack of observed difference.
similar rates of intubation (33.7 intervention versus
36.3% control, HR 0.89, 95% CI 0.62 to 1.28, p=0.54) and NOVEL THERAPEUTICS FOR ACUTE COVID-19
death at 60 days (22.4 intervention versus 23.6% control, Reis G, Moreira Silva EAS, Medeiros Silva DC, Thabane L,
HR 0.93, 95% CI 0.62 to 1.40, p=0.72) compared with usual Campos VHS, Ferreira TS, Santos CVQ, Nogueira AMR,
care. Days of mechanical ventilation, ICU use or hospital Almeida APFG, Savassi LCM, Figueiredo-Neto AD, Dias
admission did not differ between groups. Subgroup ACF, Freire Júnior AM, Bitarães C, Milagres AC, Callegari
analyses demonstrated a 56% reduction in risk of ED, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Wilson
intubation for patients who received awake prone LA, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM,
positioning and had less severe respiratory failure with Limbrick-Oldfield EH, Kanters S, Guyatt GH, Rayner CR,
a Pa02:FiO2 ratio >150 (p=0.03 for interaction). Other Kandel C, Biondi MJ, Kozak R, Hansen B, Zahoor MA,
outcomes did not differ when stratified by severity of Arora P, Hislop C, Choong I, Feld JJ, Mills EJ, Glenn JS;
respiratory failure or hypoxemia. Adverse events were TOGETHER Investigators. Early Treatment with Pegylated
reported more frequently in the prone positioning

COVID-19 31
 Clinical Year in Review

Interferon Lambda for Covid-19. N Engl J Med. 2023 Feb immunosuppression who are high-risk for severe
9;388(6):518-528. outcomes.
Summary 5. Single dose interferon lambda may be useful in
This is a Phase III, double-blind, randomized controlled patients with drug-drug interactions to Paxlovid or
trial of pegylated interferon lambda as outpatient who may be unable to take a longer course of oral
therapy for COVID-19 conducted across 17 sites in antivirals.
Canada and Brazil. Adults who were largely vaccinated
against COVID-19 with an identified high-risk condition
for severe COVID-19 within 7 days of acute infection LONG-TERM BURDEN OF PASC
were randomized to a single dose of 180 micrograms of Admon AJ, Iwashyna TJ, Kamphuis LA, Gundel SJ, Sahetya
pegylated interferon lambda versus placebo. In total, SK, Peltan ID, Chang SY, Han JH, Vranas KC, Mayer KP,
1951 participants were randomized including 933 to the Hope AA, Jolley SE, Caldwell E, Monahan ML, Hauschildt
pegylated interferon lambda group and 1018 to the K, Brown SM, Aggarwal NR, Thompson BT, Hough CL;
placebo group. The median time from onset of National Heart, Lung, and Blood Institute PETAL
symptoms to randomization was 3 days. Patients Network. Assessment of Symptom, Disability, and
treated with interferon lambda demonstrated a 53% Financial Trajectories in Patients Hospitalized for
decrease in need for COVID-19 hospitalization or ER visit COVID-19 at 6 Months. JAMA Netw Open. 2023 Feb
(2.7 interferon versus 5.6% placebo, HR 0.47, 95% CI 0.3 1;6(2):e2255795.
to 0.76). Risk of COVID-related hospitalization (2.3
interferon versus 3.9% placebo, HR 0.58, 95% CI 0.34 to Summary
0.96) or death (2.4 interferon versus 3.9% placebo, HR This prospective cohort study followed patients
0.61, 95% CI 0.36 to 0.99) was lower in the interferon hospitalized for COVID-19 pneumonia across 44 US-
lambda group compared with placebo. Time to clinical based sites with telephone-based assessment at 1-,3-
recovery did not differ significantly between groups. and 6-months post-COVID-19 hospitalization. A total of
Adverse events did not differ significantly between 825 participants were included. Multisystem symptoms,
groups (3.4, interferon versus 4.8% placebo). Observed new activities of daily living limitations and financial
benefits persisted across all pre-defined subgroups problems were highly prevalent out to 6 months after
including age, sex, days since symptom onset and COVID-19 hospitalization. Frequency of cardiopulmonary
vaccination status. symptoms (67.3 to 75.4%, p=0.001) and fatigue (40.7 to
50.8% p<0.01) increased between 1- and 6-months.
Comments Prevalence of financial problems decreased (66.1 to
1. In patients with a high-risk condition for severe 56.4%, p<0.01) between month 1 and 6 as did frequency
COVID-19, use of pegylated interferon lambda early of functional limitation (55.3 to 47.3%, p=0.004). Sixty
in the acute period was associated with a percent of participants reporting no symptoms at 1-
significant reduction in the risk of COVID-19 related month reported new symptoms by 6-months post-
hospitalization, ED visits and death compared with hospitalization. Use of supplemental oxygen was
placebo. associated with a greater odds of reporting
2. Observed effects demonstrated superiority of cardiopulmonary symptoms at 6 months post-
interferon lambda compared with placebo across hospitalization (adjusted odds ratio (OR) 1.71, 95% CI 1.10
all pre-specified subgroups. to 2.66). Non-white race/ethnicity was associated with
3. Severe outcome endpoints including death and increased odds of reporting financial problems (aOR
hospitalization were uncommon in this largely Hispanic, 3.74, 95% CI 2.24 to 6.23 and aOR non-Hispanic
vaccinated, omicron-era group of patients. Black 2.63, 95% CI 1.65 to 4.20). Results of this cohort
4. Interferon lambda may be an important therapeutic study highlight the substantial burden of disease in
consideration for patients with high-risk conditions patients recovering from a COVID-19 hospitalization.
including organ transplant and chronic Further, they demonstrate that risk for multisystem

COVID-19 32
 Clinical Year in Review

symptoms and poor outcomes after hospitalization distinct characteristics diagnostic for PASC when
persist well into the recovery period. compared with presumed non-PASC controls. The team
identified four system themes that were consistently
Comments identified across models and clusters: 1) post-COVID-19
1. Residual impairments are common after a COVID- respiratory symptoms and treatments 2) non-
19-related hospitalization independent of illness respiratory symptoms 3) pre-existing risk factors for
severity at time of hospitalization or baseline greater acute COVID severity and 4) proxies for
comorbidities. hospitalization. The most predictive factors for
2. Cardiopulmonary symptoms and fatigue were identifying PASC in patients not previously hospitalized
commonly reported at 6-months post- included younger age, dyspnea, and female sex.
hospitalization with increased odds of symptoms in Conversely, the most predictive factors for identifying
patients receiving supplemental oxygen. previously hospitalized patients included increased age,
3. Financial problems decreased between 1- and 6- lack of prior vaccination and dyspnea.
months post-hospitalization but remained highly
prevalent, occurring in over half of all respondents. Comments
4. Financial risk was greater in non-White identifying 1. Increasing recognition of sub-phenotypes of PASC
patients compared with non-Hispanic White suggesting PASC is not a singular clinical entity.
patients. 2. Risk of PASC varies amongst previously hospitalized
5. There are significant longitudinal changes in PASC and non-hospitalized patients.
symptomatology amongst patients previously 3. PASC symptomatology extends beyond the
hospitalized for COVID-19 that require longer-term respiratory system with non-respiratory symptoms
follow up and monitoring. commonly reported and potentially reflecting a
separate phenotype.
4. EHR-models can help with identification of PASC
SUB-PHENOTYPES OF POST-ACUTE SEQUELAE OF which may aid in understanding regional and
COVID-19 national prevalence.
Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer 5. A true gold standard definition of PASC is needed to
RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, refine diagnostic models and improve identification
McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; of the condition.
N3C Consortium. Identifying who has long COVID in the
USA: a machine learning approach using N3C data.
Lancet Digit Health. 2022 Jul;4(7):e532-e541. doi: EMERGING THERAPIES FOR PASC
10.1016/S2589-7500(22)00048-6. Epub 2022 May 16. Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M,
Nafilyan V, Zaccardi F, Khunti K, Alwan NA, Walker AS.
Summary Trajectory of long covid symptoms after covid-19
This retrospective, electronic-health record-based vaccination: community based cohort study. BMJ. 2022
cohort study developed a machine learning algorithm May 18;377:e069676.
to identify Post- Acute Sequelae of COVID-19 (PASC) and
PASC symptomology amongst 97, 995 patients with a Summary
diagnosis of acute COVID-19 across the United States. This article reports results of a longitudinal, prospective
Investigators identified 73,972 patients with a health cohort study aimed at understanding the association
care visit in their post-COVID period including 15, 621 between vaccination against SARS-CoV-2 and
who were previously hospitalized for COVID-19 and 58, development of PASC. Investigators surveyed
351 treated as outpatients. Using data from three individuals aged 18 to 69 years old were included using
dedicated PASC clinics to establish a silver standard random sampling of households across the United
definition of PASC, the investigators identified 20 Kingdom. Primary COVID infection was defined in the 12

COVID-19 33
 Clinical Year in Review

weeks prior to follow up using nasal swab testing or OTHER ARTICLES OF INTEREST
SARS-CoV-2 antibody testing. Vaccination status was ACUTE MANAGEMENT OF COVID-19
ascertained during in person interview as were Frat JP, Quenot JP, Badie J, Coudroy R, Guitton C,
symptoms of long COVID that comprised the primary Ehrmann S, Gacouin A, Merdji H, Auchabie J, Daubin C,
outcome. A total of 28,356 participants were included in Dureau AF, Thibault L, Sedillot N, Rigaud JP, Demoule A,
the analysis. The prevalence of long COVID across the Fatah A, Terzi N, Simonin M, Danjou W, Carteaux G,
follow up period was 23.7%. First vaccination was Guesdon C, Pradel G, Besse MC, Reignier J, Beloncle F, La
associated with a 12.8% decrease in long COVID Combe B, Prat G, Nay MA, de Keizer J, Ragot S, Thille AW;
symptoms (95% CI -18.6 to -6.6%, p<0.01). Second SOHO-COVID Study Group and the REVA Network. Effect
vaccination dose was associated with an 8.8% decrease of High-Flow Nasal Cannula Oxygen vs Standard Oxygen
(95% CI -14.1 to -3.1%, p=0.003) followed by an additional Therapy on Mortality in Patients With Respiratory
0.8% decrease per week after second dose Failure Due to COVID-19: The SOHO-COVID Randomized
administration (-1.2 to -0.4%, p<0.01). Additionally, Clinical Trial. JAMA. 2022 Sep 27;328(12):1212-1222. doi:
vaccination was associated with a reduction in reported 10.1001/jama.2022.15613.
activity limitation from long COVID. First vaccination
dose was associated with a 12.3% decrease in activity Arabi YM, Aldekhyl S, Al Qahtani S, Al-Dorzi HM,
limitation (95% CI -19.5 to -4.5%, p=0.003) while the Abdukahil SA, Al Harbi MK, Al Qasim E, Kharaba A,
second dose was associated with a 9.1% decrease (95% Albrahim T, Alshahrani MS, Al-Fares AA, Al Bshabshe A,
CI -15.6 to -2.1%, p=0.01). These results suggest Mady A, Al Duhailib Z, Algethamy H, Jose J, Al Mutairi M,
vaccination against SARS-CoV-2 may reduce long-term Al Zumai O, Al Haji H, Alaqeily A, Al Aseri Z, Al-Omari A,
symptoms after COVID-19 in addition to lessening risk Al-Dawood A, Tlayjeh H; Saudi Critical Care Trials Group.
from acute illness. Effect of Helmet Noninvasive Ventilation vs Usual
Respiratory Support on Mortality Among Patients With
Comments Acute Hypoxemic Respiratory Failure Due to COVID-19:
1. Prevalence of PASC was 23.7% in a random sample The HELMET-COVID Randomized Clinical Trial. JAMA. 2022
of adult households across the United Kingdom. Sep 20;328(11):1063-1072.
2. Vaccination against SARS-CoV-2 decreased risk of
any long COVID symptoms and activity limitation
NOVEL THERAPEUTICS FOR ACUTE COVID-19
secondary to long COVID.
3. Additional doses of vaccine provided additional Johnson MG, Puenpatom A, Moncada PA, Burgess L,
reduction in long COVID symptoms and activity Duke ER, Ohmagari N, Wolf T, Bassetti M, Bhagani S,
limitation. Ghosn J, Zhang Y, Wan H, Williams-Diaz A, Brown ML,
4. Vaccination against SARS-CoV-2 may aid in reducing Paschke A, De Anda C. Effect of Molnupiravir on
the burden of PASC in addition to lessening the risk Biomarkers, Respiratory Interventions, and Medical
of acute disease. Services in COVID-19 : A Randomized, Placebo-
5. Vaccination campaigns should consider potential Controlled Trial. Ann Intern Med. 2022 Aug;175(8):1126-
benefits for reducing PASC risk when advising 1134. doi: 10.7326/M22-0729. Epub 2022 Jun 7.
patients in the Omicron era where acute illness
severity is less.

COVID-19 34
 Clinical Year in Review

Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz Swank Z, Senussi Y, Manickas-Hill Z, Yu XG, Li JZ, Alter G,
DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Walt DR. Persistent Circulating Severe Acute Respiratory
Proper JL, Siegel LK, Klatt NR, Odde DJ, Luke DG, Syndrome Coronavirus 2 Spike Is Associated With Post-
Anderson B, Karger AB, Ingraham NE, Hartman KM, Rao acute Coronavirus Disease 2019 Sequelae. Clin Infect
V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Dis. 2023 Feb 8;76(3):e487-e490.
Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A,
Saveraid HG, Tordsen WJ, Pullen MF, Biros M, Sherwood Durstenfeld MS, Peluso MJ, Kelly JD, Win S, Swaminathan
NE, Thompson JL, Boulware DR, Murray TA; COVID-OUT S, Li D, Arechiga VM, Zepeda V, Sun K, Shao S, Hill C,
Trial Team. Randomized Trial of Metformin, Ivermectin, Arreguin MI, Lu S, Hoh R, Tai V, Chenna A, Yee BC,
and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug Winslow JW, Petropoulos CJ, Kornak J, Henrich TJ, Martin
18;387(7):599-610. JN, Deeks SG, Hsue PY. Role of antibodies, inflammatory
markers, and echocardiographic findings in postacute
Naggie S, Boulware DR, Lindsell CJ, Stewart TG, Gentile N, cardiopulmonary symptoms after SARS-CoV-2 infection.
Collins S, McCarthy MW, Jayaweera D, Castro M, JCI Insight. 2022 May 23;7(10):e157053. doi:
Sulkowski M, McTigue K, Thicklin F, Felker GM, Ginde AA, 10.1172/[Link].157053.
Bramante CT, Slandzicki AJ, Gabriel A, Shah NS, Lenert
LA, Dunsmore SE, Adam SJ, DeLong A, Hanna G, Remaly Perlis RH, Lunz Trujillo K, Safarpour A, Santillana M,
A, Wilder R, Wilson S, Shenkman E, Hernandez AF; Ognyanova K, Druckman J, Lazer D. Association of Post-
Accelerating COVID-19 Therapeutic Interventions and COVID-19 Condition Symptoms and Employment Status.
Vaccines (ACTIV-6) Study Group and Investigators. Effect JAMA Netw Open. 2023 Feb 1;6(2):e2256152.
of Ivermectin vs Placebo on Time to Sustained Recovery
in Outpatients With Mild to Moderate COVID-19: A
DEEP PHENOTYPING OF POST-ACUTE SEQUELAE OF
Randomized Clinical Trial. JAMA. 2022 Oct
COVID-19
25;328(16):1595-1603.
Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ,
Callahan TJ, Laraway B, Antonescu C, Coleman B,
Puskarich MA, Ingraham NE, Merck LH, Driver BE, Wacker
Gargano M, Wilkins KJ, Cappelletti L, Fontana T, Ammar
DA, Black LP, Jones AE, Fletcher CV, South AM, Murray TA,
N, Antony B, Murali TM, Caufield JH, Karlebach G,
Lewandowski C, Farhat J, Benoit JL, Biros MH,
McMurry JA, Williams A, Moffitt R, Banerjee J,
Cherabuddi K, Chipman JG, Schacker TW, Guirgis FW,
Solomonides AE, Davis H, Kostka K, Valentini G, Sahner
Voelker HT, Koopmeiners JS, Tignanelli CJ; Angiotensin
D, Chute CG, Madlock-Brown C, Haendel MA, Robinson
Receptor Blocker Based Lung Protective Strategies for
PN; N3C Consortium; RECOVER Consortium.
Inpatients With COVID-19 (ALPS-IP) Investigators.
Generalisable long COVID subtypes: findings from the
Efficacy of Losartan in Hospitalized Patients With
NIH N3C and RECOVER programmes. EBioMedicine. 2023
COVID-19-Induced Lung Injury: A Randomized Clinical
Jan;87:104413.
Trial. JAMA Netw Open. 2022 Mar 1;5(3):e222735. doi:
10.1001/jamanetworkopen.2022.2735. Erratum in: JAMA
Rao S, Lee GM, Razzaghi H, Lorman V, Mejias A, Pajor NM,
Netw Open. 2022 May 2;5(5):e2215958.
Thacker D, Webb R, Dickinson K, Bailey LC, Jhaveri R,
Christakis DA, Bennett TD, Chen Y, Forrest CB. Clinical
EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF PASC Features and Burden of Postacute Sequelae of SARS-
Xie, Y., Xu, E., Bowe, B. et al. Long-term cardiovascular CoV-2 Infection in Children and Adolescents. JAMA
outcomes of COVID-19. Nat Med 28, 583–590 (2022). Pediatr. 2022 Oct 1;176(10):1000-1009.
[Link]

COVID-19 35
 Clinical Year in Review

EMERGING THERAPEUTICS FOR PASC

Peluso MJ, Anglin K, Durstenfeld MS, Martin JN, Kelly JD, O'Kelly B, Vidal L, McHugh T, Woo J, Avramovic G,
Hsue PY, Henrich TJ, Deeks SG. Effect of Oral Lambert JS. Safety and efficacy of low dose naltrexone
Nirmatrelvir on Long COVID Symptoms: 4 Cases and in a long covid cohort; an interventional pre-post study.
Rationale for Systematic Studies. Pathog Immun. 2022 Brain Behav Immun Health. 2022 Oct;24:100485.
Jun 24;7(1):95-103. doi: 10.20411/pai.v7i1.518.

COVID-19 36
 Clinical Year in Review

Palliative Care
Ann L. Jennerich, MD, MS, ATSF
University of Washington
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine
Seattle, WA

EARLY PALLIATIVE CARE IN RESPIRATORY ILLNESS Comments

Sullivan, D. R., Iyer, A. S., Enguidanos, S., Cox, C. E., 1. This statement outlines seven recommendations to
Farquhar, M., Janssen, D. J. A., Lindell, K. O., Mularski, R. improve the quality of care provided to patients
A., Smallwood, N., Turnbull, A. E., Wilkinson, A. M., with serious respiratory illness, by focusing on
Courtright, K. R., Maddocks, M., McPherson, M. L., palliative care across the continuum of a patient’s
Thornton, J. D., Campbell, M. L., Fasolino, T. K., Fogelman, disease process.
P. M., Gershon, L., Gershon, T., … Reinke, L. F. (2022). 2. The recommendations are centered on the role of
Palliative Care Early in the Care Continuum among primary palliative care, which requires the basic
Patients with Serious Respiratory Illness: An Official tenets of palliative care to be a core competence
ATS/AAHPM/HPNA/SWHPN Policy Statement. American for all clinicians caring for patients with serious
Journal of Respiratory and Critical Care Medicine, 206(6), respiratory illness.
e44–e69. [Link] 3. The statement offers guidance in the application of
individualized, evidence-based symptom
Summary assessments, with routine symptom assessment an
Palliative care can provide significant benefits to important tool to support development of symptom
patients and family of patients with serious respiratory management plans.
illness (e.g., chronic obstructive pulmonary disease 4. Numerous resources for palliative care education
[COPD], interstitial lung disease [ILD], and lung cancer). and training are highlighted for clinicians as are
Despite this, palliative care, provided by non-specialists resources for caregivers of patients with serious
(primary) and specialists (secondary or specialty), is respiratory illness.
underutilized and often integrated into care only at the
end of life. In this policy statement by the American
Thoracic Society (ATS) and partnering societies, TRIGGERS USED FOR PALLIATIVE CARE CONSULTATION
recommendations are made to facilitate the integration Cox, C. E., Ashana, D. C., Haines, K. L., Casarett, D., Olsen,
of palliative care in serious respiratory illness care M. K., Parish, A., O'Keefe, Y. A., Al-Hegelan, M., Harrison, R.
across seven domains: 1) delivery models; 2) W., Naglee, C., Katz, J. N., Frear, A., Pratt, E. H., Gu, J., Riley,
comprehensive symptom assessment and management; I. L., Otis-Green, S., Johnson, K. S., & Docherty, S. L. (2022).
3) advance care planning and goals of care discussions; Assessment of Clinical Palliative Care Trigger Status vs
4) caregiver support; 5) health disparities; 6) mass Actual Needs Among Critically Ill Patients and Their
casualty events and emergency preparedness; and 7) Family Members. JAMA network open, 5(1), e2144093.
research priorities. The statement provides clinicians [Link]
and policymakers with an approach to implement these
recommendations and improve care for those living Summary
with serious respiratory illness. Patient characteristics are often used as “triggers” for
palliative care consultation in the intensive care unit
(ICU). It is unclear, however, if these triggers identify
family of patients with the greatest palliative care
needs. This was a prospective cohort study in 6 adult

Palliative Care 37
 Clinical Year in Review

medical and surgical ICUs, including patients and family PALLIATIVE CARE NEEDS IN CYSTIC FIBROSIS
of patients receiving mechanical ventilation (n=257 Dubin, E., Lowers, J., Dellon, E. P., Hempstead, S., Faro, A.,
dyads, patient and family member). They assessed the Tallarico, E., Fitzpatrick, A., Hunt, W. R., & Kavalieratos, D.
presence of any of 9 common clinical palliative care (2022). Prevalence of unmet pain and symptom
triggers and evaluated differences in self-reported management needs in adults with cystic fibrosis.
palliative care needs (Needs at the End-of-Life Journal of Cystic Fibrosis: Official Journal of the
Screening Tool [NEST], completed after 3 days of ICU European Cystic Fibrosis Society, S1569-1993(22)00643-9.
care) between those with and without a clinical trigger. Advance online publication.
Triggers included: cardiac arrest; advanced cancer; [Link]
dementia; critical acute neurologic condition; residence
in a long-term acute care facility, skilled nursing facility, Summary
or inpatient rehabilitation facility; 3 or more limitations
Burdensome symptoms are common in people living
in baseline activities of daily living; 2 or more hospital
with cystic fibrosis (CF). These may include physical
admissions or 1 or more ICU admissions within 3
(e.g., pain, dyspnea, cough, steatorrhea), psychological
months; and worsening organ dysfunction. There was
(e.g., anxiety and depression), and existential (e.g., fear
no significant difference in self-reported palliative care
of disease progression, uncertainty about the future)
needs between those with and without a clinical trigger
symptoms and concerns. In this cross-sectional study,
(median NEST scores, 21.0 vs 22.5). Moreover, the
people living with CF (n=55) completed online surveys
evaluated triggers were neither sensitive nor specific for
assessing symptom prevalence, distress, and treatment.
identifying serious palliative care needs identified by
Of 29 symptoms reported, pain was the most common
dyads.
symptom experienced (76%), followed by sinus
discharge (75%), and fatigue/lack of energy (73%). In
Summary
terms of causing distress, pain was most frequently
1. This study confirms that family of critically ill identified (64%), followed by fatigue/lack of energy
patients often have serious palliative care needs, (55%) and difficulty sleeping (51%). Participants
(33.9% had a serious total burden of needs [total specifically raised concerns about inadequate pain
NEST score ≥ 30]); however, it challenges the management. An iterative, inductive thematic analysis
concept that clinical triggers are a useful tool for of open-ended survey questions identified three
identifying those palliative care needs. themes related to symptom management: pain and
2. The fact that clinical palliative care triggers were other symptoms are underrecognized and
not associated with higher levels of unmet undermanaged; a desire for multi-modal pain
palliative care needs suggests that these triggers management approaches; and concerns about disease
may not be reliable as a prompt for specialty progression affecting symptom management options.
palliative care consultation.
3. The value of triggers for identifying serious needs Comments
was not supported with the study’s measure, given
1. Pain is a common, distressing symptom
its poor performance characteristics (sensitivity
experienced by people living with cystic fibrosis.
44.7%, specificity 55.2%) in this regard.
2. The management of pain for people living with
4. An approach which directly assesses palliative care
cystic fibrosis is suboptimal.
needs may be a more patient- and family-centered
3. The themes identified in this study represent
way to target palliative care interventions, both
significant opportunities for improvement, including
from a clinical and research perspective.
exploration of the role of primary and specialty
palliative care in the management of pain in CF.

Palliative Care 38
 Clinical Year in Review

PALLIATIVE CARE IN ILD 3. Primary palliative care should be a core skill for
Gersten, R. A., Seth, B., Arellano, L., Shore, J., O'Hare, L., providers caring for people living with ILD,
Patel, N., Safdar, Z., Krishna, R., Mageto, Y., Cochran, D., particularly in environments where specialty
Lindell, K., Danoff, S. K., & Pulmonary Fibrosis palliative care is not available.
Foundation (2022). Provider Perspectives on and Access 4. For patients with ILD, optimal timing for referral to
to Palliative Care for Patients With Interstitial Lung palliative care medicine is a topic in need of further
Disease. Chest, 162(2), 375–384. research.
[Link]

Summary SUPPORT FOR FAMILY OF THE DYING

Interstitial lung disease (ILD) is associated with high
mortality, and people living with ILD carry a significant Kentish-Barnes, N., Chevret, S., Valade, S., Jaber, S.,
symptom burden. Involvement of palliative care Kerhuel, L., Guisset, O., Martin, M., Mazaud, A., Papazian,
specialists can benefit these patients and their family L., Argaud, L., Demoule, A., Schnell, D., Lebas, E., Ethuin,
members, but referrals to palliative care medicine, F., Hammad, E., Merceron, S., Audibert, J., Blayau, C.,
when they occur, are often introduced late in the Delannoy, P. Y., Lautrette, A., … Azoulay, E. (2022). A
disease process. To understand perspectives on three-step support strategy for relatives of patients
palliative care medicine among ILD providers, surveys dying in the intensive care unit: a cluster randomised
were distributed to 68 Pulmonary Fibrosis Foundation trial. Lancet (London, England), 399(10325), 656–664.
Care Centers across the United States. The 24-question [Link]
electronic survey was completed by 128 participants,
most of whom were physicians, representing all Centers. Summary
Most respondents were knowledgeable about what Psychological distress is common in family of critically
palliative care medicine entails, including symptom ill patients, and for family of those who die, prolonged
management, advance directives, spiritual care, and grief is also a concern. Poor communication may
psychological care. A minority of providers (2%) contribute to psychological distress and grief, and
reported that they refer patients to palliative care interventions to improve communication at the end of
medicine at the time of initial ILD diagnosis. Several life are needed. This multicenter, cluster randomized
barriers to involvement of palliative care medicine were controlled trial in 34 ICUs in France evaluated a
identified, including lack of validated instruments to communication and support intervention for dying
assess symptoms, uncertainty about optimal timing of patients and their family members. Participating ICUs
palliative care medicine referral as well as uncertainty were randomly assigned to an intervention cluster and
about the need for specialized palliative care, and a control cluster, where the intervention was a
perceived lack of access to palliative care medicine. physician-driven, nurse-aided, three-step support
strategy implemented throughout the dying process
Comments and the control was standard care. For patients with a
1. This study identified several remediable barriers to decision to withdraw or withhold life-sustaining
the involvement of palliative care medicine in the therapies, the family member most involved with the
management of people living with ILD. ICU team was enrolled (17 interventional ICUs with 484
2. Barriers that can be addressed by ILD providers family members, 17 control ICUs with 391 family
include: 1) the use of scales specifically validated in members). The primary outcome was proportion of
patients with ILD, including the King’s Brief family with prolonged grief (prolonged grief-13
Interstitial Lung Disease Questionnaire and the IPF- questionnaire, score ≥30) 6 months after patient death.
specific version of the St. George’s Respiratory The intervention reduced the number of family
Questionnaire; and 2) an established awareness of members with prolonged grief symptoms (15% vs. 21%;
services available at their institutions. p=0.035), and the median PG-13 score was lower in the

Palliative Care 39
 Clinical Year in Review

intervention group than in the control group (19 vs. 21, completing a modified Bereaved Family Survey (BFS)
mean difference 2.5; 95% CI 1.04, 3.95). approximately 3 months after patient death. Family
completed 314 surveys with 117 from families where
Comments care involved the 3WP. In adjusted analyses, family of
1. This multicenter, cluster-randomized trial of a patients receiving the 3WP were more likely to respond
communication intervention showed a positive with “always” to how often they were kept informed
effect on family-centered outcomes, including about the patient’s condition and treatment (OR 2.47;
prolonged grief, family assessments of the quality 95% CI 1.30, 4.83), how often they felt emotionally
of death and dying, and symptoms of psychological supported in the last month of life (OR 2.52; 95% CI 1.37,
distress. 4.75), and how often they felt emotionally supported
2. The intervention incorporated core components of after patient death (OR 2.70; 95% CI 1.44, 5.22). Bereaved
palliative care, including high-quality family of patients whose care involved the 3WP
communication and emotional and spiritual provided higher ratings on the Emotional and Spiritual
support, and focused on identifying and meeting Support factor (adjusted mean 6.66 vs. 5.30), compared
the needs of family members. to family of patients whose care did not.
3. In addition to providing care to the patient and the
family member while the patient was alive, the Comments
intervention also involved communication with 1. Despite decades of research, few interventions have
family members after the patient’s death. been shown to improve the end-of-life care
4. It is important to note that intensivists and nurses experience for family members of critically ill
in intervention ICUs received training and practice patients.
in communication, which would be essential to 2. This 3 Wishes Program holds promise as a feasible
include in replication of this three-step support intervention with the ability to improve end-of-life
strategy. care in the ICU, at an average cost of $27 per patient
5. Overall, the intervention seems feasible and further to fulfill 389 wishes in this study.
evaluation in other cultural settings may support its 3. It is important to note that the 3WP was initiated
application on a broader scale. and implemented by ICU nurses in most cases
(77%).
4. Larger scale studies are needed to confirm the 3
END OF LIFE IN THE ICU Wishes Program’s effectiveness and promote its
Neville, T. H., Taich, Z., Walling, A. M., Bear, D., Cook, D. J., broader applicability.
Tseng, C. H., & Wenger, N. S. (2023). The 3 Wishes
Program Improves Families' Experience of Emotional
and Spiritual Support at the End of Life. Journal of OTHER ARTICLES OF INTEREST
general internal medicine, 38(1), 115–121.
[Link] PALLIATIVE CARE IN THE ICU
Andersen, S. K., Butler, R. A., Chang, C. H., Arnold, R.,
Summary Angus, D. C., & White, D. B. (2023). Prevalence of long-
The dying process is challenging for family of critically term decision regret and associated risk factors in a
ill patients. Neville and colleagues developed the 3 large cohort of ICU surrogate decision makers. Critical
Wishes Program (3WP), a quality improvement Care (London, England), 27(1), 61.
intervention based on the concept that asking about [Link]
and fulfilling small wishes for dying patients and their
family members may improve the end-of-life
experience. A cohort of dying patients in the ICU was
identified from a single health system, with family

Palliative Care 40
 Clinical Year in Review

Cox, C. E., Olsen, M. K., Parish, A., Gu, J., Ashana, D. C., PALLIATIVE CARE AND COPD
Pratt, E. H., Haines, K., Ma, J., Casarett, D. J., Al-Hegelan, M. Tavares, N., Jarrett, N., Wilkinson, T. M. A., & Hunt, K. J.
S., Naglee, C., Katz, J. N., O'Keefe, Y. A., Harrison, R. W., (2023). Patient-Centered Discussions About Disease
Riley, I. L., Bermejo, S., Dempsey, K., Wolery, S., Jaggers, J., Progression, Symptom, and Treatment Burden in
Johnson, K. S., … Docherty, S. L. (2022). Palliative care Chronic Obstructive Pulmonary Disease Could Facilitate
phenotypes among critically ill patients and family the Integration of End-of-Life Discussions in the
members: intensive care unit prospective cohort study. Disease Trajectory: Patient, Clinician, and Literature
BMJ supportive & palliative care, bmjspcare-2022- Perspectives: A Multimethod Approach. Journal of
003622. Advance online publication. palliative medicine, 26(3), 353–359.
[Link] [Link]

Eaton, T. L., Lewis, A., Donovan, H. S., Davis, B. C., Butcher,

B. W., Alexander, S. A., Iwashyna, T. J., Scheunemann, L. PALLIATIVE CARE AND CYSTIC FIBROSIS
P., & Seaman, J. (2023). Examining the needs of survivors Obregon, L. L., Jeong, K., Hoydich, Z. P., Yabes, J., Pilewski,
of critical illness through the lens of palliative care: A J., Richless, C., Moreines, L. T., Dellon, E. P., Goss, C. H.,
qualitative study of survivor experiences. Intensive & Arnold, R. M., & Kavalieratos, D. (2022). Associations
critical care nursing, 75, 103362. between demographic characteristics and unmet
[Link] supportive care needs in adults with cystic fibrosis. BMJ
supportive & palliative care, 12(e2), e281–e284.
Lincoln, T. E., Buddadhumaruk, P., Arnold, R. M., [Link]
Scheunemann, L. P., Ernecoff, N. C., Chang, C. H., Carson,
S. S., Hough, C. L., Curtis, J. R., Anderson, W., Steingrub, J.,
PALLIATIVE CARE AND ILD
Peterson, M. W., Lo, B., Matthay, M. A., & White, D. B.
(2022). Association Between Shared Decision-Making Chai, G. T., Neo, H. Y., Abisheganaden, J., & Hum, A. Y. M.
During Family Meetings and Surrogates' Trust in Their (2022). Impact of Palliative Care in End-of-Life of
ICU Physician. Chest, S0012-3692(22)04043-0. Advance Fibrotic Interstitial Lung Disease Patients. The American
online publication. journal of hospice & palliative care, 39(12), 1443–1451.
[Link] [Link]

Tong, W., Murali, K. P., Fonseca, L. D., Blinderman, C. D.,

Shelton, R. C., & Hua, M. (2022). Interpersonal Conflict PALLIATIVE CARE AND PULMONARY HYPERTENSION
between Clinicians in the Delivery of Palliative and End- Brown, C. E., Steiner, J. M., Leary, P. J., Curtis, J. R., &
of-Life Care for Critically Ill Patients: A Secondary Engelberg, R. A. (2023). A World of Maximalist Medicine:
Qualitative Analysis. Journal of palliative medicine, Physician Perspectives on Palliative Care and End-of-
25(10), 1501–1509. [Link] life for Patients With Pulmonary Arterial Hypertension.
Journal of pain and symptom management, 65(4), e329–
Torke, A. M., Varner-Perez, S. E., Burke, E. S., Taylor, T. A., e335. [Link]
Slaven, J. E., Kozinski, K. L., Maiko, S. M., Pfeffer, B. J., &
Banks, S. K. (2023). Effects of Spiritual Care on Well- Rohlfing, A. B., Bischoff, K. E., Kolaitis, N. A., Kronmal, R.
Being of Intensive Care Family Surrogates: A Clinical A., Kime, N. A., Gray, M. P., Bartolome, S., Chakinala, M. M.,
Trial. Journal of pain and symptom management, 65(4), Frantz, R. P., Ventetuolo, C. E., Mathai, S. C., De Marco, T.,
296–307. & PHAR investigators (2023). Palliative care referrals in
[Link] patients with pulmonary arterial hypertension: The
Pulmonary Hypertension Association Registry.
Respiratory medicine, 206, 107066.
[Link]

Palliative Care 41
 Clinical Year in Review

PALLIATIVE CARE AND LUNG CANCER

Taniguchi, Y., Matsuda, Y., Mori, M., Ito, M., Ikari, T., Cullum, K. G., Madani, C. A., Cutler, E. R., & Reavis, K. J.
Tokoro, A., Aiki, S., Hoshino, S., Kiuchi, D., Suzuki, K., (2022). The Lived Experience of Respiratory Therapists
Igarashi, Y., Odagiri, T., Oya, K., Kubo, E., & Yamaguchi, T. During Withdrawal of Advanced Life-Sustaining
(2022). Effectiveness and safety of opioids for dyspnea Therapies at End of Life in the ICU. Respiratory care,
in patients with lung cancer: secondary analysis of 67(12), 1568–1577. [Link]
multicenter prospective observational study.
Translational lung cancer research, 11(12), 2395–2402. Nicoll, J., Dryden-Palmer, K., Frndova, H., Gottesman, R.,
[Link] Gray, M., Hunt, E. A., Hutchison, J. S., Joffe, A. R., Lacroix, J.,
Middaugh, K., Nadkarni, V., Szadkowski, L., Tomlinson, G.
A., Wensley, D., Parshuram, C. S., & Farrell, C. (2022).
END-OF-LIFE CARE Death and Dying in Hospitalized Pediatric Patients: A
Abedini, N. C., Downey, L., Engelberg, R. A., Curtis, J. R., & Prospective Multicenter, Multinational Study. Journal of
Sharma, R. K. (2022). End-of-life healthcare utilization palliative medicine, 25(2), 227–233.
and palliative care use among older adults with limited [Link]
English proficiency. Journal of the American Geriatrics
Society, 70(10), 2847–2857.
[Link]

Palliative Care 42
 Clinical Year in Review

Critical Care
Tiffanie Jones, MD, MPH
University of Pennsylvania
Division of Pulmonary, Allergy, and Critical Care Medicine
Philadelphia, PA

ICU-ACQUIRED WEAKNESS AND EARLY MOBILIZATION Comments

TEAM Study Investigators and the ANZICS Clinical Trials 1. The patients in the intervention group only received
Group; Hodgson CL, Bailey M, Bellomo R, Brickell K, protocolized early mobilization in the ICU, and post-
Broadley T, Buhr H, Gabbe BJ, Gould DW, Harrold M, ICU care including physical therapy has been
Higgins AM, Hurford S, Iwashyna TJ, Serpa Neto A, Nichol described to influence patient outcomes.
AD, Presneill JJ, Schaller SJ, Sivasuthan J, Tipping CJ, 2. Both the intervention and control groups
Webb S, Young PJ. Early Active Mobilization during demonstrate similar lowest daily Richmond
Mechanical Ventilation in the ICU. N Engl J Med. 2022 Agitation-Sedation Scale (RASS) scores, which may
Nov 10;387(19):1747-1758. have muted the potential benefits of early
mobilization.
Summary 3. These findings warrant contextualization with other
Hodgson et. al. report findings from an international, studies indicating that early mobilization may
multicenter, randomized controlled trial to evaluate if improve long-term cognitive and functional
early active mobilization for adult patients in the ICU outcomes.
receiving mechanical ventilation increases the number 4. Early mobilization merits further study as there may
of days alive and out of the hospital. They randomized be specific populations of critically ill patients who
750 patients in 1:1 allocation. The intervention group are most likely to benefit.
received early mobilization with sessions designed to
achieve the highest possible level of mobilization that
was safe for as long as possible. The control group PREVENTION OF DELIRIUM IN THE ICU
received usual care. For the primary outcome, there
Wibrow B, Martinez FE, Myers E, Chapman A, Litton E, Ho
was no statistically significant difference in the median
KM, Regli A, Hawkins D, Ford A, van Haren FMP, Wyer S,
number days alive and out of the hospital at day 180
McCaffrey J, Rashid A, Kelty E, Murray K, Anstey M.
[(143 days vs. 145 days, Difference -2, (95%CI -10 to 6,
Prophylactic melatonin for delirium in intensive care
p=0.62)]. There were no statistically significant
(Pro-MEDIC): a randomized controlled trial. Intensive
differences in the secondary outcomes including death
Care Med. 2022 Apr;48(4):414-425.
at 180 days, median ventilator free days, median ICU
free days, or functional outcome scores. There was a
Summary
higher cumulative incidence of serious adverse events
in the intervention group as compared to the control Delirium is commonly diagnosed in critically ill patients.
group (7 vs. 1). Therefore, the authors concluded that Despite the increased risk of in-hospital morbidity and
early active mobilization in this study was associated mortality, there are limited strategies for delirium
with an increased risk of adverse events without an prevention. Wilbrow and colleagues describe a
improvement in the number of days alive and out of the multicenter, randomized placebo-controlled, double-
hospital. blind trial developed to assess if melatonin
administration decreases the prevalence of delirium.
They enrolled 847 critically ill, adult patients with an
estimated ICU length of stay (LOS) greater than 72 hours

Critical Care 43
 Clinical Year in Review

using 1:1 randomization allocation. The intervention NUTRITIONAL SUPPORT DURING CRITICAL ILLNESS
group received melatonin 4 mg in 2 mL solution orally Heyland DK, Patel J, Compher C, Rice TW, Bear DE, Lee
or via gastric tube for 14 days or until ICU discharge ZY, González VC, O'Reilly K, Regala R, Wedemire C,
while the control group received 2 mL of placebo. The Ibarra-Estrada M, Stoppe C, Ortiz-Reyes L, Jiang X, Day
melatonin was administered nightly at 21:00 hours. AG; EFFORT Protein Trial team. The effect of higher
Delirium was evaluated twice daily using the Confusion protein dosing in critically ill patients with high
Assessment Method for the ICU (CAM-ICU). There was no nutritional risk (EFFORT Protein): an international,
statistically significant difference in the average multicentre, pragmatic, registry-based randomised trial.
proportion of delirium-free evaluations between the Lancet. 2023 Feb 18;401(10376):568-576.
intervention and control groups (79% vs. 80%, p=0.55).
Similarly, there were no statistically significant Summary
differences in the secondary outcomes including ICU
Nutritional support guidelines vary regarding the
LOS, hospital LOS, and mortality at 90 days. The authors
recommended protein dosing during critical illness.
concluded that the findings of this study do not support
Heyland and colleagues report the findings of a
the routine administration of melatonin for primary
pragmatic multicenter, randomized controlled trial
prevention of delirium in the ICU setting.
designed to examine the effect of high-dose versus
standard-dose protein on patient outcomes. The
Comments
investigators studied 1,301 recently admitted, critically
1. There was a high rate of missingness in the ill, adult patients receiving mechanical ventilation with
delirium assessments which the study addressed by at least one nutritional risk factor such as moderate to
augmentation in sample size, but this limitation has severe malnutrition, low or high BMI, frailty, sarcopenia,
relevance for the primary outcome. or projected duration of mechanical ventilation greater
2. The selected dosage and/or timing of than 4 days. The patients were randomized in a 1:1 ratio
administration may have influenced the observed to receive either high-dose protein (>2.2 g/kg per day)
lack of efficacy of melatonin for delirium or usual dose protein (>1.2 g/kg per day) within 96
prevention. hours of ICU admission or mechanical ventilation
3. While the study observed no significant difference initiation. The treatment continued for 28 days unless
in sleep quantity or quality between the two groups, transition to oral feeding or death occurred. The
previous studies have found that melatonin cumulate incidence of alive hospital discharge did not
decreases sleep onset latency and improves sleep differ between the two groups [46.1% vs. 50.2%, (HR 0.91,
efficiency. 95% CI 0.77-1.07; p=0.27)]. The authors concluded that
4. Specific patient populations have been high dose protein did not improve alive hospital
demonstrated to be more vulnerable to disruptions discharge for critically ill patients requiring mechanical
in circadian rhythm and delirium (e.g. elderly ventilation, but further research is merited to determine
patients or patients with pre-existing mental health if certain subgroups may derive benefit.
disorders), and these groups may benefit from
additional study. Comments
1. Since the trial was pragmatic, the approach to
achieve the high-dose or low-dose protein targets
was not protocolized.
2. While the study protocol encouraged the
application of the international guidelines to
mitigate the potential for over-feeding, the trial did
not assess or control for total energy dose.
3. Enrollment into the trial was affected by the COVID-
19 pandemic, and the investigators were unable to

Critical Care 44
 Clinical Year in Review

assess mortality at 60 days as the original primary to 5.94, p=0.004). The authors concluded that there is
outcome for the study. no significant difference in the development of
4. In the subgroup of patients with acute kidney injury moderately severe or severe pancreatitis based on the
or high organ failure scores, high dose protein may fluid resuscitation strategy.
be associated with harm.
5. The authors propose future work to assess the Comments
potential benefit of high-dose protein in burn, 1. Since the study was discontinued at the first interim
trauma, obese, and post-operative critically ill analysis, the analysis may have been underpowered
patients. to detect differences in the primary outcome.
2. Acknowledging the early termination of the trial, the
study did not observe a difference in any of the
FLUID RESUSCITATION IN PANCREATITIS secondary outcomes including severe pancreatitis,
de-Madaria E, Buxbaum JL, Maisonneuve P, García local complications (e.g., necrotizing or infected
García de Paredes A, Zapater P, Guilabert L, Vaillo- necrotizing pancreatitis), persistent organ failure, or
Rocamora A, Rodríguez-Gandía MÁ, Donate-Ortega J, death.
Lozada-Hernández EE, Collazo Moreno AJR, Lira-Aguilar 3. The study protocol only followed the administration
A, Llovet LP, Mehta R, Tandel R, Navarro P, Sánchez- of lactated ringers. It is unclear if additional fluids
Pardo AM, Sánchez-Marin C, Cobreros M, Fernández- may have been administered outside of the
Cabrera I, Casals-Seoane F, Casas Deza D, Lauret-Braña protocol or prior to enrollment, which could have
E, Martí-Marqués E, Camacho-Montaño LM, Ubieto V, influenced the primary outcome.
Ganuza M, Bolado F; ERICA Consortium. Aggressive or 4. The investigators were unblinded in this study.
Moderate Fluid Resuscitation in Acute Pancreatitis. N
Engl J Med. 2022 Sep 15;387(11):989-1000.
MANGEMENT OF VOLUME STATUS FOR PULMONARY
EMBOLISM
Summary
Ferrari E, Sartre B, Labbaoui M, Heme N, Asarisi F,
Acute pancreatitis is commonly managed with early
Redjimi N, Fourrier E, Squara F, Bun S, Berkane N,
fluid resuscitation, but the evidence for this widespread
Breittmayer JP, Doyen D, Moceri P. Diuretics Versus
practice remains limited. To determine if aggressive
Volume Expansion in the Initial Management of Acute
fluid resuscitation as compared to moderate fluid
Intermediate High-Risk Pulmonary Embolism. Lung. 2022
resuscitation would reduce the incidence of moderately
Apr;200(2):179-185.
severe or severe pancreatitis during the hospitalization,
the authors conducted a multi-center, open-label,
Summary
parallel-group randomized controlled trial. The authors
enrolled adult patients with acute pancreatitis within 24 Anticoagulation remains a cornerstone of acute
hours of pain onset. The patients were randomized in a pulmonary embolism (PE) management, yet there is
1:1 ratio to receive either aggressive fluid resuscitation limited evidence regarding the management of volume
(e.g. a bolus of 20 mL per kilogram of body weight, status. Ferrari and colleagues sought to compare the
followed by 3 ml per kilogram per hour) or moderate effects of diuretic therapy versus volume expansion in
fluid resuscitation (e.g. a bolus of 10 mL per kilogram in hospitalized patients with intermediate high-risk PE on
patients with hypovolemia or no bolus if euvolemia). time to troponin normalization. The investigators
Ultimately, the trial was halted after an interim analysis conducted a multicenter, open-label, randomized
of 249 patients demonstrating differences in safety controlled trial with 1:1 allocation. The study enrolled
outcomes without a difference in the incidence of the 60 adult patients with acute PE on computed
primary outcome. The authors observed fluid overload tomography with right ventricular dilation on
in 20.5% of the aggressive resuscitation group vs. 6.3% echocardiogram, positive troponin (>70 ng/L), and
in the moderate resuscitation group (RR 2.85, 95%CI 1.36 elevated BNP (>100 pg/mL). The diuretic group received

Critical Care 45
 Clinical Year in Review

furosemide 40 mg IV on admission followed by an Schmidt H, Kjaergaard J, Hassager C, Mølstrøm S, Grand

additional dose if the diuresis output remained below J, Borregaard B, Roelsgaard Obling LE, Venø S, Sarkisian
500 mL after 4 hours whereas the volume expansion L, Mamaev D, Jensen LO, Nyholm B, Høfsten DE,
group received 500 mL saline infusion over 4 hours Josiassen J, Thomsen JH, Thune JJ, Lindholm MG,
followed by 1000 mL saline infusion per day. Both Stengaard Meyer MA, Winther-Jensen M, Sørensen M,
groups received therapeutic anticoagulation. The study Frydland M, Beske RP, Frikke-Schmidt R, Wiberg S,
found no difference in the time to troponin Boesgaard S, Lind Jørgensen V, Møller JE. Oxygen Targets
normalization in the diuretic group versus the volume in Comatose Survivors of Cardiac Arrest. N Engl J Med.
expansion group (76 hours vs. 72 hours, p= 0.74). 2022 Oct 20;387(16):1467-1476. doi:
However, there was a significant difference in time to 10.1056/NEJMoa2208686. Epub 2022 Aug 27. PMID:
BNP normalization (56 hours vs. 108 hours, p=0.05). The 36027567.
authors concluded that diuretic therapy in acute PE is
safe and warrants further study with clinical outcomes. SuDDICU Investigators for the Australian and New
Zealand Intensive Care Society Clinical Trials Group;
Comments Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M,
1. In general, the administration of furosemide was Davis JS, Gordon AC, Hammond NE, Iredell J, Li Q,
well tolerated in the diuretic group without Micallef S, Miller J, Mysore J, Taylor C, Young PJ,
significant adverse events. Cuthbertson BH, Finfer SR. Effect of Selective
2. Patients with cardiogenic shock were excluded from Decontamination of the Digestive Tract on Hospital
this study. Mortality in Critically Ill Patients Receiving Mechanical
3. The significance of normalization of BNP as a Ventilation: A Randomized Clinical Trial. JAMA. 2022 Nov
surrogate endpoint is unclear, which can be 15;328(19):1911-1921. doi: 10.1001/jama.2022.17927. PMID:
addressed in future studies using clinical endpoints 36286097; PMCID: PMC9607966.
such as development of shock or mortality.
4. The dynamics of cardiac troponin release in Russell DW, Casey JD, Gibbs KW, Ghamande S, Dargin JM,
pulmonary embolism have been demonstrated to Vonderhaar DJ, Joffe AM, Khan A, Prekker ME, Brewer JM,
vary based on the time from symptom onset to Dutta S, Landsperger JS, White HD, Robison SW, Wozniak
clinical presentation, which has relevance for the JM, Stempek S, Barnes CR, Krol OF, Arroliga AC, Lat T,
primary outcome. Gandotra S, Gulati S, Bentov I, Walters AM, Dischert KM,
5. A prior study by the investigators associated the Nonas S, Driver BE, Wang L, Lindsell CJ, Self WH, Rice TW,
administration of diuretics for management of Janz DR, Semler MW; PREPARE II Investigators and the
pulmonary embolism with improvements in heart Pragmatic Critical Care Research Group. Effect of Fluid
rate and peak tricuspid annular systolic velocity. Bolus Administration on Cardiovascular Collapse Among
Critically Ill Patients Undergoing Tracheal Intubation: A
Randomized Clinical Trial. JAMA. 2022 Jul 19;328(3):270-
OTHER ARTICLES OF INTEREST 279. doi: 10.1001/jama.2022.9792. PMID: 35707974; PMCID:
Kjaergaard J, Møller JE, Schmidt H, Grand J, Mølstrøm S, PMC9204618.
Borregaard B, Venø S, Sarkisian L, Mamaev D, Jensen LO,
Nyholm B, Høfsten DE, Josiassen J, Thomsen JH, Thune JJ, Castro I, Relvas M, Gameiro J, Lopes JA, Monteiro-Soares
Obling LER, Lindholm MG, Frydland M, Meyer MAS, M, Coentrão L. The impact of early versus late initiation
Winther-Jensen M, Beske RP, Frikke-Schmidt R, Wiberg S, of renal replacement therapy in critically ill patients
Boesgaard S, Madsen SA, Jørgensen VL, Hassager C. with acute kidney injury on mortality and clinical
Blood-Pressure Targets in Comatose Survivors of outcomes: a meta-analysis. Clin Kidney J. 2022 May
Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1456- 12;15(10):1932-1945. doi: 10.1093/ckj/sfac139. PMID:
1466. doi: 10.1056/NEJMoa2208687. Epub 2022 Aug 27. 36158157; PMCID: PMC9494521.
PMID: 36027564.

Critical Care 46
 Clinical Year in Review

Naorungroj T, Neto AS, Wang A, Gallagher M, Bellomo R. Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays MA,
Renal outcomes according to renal replacement Stollings JL, Buell KG, Brems JH, Qian ET, Seitz KP, Wang
therapy modality and treatment protocol in the ATN L, Lindsell CJ, Freundlich RE, Wanderer JP, Han JH,
and RENAL trials. Crit Care. 2022 Sep 6;26(1):269. doi: Bernard GR, Self WH, Rice TW; PILOT Investigators and
10.1186/s13054-022-04151-5. PMID: 36068554; PMCID: the Pragmatic Critical Care Research Group. Oxygen-
PMC9450407. Saturation Targets for Critically Ill Adults Receiving
Mechanical Ventilation. N Engl J Med. 2022 Nov
Andersen-Ranberg NC, Poulsen LM, Perner A, Wetterslev 10;387(19):1759-1769. doi: 10.1056/NEJMoa2208415. Epub
J, Estrup S, Hästbacka J, Morgan M, Citerio G, Caballero J, 2022 Oct 24. PMID: 36278971; PMCID: PMC9724830.
Lange T, Kjær MN, Ebdrup BH, Engstrøm J, Olsen MH,
Oxenbøll Collet M, Mortensen CB, Weber SO, Andreasen Voors AA, Angermann CE, Teerlink JR, Collins SP,
AS, Bestle MH, Uslu B, Scharling Pedersen H, Gramstrup Kosiborod M, Biegus J, Ferreira JP, Nassif ME, Psotka MA,
Nielsen L, Toft Boesen HC, Jensen JV, Nebrich L, La Cour Tromp J, Borleffs CJW, Ma C, Comin-Colet J, Fu M,
K, Laigaard J, Haurum C, Olesen MW, Overgaard- Janssens SP, Kiss RG, Mentz RJ, Sakata Y, Schirmer H,
Steensen C, Westergaard B, Brand B, Kingo Vesterlund G, Schou M, Schulze PC, Spinarova L, Volterrani M, Wranicz
Thornberg Kyhnauv P, Mikkelsen VS, Hyttel-Sørensen S, JK, Zeymer U, Zieroth S, Brueckmann M, Blatchford JP,
de Haas I, Aagaard SR, Nielsen LO, Eriksen AS, Salsali A, Ponikowski P. The SGLT2 inhibitor
Rasmussen BS, Brix H, Hildebrandt T, Schønemann-Lund empagliflozin in patients hospitalized for acute heart
M, Fjeldsøe-Nielsen H, Kuivalainen AM, Mathiesen O; failure: a multinational randomized trial. Nat Med. 2022
AID-ICU Trial Group. Haloperidol for the Treatment of Mar;28(3):568-574. doi: 10.1038/s41591-021-01659-1. Epub
Delirium in ICU Patients. N Engl J Med. 2022 Dec 2022 Feb 28. PMID: 35228754; PMCID: PMC8938265.
29;387(26):2425-2435. doi: 10.1056/NEJMoa2211868. Epub
2022 Oct 26. PMID: 36286254. Fischer U, Kaesmacher J, Strbian D, Eker O, Cognard C,
Plattner PS, Bütikofer L, Mordasini P, Deppeler S, Pereira
Wolfrum S, Roedl K, Hanebutte A, Pfeifer R, Kurowski V, VM, Albucher JF, Darcourt J, Bourcier R, Benoit G,
Riessen R, Daubmann A, Braune S, Söffker G, Bibiza- Papagiannaki C, Ozkul-Wermester O, Sibolt G, Tiainen M,
Freiwald E, Wegscheider K, Schunkert H, Thiele H, Kluge Gory B, Richard S, Liman J, Ernst MS, Boulanger M,
S; Hypothermia After In-Hospital Cardiac Arrest Study Barbier C, Mechtouff L, Zhang L, Marnat G, Sibon I,
Group. Temperature Control After In-Hospital Cardiac Nikoubashman O, Reich A, Consoli A, Lapergue B, Ribo
Arrest: A Randomized Clinical Trial. Circulation. 2022 M, Tomasello A, Saleme S, Macian F, Moulin S, Pagano P,
Nov;146(18):1357-1366. doi: Saliou G, Carrera E, Janot K, Hernández-Pérez M, Pop R,
10.1161/CIRCULATIONAHA.122.060106. Epub 2022 Sep 28. Schiava LD, Luft AR, Piotin M, Gentric JC, Pikula A,
PMID: 36168956. Pfeilschifter W, Arnold M, Siddiqui AH, Froehler MT,
Furlan AJ, Chapot R, Wiesmann M, Machi P, Diener HC,
Sadeghipour P, Jenab Y, Moosavi J, Hosseini K, Mohebbi Kulcsar Z, Bonati LH, Bassetti CL, Mazighi M, Liebeskind
B, Hosseinsabet A, Chatterjee S, Pouraliakbar H, Shirani DS, Saver JL, Gralla J; SWIFT DIRECT Collaborators.
S, Shishehbor MH, Alizadehasl A, Farrashi M, Rezvani MA, Thrombectomy alone versus intravenous alteplase plus
Rafiee F, Jalali A, Rashedi S, Shafe O, Giri J, Monreal M, thrombectomy in patients with stroke: an open-label,
Jimenez D, Lang I, Maleki M, Goldhaber SZ, Krumholz HM, blinded-outcome, randomised non-inferiority trial.
Piazza G, Bikdeli B. Catheter-Directed Thrombolysis vs Lancet. 2022 Jul 9;400(10346):104-115. doi: 10.1016/S0140-
Anticoagulation in Patients With Acute Intermediate- 6736(22)00537-2. PMID: 35810756.
High-risk Pulmonary Embolism: The CANARY
Randomized Clinical Trial. JAMA Cardiol. 2022 Dec
1;7(12):1189-1197. doi: 10.1001/jamacardio.2022.3591. PMID:
36260302; PMCID: PMC9582964.

Critical Care 47
 Clinical Year in Review

Ostadal P, Rokyta R, Karasek J, Kruger A, Vondrakova D, Landais M, Nay MA, Auchabie J, Hubert N, Frerou A, Yehia
Janotka M, Naar J, Smalcova J, Hubatova M, Hromadka M, A, Mercat A, Jonas M, Martino F, Moriconi M, Courte A,
Volovar S, Seyfrydova M, Jarkovsky J, Svoboda M, Linhart Robert-Edan V, Conia A, Bavozet F, Egreteau PY, Bruel C,
A, Belohlavek J; ECMO-CS Investigators. Extracorporeal Renault A, Huet O, Feller M, Chudeau N, Ferrandiere M,
Membrane Oxygenation in the Therapy of Cardiogenic Rebion A, Robert A, Giraudeau B, Reignier J, Thille AW,
Shock: Results of the ECMO-CS Randomized Clinical Tavernier E, Ehrmann S; REVA network and CRICS-
Trial. Circulation. 2023 Feb 7;147(6):454-464. doi: TriggerSEP F-CRIN research network. Continued enteral
10.1161/CIRCULATIONAHA.122.062949. Epub 2022 Nov 6. nutrition until extubation compared with fasting before
PMID: 36335478 extubation in patients in the intensive care unit: an
. open-label, cluster-randomised, parallel-group, non-
inferiority trial. Lancet Respir Med. 2023 Jan 20:S2213-
2600(22)00413-1. doi: 10.1016/S2213-2600(22)00413-1.
Epub ahead of print. PMID: 36693402.

Patel BK, Wolfe KS, Patel SB, Dugan KC, Esbrook CL,
Pawlik AJ, Stulberg M, Kemple C, Teele M, Zeleny E,
Hedeker D, Pohlman AS, Arora VM, Hall JB, Kress JP.
Effect of early mobilisation on long-term cognitive
impairment in critical illness in the USA: a randomised
controlled trial. Lancet Respir Med. 2023 Jan 20:S2213-
2600(22)00489-1. doi: 10.1016/S2213-2600(22)00489-1.
Epub ahead of print. PMID: 36693400.

Critical Care 48
 Clinical Year in Review

Asthma
Vanessa McDonald, PhD
The University of Newcastle
School of Nursing and Midwifery
Newcastle NSW

CONSUMER PRIORITIES directed to areas of high priority for end-users of

Majellano EC, Bell RL, Flynn AW, Mckenzie A, Sivamalai S, asthma research.
Goldman M, Vaughan L, Gibson PG. Identifying the 4. Reinforces contemporary issues in asthma
asthma research priorities of people with asthma, their management
carers and other stakeholders. Respirology. 2023 Mar 15. 5. Highlights the importance of comorbidities in the
doi: 10.1111/resp.14492. Epub ahead of print. PMID: management of asthma from the end user
36921924. perspective.

Summary CLIMATE
This study was led by Asthma Australia to identify the Woodcock A, Janson C, Rees J, Frith L, Löfdahl M, Moore
research priorities of consumers. The researchers used A, Hedberg M, Leather D. Effects of switching from a
a modified James Lind Alliance methodology and metered dose inhaler to a dry powder inhaler on
performed a national cross sectional mixed methods climate emissions and asthma control: post-hoc
study to understand the priorities of research end users analysis. Thorax. 2022 Dec;77(12):1187-1192.
including patients, carers, health care provider and
policy makers. Almost 600 end users participated in the Summary
priority setting exercise. The top 10 priorities were: Climate change is having a real and significant impact
asthma and children, COVID 19 and asthma, asthma leading to global health emergencies for people with
care and self-management, causes, prevention and asthma (thunderstorm asthma, landscape fires).
features of asthma, mental health, asthma and aging, Despite the recognition of this the health care sectors
severe asthma, and asthma and other health contribute significantly to greenhouse gas emission.
conditions. The identification of these priorities Hydrofluorocarbons in pressurized inhaler devices
informs the research agenda, will reduce the mismatch (pMDI) is one source of the healthcare sector’s
in the prioritisation of research that is often seen by contribution. These potent greenhouse gases that are
funders and the end user, and will ensure the necessary now being phased down. In a post-hoc analysis of 2236
voice of consumers are driving the future direction. This patients in the Salford Lung Study in Asthma, Woolcock
is a great example of consumer-focused research and colleagues sort to determine the effect of switching
performed to maximize research and clinical impact. from a pMDI to dry powder device compared to usual
asthma care on 1). Greenhouse emissions and 2).
Comments Asthma control. The results indicate that switching
1. Uses a rigorous method to capture the voice of the from pMDI to DPI more than halved the carbon
consumer footprint, without any loss of asthma control. These
2. Important national project to align asthma research data suggest that in many people with asthma switching
and practice with the priorities of the consumers from pMDI to DPI is an acceptable consideration that
3. Dissemination to researchers, healthcare significantly reduce emissions.
organizations, and external funders, will enable
planning and future research to be coordinated and

Asthma 49
 Clinical Year in Review

Comments treatment step with maintenance inhaled

1. Asthma inhaler medications contribute to climate corticosteroid–long-acting β2-agonist plus short-
emissions. acting β2-agonist reliever therapy is supported by
2. Under the Kigali Amendment to the Montreal level one evidence for reducing time to
Protocol in 2016 HFC in pMDIs are being phased exacerbation.
down 2. The analysis was limited to RCTs of the budesonide-
3. The impact of inhalers on the carbon footprint formoterol SMART regimen versus fixed dose ICS-
could be reduced in many patients with asthma LABA plus.
through considered selection of inhaler devices.
ASTHMA TREATMENT OF COMORBITIES
ASTHMA TREATMENT Johnson O, Gerald LB, Harvey J, Roy G, Hazucha H, Large
Beasley R, Harrison T, Peterson S, Gustafson P, Hamblin C, Burke A, McCormack M, Wise RA, Holbrook JT, Dixon
A, Bengtsson T, Fagerås M. Evaluation of Budesonide- AE. An Online Weight Loss Intervention for People With
Formoterol for Maintenance and Reliever Therapy Obesity and Poorly Controlled Asthma. J Allergy Clin
Among Patients With Poorly Controlled Asthma: A Immunol Pract. 2022 Jun;10(6):1577-1586.e3. doi:
Systematic Review and Meta-analysis. JAMA Netw Open. 10.1016/[Link].2022.02.040. Epub 2022 Mar 15. PMID:
2022 Mar 1;5(3):e220615. 35304842; PMCID: PMC9188993.

Summary Summary
The Global Initiative for Asthma (GINA) has two Obesity is associated with difficult to control asthma,
alternate treatment tracks for adolescents and adults. worsened symptoms, lung function and lower exercise
The preferred treatment track for patients in GINA step capacity. Obesity is increasing and this represents a
3-5 is single inhaler combination inhaled significant public health issue. RCTs of weight loss
corticosteroid– interventions in asthma indicate that losing 5-10% of
formoterol as both maintenance and reliever (SMART). body weight leads to significant improvements in
This is based on level one evidence that using ICS- asthma control. Interventions for weight loss include
formoterol as maintenance and reliever reduces the calorie restriction, physical activity, lifestyle changes,
risk of exacerbations compared with using an ICS-LABA pharmacotherapy or bariatric surgery depending on the
plus SABA reliever. In this systematic review and meta- degree of obesity. Online and digital health
analysis Beasley et al sought to determine if switching interventions are increasing and enable greater access
to SMART in patients with poorly controlled asthma was to health care interventions. This study tested an online
associated with longer time to exacerbation compared weight loss intervention to determine its effect on
to step up or continuation of ICS LABA plus SABA. weight loss and asthma control. The design was a single
Included were 5 RCTS involving 4863 patients. The arm futility study. At 6 months 23% of participants lost
findings showed that the use of SMART in patients with at least 5% of their initial weight and this loss was
poorly controlled asthma was associated with longer associated with both clinically and statistically
time to first exacerbation compared to step up or significant improvements in asthma control. Accessible
continuation of GINA treatment step with ICS-LABA plus and effective weight loss interventions are an urgent
SABA. priority for people with asthma. Effective online
interventions are needed for the future of asthma care.
Comments
Comments
1. When adult or adolescent patients receiving
treatment at GINA step 3 or 4 have poorly 1. Obesity rates are increasing.
controlled asthma, switching to the SMART regimen 2. Obesity worsens asthma.
rather than to step up or continue the GINA

Asthma 50
 Clinical Year in Review

3. Achieving a 5-10% loss of body weight leads to Comments

improved asthma control. 1. Monoclonal antibody therapies have had an
4. This online weight loss intervention leads to weight important impact on people with severe asthma
loss associated with improved asthma control in a reducing exacerbations significantly.
significant proportion of participants. 2. There is however a residual exacerbation burden
5. Needs a definitive RCT. for people with severe asthma and understanding
the mechanisms of these exacerbations is needed.
ASTHMA PHENOTYPES 3. Poor asthma symptom control, female sex, obesity,
restrictive lung function, and multiple unscheduled
McDowell PJ, Busby J, Hanratty CE, Djukanovic R,
prior healthcare visits for exacerbation events in
Woodcock A, Walker S, Hardman TC, Arron JR, Choy DF,
the prior year to study were factors associated with
Bradding P, Brightling CE, Chaudhuri R, Cowan D, Mansur
exacerbation.
AH, Fowler SJ, Diver SE, Howarth P, Lordan J, Menzies-
4. Exacerbation phenotype is not stable at the time of
Gow A, Harrison T, Robinson DS, Holweg CTJ, Matthews
exacerbation
JG, Pavord ID, Heaney LG. Exacerbation Profile and Risk
5. This study identifies T2low asthma as an important
Factors in a Type-2-Low Enriched Severe Asthma Cohort:
unmet need.
A Clinical Trial to Assess Asthma Exacerbation
Phenotypes. Am J Respir Crit Care Med. 2022 Sep
1;206(5):545-553. OTHER ARTICLES OF INTEREST
Wechsler ME, Menzies-Gow A, Brightling CE, Kuna P, Korn
Summary S, Welte T, Griffiths JM, Sałapa K, Hellqvist Å, Almqvist G,
This paper reports a prespecified secondary endpoint Lal H, Kaur P, Skärby T, Colice G; SOURCE study group.
analysis of asthma exacerbations from a 48-week RCT Evaluation of the oral corticosteroid-sparing effect of
(N=301) that evaluated a biomarker versus symptom- tezepelumab in adults with oral corticosteroid-
based treatment titration in patients with severe dependent asthma (SOURCE): a randomised, placebo-
asthma. The study enrolled a population of patients controlled, phase 3 study. Lancet Respir Med. 2022
with a FENO of <45 ppb to enrich for T2-low population. Jul;10(7):650-660. doi: 10.1016/S2213-2600(21)00537-3.
The aims of this analysis were to 1). Explore the Epub 2022 Mar 29. Erratum in: Lancet Respir Med. 2022
differences between participants who exacerbated and Apr 5;: PMID: 35364018.
those that did not, 2). To describe the physiological
changes at exacerbation of T2 high and T2 low Menzies-Gow A, Gurnell M, Heaney LG, Corren J, Bel EH,
participants, and to evaluate the stability of Maspero J, Harrison T, Jackson DJ, Price D, Lugogo N,
inflammatory phenotypes when stable and at Kreindler J, Burden A, de Giorgio-Miller A, Padilla K,
exacerbation. The analysis indicated that asthma Martin UJ, Garcia Gil E. Oral corticosteroid elimination
exacerbations in participants with a T2 low and T2 high via a personalised reduction algorithm in adults with
phenotype were physiologically and symptomatically severe, eosinophilic asthma treated with benralizumab
similar. Furthermore, the phenotype of T2 low asthma (PONENTE): a multicentre, open-label, single-arm study.
was unstable at exacerbation, highlighting the need for Lancet Respir Med. 2022 Jan;10(1):47-58. doi:
phenotyping at the time of each exacerbation. 10.1016/S2213-2600(21)00352-0. Epub 2021 Oct 4. Erratum
Exacerbations in participants without evidence of T2 in: Lancet Respir Med. 2021 Dec;9(12):e114. PMID:
biology at the time of exacerbation highlights a 34619104.
demanding and unmet need in asthma management
which requires a better understanding of mechanisms
of T2 low asthma.

Asthma 51
 Clinical Year in Review

Busby J, Matthews JG, Chaudhuri R, Pavord ID, Hardman Redmond, C., Heaney, L. G., Chaudhuri, R., Jackson, D. J.,
TC, Arron JR, Bradding P, Brightling CE, Choy DF, Cowan Menzies-Gow, A., Pfeffer, P., Busby, J., & UK Severe
DC, Djukanovic R, Hanratty CE, Harrison TW, Holweg CT, Asthma Registry (2022). Benefits of specialist severe
Howarth PH, Fowler SJ, Lordan JL, Mansur AH, Menzies- asthma management: demographic and geographic
Gow A, Niven RM, Robinson DS, Walker SM, Woodcock A, disparities. The European respiratory journal, 60(6),
Heaney LG; investigators for the MRC Refractory Asthma 2200660. [Link]
Stratification Programme. Factors affecting adherence
with treatment advice in a clinical trial of patients with Andreasson KH, Skou ST, Ulrik CS, Madsen H, Sidenius K,
severe asthma. Eur Respir J. 2021 Sep 24;59(4):2100768. Assing KD, Porsbjerg C, Bloch-Nielsen J, Thomas M,
doi: 10.1183/13993003.00768-2021. PMID: 34561291; PMCID: Bodtger U. Breathing Exercises for Patients with Asthma
PMC9202483. in Specialist Care: A Multicenter Randomized Clinical
Trial. Ann Am Thorac Soc. 2022 Sep;19(9):1498-1506. doi:
Thomas D, McDonald VM, Pavord ID, Gibson PG. Asthma 10.1513/AnnalsATS.202111-1228OC. PMID: 35588357;
remission: what is it and how can it be achieved? Eur PMCID: PMC9447391.
Respir J. 2022 Nov 3;60(5):2102583. doi:
10.1183/13993003.02583-2021. PMID: 35361633; PMCID: Osadnik CR, Gleeson C, McDonald VM, Holland AE.
PMC9630609. Pulmonary rehabilitation versus usual care for adults
with asthma. Cochrane Database Syst Rev. 2022 Aug
22;8(8):CD013485. doi: 10.1002/14651858.CD013485.pub2.
PMID: 35993916; PMCID: PMC9394585.

McLoughlin RF, Clark VL, Urroz PD, Gibson PG, McDonald

VM. Increasing physical activity in severe asthma: a
systematic review and meta-analysis. Eur Respir J. 2022
Dec 15;60(6):2200546. doi: 10.1183/13993003.00546-2022.
PMID: 35896208; PMCID: PMC9753478.

Asthma 52
 Clinical Year in Review

Sarcoidosis
Michelle Sharp MD, MHS
Johns Hopkins University
Medicine
Baltimore, MD

OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES IN Comments

SARCOIDOSIS 1. This prospective study utilized the GRADS cohort to
Ryan SM, Mroz MM, Herzog EL, Ryu C, Fingerlin TE, Maier evaluate environmental and occupational
LA, Gulati M. Occupational and environmental exposures among patients with sarcoidosis.
exposures in the Genomic Research in Alpha-1 2. It is the first study to evaluate the association
Antitrypsin Deficiency and Sarcoidosis (GRADS) study. between clinical sarcoidosis phenotypes and
Respir Med. 2022 Aug-Sep;200:106923. environmental and occupational exposures.
3. Results showed sex and race differences in the
Summary clinical phenotypes and exposures.
This prospective study sought to explore associations 4. There were no significant occupational or
between environmental and occupational exposures environmental exposures associated with
and sarcoidosis clinical phenotypes within the Genomic developing sarcoidosis in the lungs only, between
Research in Alpha-1 Antitrypsin Deficiency and the Scadding stage groups, acute/remitting versus
Sarcoidosis (GRADS) cohort, a NIH multicenter study non-acute/non-remitting disease, or chronic versus
sponsored by the NHLBI. The study evaluated non-chronic sarcoidosis.
occupational and environmental exposures between 5. Radiation exposure was associated with higher risk
five disease outcomes: pulmonary only versus of cardiac versus non-cardiac disease.
extrapulmonary with or without pulmonary
involvement; Scadding Stage II/III/IV versus Scadding
Stage 0/I; cardiac involvement (yes/no); acute or NEW THERAPIES IN PULMONARY SARCOIDOSIS
remitting disease (onset of disease less than 1 month) Culver DA, Aryal S, Barney J, Hsia CCW, James WE, Maier
versus non-acute or non-remitting disease; and chronic LA, Marts LT, Obi ON, Sporn PHS, Sweiss NJ, Shukla S,
disease defined as active disease for more than 2 years Kinnersley N, Walker G, Baughman R. Efzofitimod for the
(yes/no). Results found that both clinical phenotypes Treatment of Pulmonary Sarcoidosis. Chest. 2022 Nov
and exposures differed by sex and racial groups. 8:S0012-3692(22)04053-3.
Females had a higher percentage of Scadding Stage 0/1
compared to males. Exposure differences by sex were Summary
found among jobs and hobbies. In the cohort, Black Based on consensus guidelines, glucocorticosteroids
individuals had more extrapulmonary disease, a higher are considered first line therapy in most patients with
proportion of Scadding Stage IV, and were more likely sarcoidosis who have indications for treatment, but can
to have chronic disease compared to White individuals. be associated with significant side effects. Novel
Job exposures differed between the racial groups. There therapies are urgently needed in sarcoidosis. Neuropilin
were no significant occupational or environmental 2 is a pleiotropic receptor that is upregulated on the
exposures associated with any of the studied outcomes, surface of activated immune cells responsible for
with the exception that having occupational radiation inflammation and granuloma formation in the lungs of
exposure was statistically significantly associated with a patients with pulmonary sarcoidosis. ATYR1923 is a
higher risk of cardiac sarcoidosis. novel IV biologic immunomodulator composed of a
splice variant of histidyl-tRNA synthetase that encodes

Sarcoidosis 53
 Clinical Year in Review

the immunomodulatory domain that binds to the included. Using baseline FVC, FEV1, and DLCO % predicted
neuropilin 2 receptor protein. This study is a phase II, calculated using Global Lung Function Initiative
randomized, double-blind, placebo-controlled study reference equations, five pulmonary function
evaluating multiple doses of efzofitimod (ATYR1923) to phenotypes were defined: normal, restriction,
assess for tolerability, safety, and clinical efficacy. No obstruction, combined restriction and obstruction
deaths or drug-related serious adverse events (AEs) (combined), and isolated reduction in DLCO. Of 602
were observed. Overall, the proportion of patients with individuals with sarcoidosis, 93% had pulmonary
an AE was similar between the placebo and efzofitimod involvement defined by the GRADS organ assessment
treatment groups. Exploratory analyses suggest tool, 64% were female, and 57% were Black. Of those
clinically meaningful improvements at 24 weeks in the 5 with pulmonary involvement, the pulmonary function
mg/kg efzofitimod arm. These improvements were seen phenotype prevalence was 44% normal, 27% restriction
in both lung function parameters and patient reported (47% of abnormal individuals), 13% obstruction (22% of
outcomes compared with placebo. The results of this abnormal individuals), 9% combined (16% of abnormal
study support further evaluation of efzofitimod in individuals), and 8% isolated reduction in DLCO (15% of
pulmonary sarcoidosis. abnormal individuals). Restriction was the most
common pulmonary function phenotype among Black
Comments individuals, while normal was the most common among
1. Novel therapies are needed in sarcoidosis. White individuals. Black individuals had significantly
2. Efzofitimod (ATYR1923) selectively binds neuropilin worse pulmonary function compared with White
2, which is upregulated on immune cells in individuals including FVC% predicted, FEV1% predicted
response to lung inflammation. and DLCO % predicted. Males had obstruction more
3. This is a phase II, randomized, double-blind, frequently than females, but females had restriction
placebo-controlled evaluating multiple doses of more frequently than males.
efzofitimod (ATYR1923).
4. Similar adverse events occurred in the efzofitimod Comments
and placebo groups with suggestion of clinical 1. This is the first study to describe the prevalence of
improvement in the 5mg/kg efzofitimod group pulmonary function phenotypes in a large, diverse
compared to placebo. sarcoidosis cohort in the US.
5. The results of this study support further evaluation 2. Among individuals with sarcoidosis and pulmonary
of efzofitimod in pulmonary sarcoidosis. function impairment, less than half demonstrated a
restrictive phenotype.
RACIAL AND SEX DIFFERENCES IN PULMONARY 3. Spirometry may miss clinical progression in a
SARCOIDOSIS substantial proportion of individuals.
Sharp M, Psoter KJ, Balasubramanian A, Pulapaka AV, 4. Black individuals had worse pulmonary function
Chen ES, Brown SW, Mathai SC, Gilotra NA, Chrispin J, compared with White individuals, and these
Bascom R, Bernstein R, Eakin MN, Wise RA, Moller DR, differences were seen in all pulmonary function
McCormack MC. Heterogeneity of Lung Function phenotypes except the combined phenotype.
Phenotypes in Sarcoidosis: Role of Race and Sex 5. The results demonstrated significant differences in
Differences. Ann Am Thorac Soc. 2023 Jan;20(1):30-37. pulmonary function phenotypes by race and sex.

Summary
This study characterized the prevalence of different
pulmonary function phenotypes in a retrospective
cohort of patients with sarcoidosis. Patients seen
between 2005-2015 with a diagnosis of sarcoidosis and
lung function measurements (spirometry and DLCO) were

Sarcoidosis 54
 Clinical Year in Review

IMPACT OF NEIGHBOURHOOD DISADVANTAGE IN 4. ADI was associated with greater decline in DLCO per
SARCOIDOSIS year, but no significance was seen with CMID in the
Goobie GC, Ryerson CJ, Johannson KA, Keil S, Schikowski fully adjusted models.
E, Khalil N, Marcoux V, Assayag D, Manganas H, Fisher JH, 5. Further work is needed to understand whether
Kolb MRJ, Chen X, Gibson KF, Kass DJ, Zhang Y, Lindell policies aimed at reducing neighborhood-level
KO, Nouraie SM. Neighborhood disadvantage impacts inequities may mitigate these outcome disparities
on pulmonary function in patients with sarcoidosis. ERJ in patients with sarcoidosis and other chronic
Open Res. 2022 Oct 24;8(4):00357-2022. diseases.

Summary LUNG TRANSPLANT IN SARCOIDOSIS

This study assesses the association between Gupta R, Zheng M, Gangemi AJ, Zhao H, Cordova FC,
neighborhood-level disadvantage and clinical outcomes Criner GJ, Mamary AJ, Sehgal S. Predictors of lung
in a prospective cohort from the United States (US) transplant waitlist mortality for sarcoidosis. Respir Med.
enrolled between 2000-2021 and a prospective cohort 2022 Dec;205:107008.
from Canada enrolled between 2015-2021.
Neighborhood-level disadvantage was measured by the Summary
area deprivation index (ADI) in the US cohort and the This retrospective study aimed to identify predictors for
Canadian Index of Multiple Deprivation (CIMD) in the transplant waitlist mortality among individuals with
Canadian cohort. Analyses included adjustments for co- sarcoidosis. The cohort consisted of 1034 sarcoidosis
variates including age at diagnosis, sex, race, and patients listed for lung transplantation from May 2005
smoking status. The primary outcomes were pulmonary to May 2019 in the Scientific Registry of Transplant
function parameters (FVC and DLCO). The US and Recipients (SRTR) database after LAS implementation.
Canadian cohorts included 477 and 122 patients with The study also compared outcomes pre-LAS and post-
median follow up of 8.3 years and 4.1 years, LAS. After LAS implementation, the proportion of
respectively. Neither ADI nor CIMD was significantly candidates who were transplanted increased
associated baseline % predicted FVC in the fully significantly and the proportion of candidates that died
adjusted analyses. There was a significant association on the waitlist decreased significantly. Of the post-LAS
with between ADI, but not CMID, and baseline % cohort, 704 were transplanted and 110 died on the
predicted DLCO. In both cohorts, the highest quartile of waitlist. Significant predictors of waitlist mortality in
ADI and CIMD (most disadvantaged neighborhoods) was multivariate analyses were female gender (OR 2.45; 95%
associated with greater decline in FVC % predicted per CI 1.51–3.95) and severe pulmonary hypertension (OR
year compared to the lowest quartile. ADI was 1.62; 95% CI 1.07–2.46). Taller minimum donor height (OR
associated with greater decline in DLCO per year by 0.61; 95% CI 0.38–0.97) and blood type B (OR 0.52; 95% CI
continuous measurements and quartile measurements, 0.28–0.98) were associated with decreased likelihood of
but no significance was seen with CMID in the fully death on the waitlist.
adjusted models.
Comments
Comments 1. Criteria for lung transplant referral in sarcoidosis
1. Significant health disparities among socioeconomic are not well established.
status, race, and gender exist in sarcoidosis. 2. The LAS has increased the proportion of listed
2. This is the first study to evaluate of neighborhood- patients with sarcoidosis who receive transplants
level disadvantage in sarcoidosis. and decreased wait list mortality.
3. Participants in the highest quartile of ADI and CIMD 3. Female gender and severe pulmonary hypertension
had greater decline in FVC % predicted per year were predictors of waitlist mortality
compared to individuals in the lowest quartile of 4. Clinicians should be mindful of the increased
ADI and CIMD respectively. mortality in patients with pulmonary hypertension

Sarcoidosis 55
 Clinical Year in Review

and sarcoidosis and consider early referral for lung 3. The intervention (eMBCT) improved fatigue, anxiety,
transplantation. depression, mindfulness, and health status in
patients with sarcoidosis-associated fatigue.
TREATMENT FOR FATIGUE IN SARCOIDOSIS 4. The beneficial effects of eMBCT persisted during
Kahlmann V, Moor CC, van Helmondt SJ, Mostard RLM, follow-up 12 weeks after completion of the program.
van der Lee ML, Grutters JC, Wijsenbeek MS, Veltkamp M.
Online mindfulness-based cognitive therapy for fatigue
in patients with sarcoidosis (TIRED): a randomised OTHER ARTICLES OF INTEREST
controlled trial. Lancet Respir Med. 2023 Mar;11(3):265- Seedahmed MI, Baugh AD, Albirair MT, Luo Y, Chen J,
272. McCulloch CE, Whooley MA, Koth LL, Arjomandi M.
Epidemiology of Sarcoidosis in U.S. Veterans from 2003
Summary to 2019. Ann Am Thorac Soc. 2023 Feb 1.
Fatigue affects up to 90% of patients with sarcoidosis
and is often associated with psychological symptoms Lin NW, Arbet J, Mroz MM, Liao SY, Restrepo CI, Mayer AS,
such as anxiety and depression. This study is a Li L, Barkes BQ, Schrock S, Hamzeh N, Fingerlin TE,
prospective, open-label, multicenter randomized Carlson NE, Maier LA. Clinical phenotyping in
controlled trial assessing the effects of a 12-week online sarcoidosis using cluster analysis. Respir Res. 2022 Apr
mindfulness-based cognitive therapy (eMBCT) on 9;23(1):88.
fatigue. Of 99 patients who were randomized, 52 were
assigned to eMBCT and 47 were assigned to the control Alqalyoobi S, Liao SY, Qureshi W, Obi ON. National
group (usual care). The primary outcome of the study Temporal Trends in Hospitalization and Inpatient
was the between-group difference in change of fatigue, Mortality in Patients With Pulmonary Sarcoidosis in the
measured by the fatigue assessment scale (FAS), at T1 United States Between 2007 and 2018. Chest. 2022
(completion of intervention or 12 weeks after Jan;161(1):152-168. doi: 10.1016/[Link].2021.07.2166.
enrollment if control). FAS has a minimal clinical
important difference of 4.0. Secondary outcomes Ascoli C, Schott CA, Huang Y, Turturice BA, Wang W,
included the Hospital Anxiety and Depression Scale, the Ecanow N, Sweiss NJ, Perkins DL, Finn PW. Altered
Freiburg Mindfulness Inventory–Short Form, and the transcription factor targeting is associated with
Kings Sarcoidosis Questionnaire. In the intervention differential peripheral blood mononuclear cell
group, there was a clinically and statistically significant proportions in sarcoidosis. Front Immunol. 2022 Oct
improvement in FAS score (-4.53) between T0 (baseline) 13;13:848759. doi: 10.3389/fimmu.2022.848759.
and T1. In the control group, the mean change in FAS
was -1.28. Patients in the eMBCT group had significantly Vis R, Mathijssen H, Keijsers RGM, van de Garde EMW,
more improvement in anxiety, depressive symptoms, Veltkamp M, Akdim F, Post MC, Grutters JC. Prednisone
health status, and mindfulness score compared with vs methotrexate in treatment naïve cardiac sarcoidosis.
the control group. Beneficial effects within the J Nucl Cardiol. 2023 Jan 14.
intervention group persisted 12 weeks (T2) after
completion of the eMBCT program. Wand AL, Pavlovic N, Duvall C, Rosen NS, Chasler J,
Griffin JM, Okada DR, Jefferson A, Chrispin J, Tandri H,
Comments Mathai SC, Sharp M, Chen ES, Kasper EK, Hays AG, Gilotra
NA. Effect of Corticosteroids on Left Ventricular Function
1. Fatigue in patients with sarcoidosis is highly
in Patients With Cardiac Sarcoidosis. Am J Cardiol. 2022
prevalent, affecting up to 90% of patients.
Aug 15;177:108-115. doi: 10.1016/[Link].2022.04.051.
2. This study is the first randomized control trial
investigating the effects of a 12-week online
mindfulness-based cognitive therapy (eMBCT) on
sarcoidosis-associated fatigue.

Sarcoidosis 56
 Clinical Year in Review

Miyakuni S, Maeda D, Matsue Y, Yoshioka K, Dotare T, Roeder M, Sievi NA, Schneider A, Osswald M, Malesevic
Sunayama T, Nabeta T, Naruse Y, Kitai T, Taniguchi T, S, Kolios A, Nilsson J, Kohler M, Franzen D. The
Tanaka H, Okumura T, Baba Y, Matsumura A, Minamino prevalence of obstructive sleep apnea in sarcoidosis
T. The Prognostic Value of B-Type Natriuretic Peptide in and its impact on sleepiness, fatigue, and sleep-
Patients With Cardiac Sarcoidosis Without Heart Failure: associated quality of life: a cross-sectional study with
Insights From ILLUMINATE-CS. J Am Heart Assoc. 2022 matched controls (the OSASA study). J Clin Sleep Med.
Dec 20;11(24):e025803. doi: 10.1161/JAHA.122.025803. 2022 Oct 1;18(10):2415-2422.

Lawrie A, Hamilton N, Wood S, Exposto F, Muzwidzwa R, Khassawneh B, Zhu C, Barkes B, Vestal B, Shrock S,
Raiteri L, Beaudet A, Muller A, Sauter R, Pillai N, Kiely DG. Gillespie M, Pacheco K, Deane KD, Maier LA, Li QZ,
Healthcare resource utilization and quality of life in Hamzeh N; GRADS investigators. Autoantibody profile in
patients with sarcoidosis-associated pulmonary sarcoidosis, analysis from the GRADS sarcoidosis
hypertension. Pulm Circ. 2022 Sep 30;12(4):e12136. cohort. PLoS One. 2022 Oct 20;17(10):e0274381.

Hoth KF, Simmering J, Croghan A, Hamzeh NY; GRADS Knudsen KS, Lehmann S, Nielsen R, Tangedal S, Paytuvi-
Investigators. Cognitive Difficulties and Health-Related Gallart A, Sanseverino W, Martinsen EMH, Hiemstra PS,
Quality of Life in Sarcoidosis: An Analysis of the GRADS Eagan TM. The lower airways microbiota and
Cohort. J Clin Med. 2022 Jun 22;11(13):3594. antimicrobial peptides indicate dysbiosis in sarcoidosis.
Microbiome. 2022 Oct 19;10(1):175.

Gayen S, Sosa DF, Zheng M, Gangemi A, Sehgal S, Zhao H,

Marchetti N, Criner GJ, Gupta R, Mamary AJ. Lung
Transplantation Waitlist Mortality Among Sarcoidosis
Patients by Lung Allocation Score Grouping. Transplant
Proc. 2023 Feb 15:S0041-1345(23)00011-8.

Sarcoidosis 57
 Clinical Year in Review

Sepsis
Sivasubramanium Bhavani, MD, MS
Emory University
Department of Medicine
Atlanta, GA

FLUID RESUSCITATION IN SEPSIS outcomes with either a restrictive or liberal fluid

National Heart, Lung, and Blood Institute Prevention strategy.
and Early Treatment of Acute Lung Injury Clinical Trials
Network; Shapiro NI, Douglas IS, Brower RG, Brown SM, Comments
Exline MC, Ginde AA, Gong MN, Grissom CK, Hayden D, 1. Study patients received pre-randomization
Hough CL, Huang W, Iwashyna TJ, Jones AE, Khan A, Lai P, intravenous fluids (median of 2 liters in both
Liu KD, Miller CD, Oldmixon K, Park PK, Rice TW, groups), and this trial was not designed to
Ringwood N, Semler MW, Steingrub JS, Talmor D, investigate the initial fluid resuscitation
Thompson BT, Yealy DM, Self WH. Early Restrictive or recommendation of 30 ml/kg.
Liberal Fluid Management for Sepsis-Induced 2. The restrictive group received 1.3 liters while the
Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. liberal group received 3.4 liters in the first 24 hours
after randomization.
Summary 3. A secondary finding of interest was the safety of
The 2021 SCCM guidelines suggest 30 ml/kg of initial peripheral vasopressors, which were allowed
intravenous fluid resuscitation, but the guidelines do through a 20 gauge or larger peripheral catheter
not have a recommendation on further fluid and resulted in only three instances of
management and do not differentiate between a extravasation among 500 patients, with all three
restrictive and liberal fluid strategy. The Crystalloid cases resolving without intervention.
Liberal or Vasopressors Early Resuscitation in Sepsis 4. Compared to the CLASSIC trial detailed below, both
(CLOVERS) trial was an unblinded randomized arms in the CLOVERS trial were protocolized
controlled trial comparing a restrictive fluid protocol (compared to protocolized vs standard of care in
(i.e., early vasopressors) to a liberal protocol in patients CLASSIC) and the protocols were followed for only
with sepsis associated hypotension, defined as 24 hours (compared to up to 90 days in CLASSIC).
hypotension despite 1 to 3 liters of intravenous fluid
resuscitation. The restrictive protocol prioritized
vasopressors as the primary treatment, allowing for
“rescue fluids” for prespecified indications, while the
liberal protocol started with an initial 2-liter
intravenous infusion, and prioritized fluid boluses with
“rescue vasopressors”. The protocols were continued
for 24 hours. In total, 782 patients were randomized to
restrictive and 781 patients to liberal protocols. There
was no significant difference in the primary outcome of
90-day mortality in the restrictive vs liberal group (14%
vs 14.9%). There were no differences in secondary
outcomes and no differential benefit in prespecified
subgroup analyses. In patients with sepsis-induced
hypotension, there was no significant difference in

Sepsis 58
 Clinical Year in Review

FLUID RESUSCITATION IN SEPSIS secondary outcomes (including renal function) or the

Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake prespecified subgroup analysis.
JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M,
Ostermann M, Malbrain M, Pettilä V, Møller MH, Kjær MN, Comments
Lange T, Overgaard-Steensen C, Brand BA, Winther- 1. Study patients received 3 liters of intravenous fluids
Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, pre-randomization, and thus this study was not
Hjortsø CJS, Meier N, Jensen TS, Engstrøm J, Nebrich L, designed to investigate the question of initial fluid
Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen resuscitation strategy.
LM, Herløv LS, Sølling CG, Pedersen SK, Knudsen KK, 2. During the 90-day trial period, the restrictive fluid
Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, group received 1.8 liters of fluid, compared to 3.8
Aagaard SR, Hildebrandt T, Russell L, Bestle MH, liters in the standard group, with a cumulative (net)
Schønemann-Lund M, Brøchner AC, Elvander CF, fluid balance of +1.6 liters compared to +2.4 liters.
Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, 3. The control group (standard therapy) may not have
Seter H, Aslam TN, Ådnøy S, Seidel P, Strand K, Johnstad been managed distinctly different enough from the
B, Joelsson-Alm E, Christensen J, Ahlstedt C, restrictive group to detect differences in outcomes
Pfortmueller CA, Siegemund M, Greco M, Raděj J, Kříž M, (as evidenced by the <1 liter difference in net fluid
Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC balance at 90 days).
Trial Group. Restriction of Intravenous Fluid in ICU 4. Both the CLASSIC and CLOVERS trials evaluate broad
Patients with Septic Shock. N Engl J Med. 2022 Jun protocolized strategies of restriction and
30;386(26):2459-2470. liberalization of intravenous fluids and are not
designed to provide insights into individualized
strategies for fluid therapy (e.g., dynamic measures
Summary of fluid responsiveness).
The Conservative versus Liberal Approach to Fluid
Therapy of Septic Shock in Intensive Care (CLASSIC) trial EXPERIMENTAL AND EMERGING THERAPIES IN SEPSIS
compared restrictive intravenous fluid therapy to SuDDICU Investigators for the Australian and New
standard intravenous fluid therapy in patients with Zealand Intensive Care Society Clinical Trials Group;
septic shock on vasopressors in the ICU, who had Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M,
received at least 1 liter in the 24 hours prior to Davis JS, Gordon AC, Hammond NE, Iredell J, Li Q,
enrollment. The patients in the restrictive fluid arm Micallef S, Miller J, Mysore J, Taylor C, Young PJ,
received intravenous fluids in small boluses only for Cuthbertson BH, Finfer SR. Effect of Selective
the indications of 1) severe hypoperfusion, 2) to replace Decontamination of the Digestive Tract on Hospital
documented fluid losses, 3) to correct dehydration and Mortality in Critically Ill Patients Receiving Mechanical
electrolyte deficiencies, or 4) to ensure minimal fluid Ventilation: A Randomized Clinical Trial. JAMA. 2022 Nov
intake. Patients in the standard therapy arm had no 15;328(19):1911-1921.
restrictions on the volume of fluids to be administered.
The restrictive or standard care was continued for the Summary
length of the patients’ ICU stay, up to a maximum of 90 Selective decontamination of the digestive tract (SDD) is
days. The trial enrolled 1554 patients across 31 ICUs in a long-studied intervention of interest with the goal of
Europe and was conducted between November 2018 reducing the incidence of infections in mechanically
and November 2021. The results showed that at 90 days ventilated patients. Although there has been clinical
after randomization, there was no significant difference research into SDD for over 30 years, SDD has not
in death between the restrictive fluid group (42.3%) and become standard practice in most countries. The
the standard fluid group (42.1%). The authors found no Selective Decontamination of the Digestive Tract in the
significant differences in any of the prespecified Intensive Care Unit (SuDDICU) trial was a cluster
randomized unblinded study that randomized ICUs to

Sepsis 59
 Clinical Year in Review

SDD or standard care for patients who were

mechanically ventilated and predicted to need Summary
mechanical ventilation for at least 48 hours. The SDD It has been hypothesized that Vitamin C therapy has
intervention consisted of colistin, tobramycin, and antioxidant effects that could benefit critically ill
nystatin as an oral paste and a gastric suspension, patients with sepsis. An initial single-center study
along with a 4-day course of IV antibiotics with gram- showed significant mortality benefit from a
negative coverage. In total, 5982 patients were enrolled combination of Vitamin C, thiamine, and
from 19 ICUs. There was no statistically significant hydrocortisone. However, multiple subsequent multi-
difference in the primary outcome of in-hospital deaths center trials including VITAMINS and VICTAS have failed
between the SDD and standard care groups (odds ratio, to replicate the mortality benefit from the combination
0.91 [95% CI, 0.82-1.02]; P = .12). Of the 8 prespecified therapy. The CITRIS-ALI trial tested Vitamin C
secondary outcomes, 6 showed no significant monotherapy in a high-dose formulation in patients
differences. In the ecological assessment, the use of with sepsis associated acute lung injury and found no
SDD was not shown to be noninferior to standard care difference in the primary outcome, but 28-day mortality
(i.e., SDD did not lead to development of new antibiotic (one of 46 secondary outcomes) was significantly lower
resistant organisms). in patients randomized to Vitamin C. The LOVIT trial is a
randomized placebo-controlled multi-center clinical
Comments trial investigating high-dose intravenous Vitamin C in
1. Although the trial’s primary outcome of mortality adults with sepsis requiring vasopressor infusions in
did not reach significance, the confidence interval the ICU, with the primary composite outcome of death
includes a clinically significant benefit that is or persistent organ dysfunction on day 28. This study
further supported by meta-analyses confirming involved 872 patients, with 435 in the Vitamin C group
likely mortality benefit from SDD. and 437 in the control group. The study surprisingly
2. Of the secondary outcomes, there was no difference found that the composite primary outcome of death or
in new Clostridium difficile infections between the persistent organ dysfunction occurred more frequently
SDD and standard care arms. in the Vitamin C group (44.5% vs 38.5%, p=0.01). There
3. Of the secondary outcomes, the patients in the SDD were no significant differences between the two groups
arm had lower rates of new positive blood cultures in terms of secondary outcomes.
and antibiotic resistant organisms in cultures.
Comments

EXPERIMENTAL AND EMERGING THERAPIES IN SEPSIS 1. This trial did not specifically address whether there
could be a benefit in patients with sepsis and acute
Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R,
lung injury (to mirror the CITRIS-ALI trial).
Heyland DK, Cook DJ, Battista MC, Day AG, Guyatt GH,
2. Although the trial measured five biomarkers of
Kanji S, Parke R, McGuinness SP, Tirupakuzhi
tissue dysoxia, inflammation, and endothelial injury,
Vijayaraghavan BK, Annane D, Cohen D, Arabi YM, Bolduc
there were no findings to identify the mechanism of
B, Marinoff N, Rochwerg B, Millen T, Meade MO, Hand L,
harm from Vitamin C.
Watpool I, Porteous R, Young PJ, D'Aragon F, Belley-Cote
3. This trial adds to the pool of evidence for either a
EP, Carbonneau E, Clarke F, Maslove DM, Hunt M, Chassé
null effect or even potential harm from Vitamin C in
M, Lebrasseur M, Lauzier F, Mehta S, Quiroz-Martinez H,
patients with sepsis requiring vasopressors.
Rewa OG, Charbonney E, Seely AJE, Kutsogiannis DJ,
LeBlanc R, Mekontso-Dessap A, Mele TS, Turgeon AF,
Wood G, Kohli SS, Shahin J, Twardowski P, Adhikari NKJ;
LOVIT Investigators and the Canadian Critical Care Trials
Group. Intravenous Vitamin C in Adults with Sepsis in
the Intensive Care Unit. N Engl J Med. 2022 Jun
23;386(25):2387-2398.

Sepsis 60
 Clinical Year in Review

EXPERIMENTAL AND EMERGING THERAPIES IN SEPSIS intervention, and any positive results should be
Drewry AM, Mohr NM, Ablordeppey EA, Dalton CM, Doctor considered in this context.
RJ, Fuller BM, Kollef MH, Hotchkiss RS. Therapeutic 3. If there is a true mortality benefit from therapeutic
Hyperthermia Is Associated With Improved Survival in hyperthermia, the biological mechanism was not
Afebrile Critically Ill Patients With Sepsis: A Pilot identified in this study as both HLA-DR expression
Randomized Trial. Crit Care Med. 2022 Jun 1;50(6):924- and IFN-γ production did not differ between groups.
934. 4. There was no increase in adverse events in the
therapeutic hyperthermia group, and it was well
Summary tolerated.
Fever is known to have beneficial effects in the immune
response to infection. Afebrile patients with infection POST-HOSPITALIZATION SEPSIS CARE
(specifically, hypothermic patients) have worse Taylor SP, Murphy S, Rios A, McWilliams A, McCurdy L,
outcomes. It is unknown whether artificially inducing a Chou SH, Hetherington T, Rossman W, Russo M, Gibbs M,
fever (i.e., therapeutic hyperthermia) through external Kowalkowski MA. Effect of a Multicomponent Sepsis
warming could reproduce the immune effects and Transition and Recovery Program on Mortality and
potentially improve patient outcomes. There is Readmissions After Sepsis: The Improving Morbidity
literature surrounding this practice in oncology and During Post-Acute Care Transitions for Sepsis
surgery (with an older trial showing decreased post- Randomized Clinical Trial. Crit Care Med. 2022 Mar
surgical wound infections in patients randomized to 1;50(3):469-479.
warming). This current study was a single-center,
prospective, open-label, randomized controlled trial Summary
involving mechanically ventilated septic adults, with
While in-hospital mortality from sepsis has decreased,
patients randomized to external warming versus
sepsis survivors are burdened by high risk of post-
control. External warming consisted of the use of a
discharge mortality and readmissions. The Sepsis
forced-air warming blanket for 48 hours, with a goal
Transition and Recovery (STAR) program was developed
temperature 1.5°C above the lowest temperature
to address persistent morbidity and mortality for sepsis
documented in the previous 24 hours. The primary
survivors. The STAR program delivers post-sepsis care
outcome was monocyte human leukocyte antigen
through a remote nurse navigator who addresses
(HLA)-DR expression. The study enrolled 56 patients (28
medication optimization, screening for new
in each arm) and showed no differences in the primary
impairments, anticipation and mitigation of health risks,
outcome of HLA-DR expression or secondary outcome
and palliative care. The Improving Morbidity during
of IFN-γ production between the groups. Surprisingly,
Post-Acute Care Transitions for Sepsis (IMPACTS) trial
the patients randomized to external warming had a
tested the hypothesis that high-risk patients with
significantly lower 28-day mortality rate compared to
suspected sepsis randomized to the STAR program
control (18% vs 43%; absolute risk reduction, 25%; 95%
would have a reduction in a composite outcome of 30-
CI, 2-48%).
day readmission and mortality. The study was
conducted across three hospitals and enrolled 691
Comments
patients (349 randomized to STAR and 343 randomized
1. Small single-center studies are susceptible to type I to usual care). The STAR group had significantly lower
errors/false positives, and the findings need to be incidence of the primary outcome compared to usual
validated in a larger study with the designated care (28.7% vs 33.3%), with 9.5% compared to 12%
primary outcome of mortality. mortality. The intervention benefit was most significant
2. Pilot studies are designed to determine feasibility for the patients in the lower 3 quartiles of predicted
of enrolling patients and performing the mortality risk, while not of significant benefit in patients
intervention rather than to evaluate efficacy of the in the top quartile of predicted risk. The IMPACTS trial
demonstrated that a post-discharge transition program

Sepsis 61
 Clinical Year in Review

decreased short-term mortality and rehospitalization Russell DW, Casey JD, Gibbs KW, Ghamande S, Dargin JM,
after discharge for patients with sepsis. Vonderhaar DJ, Joffe AM, Khan A, Prekker ME, Brewer JM,
Dutta S, Landsperger JS, White HD, Robison SW, Wozniak
Comments JM, Stempek S, Barnes CR, Krol OF, Arroliga AC, Lat T,
1. The enrolled patients were deemed high-risk using Gandotra S, Gulati S, Bentov I, Walters AM, Dischert KM,
a locally derived risk-stratification tool, with unclear Nonas S, Driver BE, Wang L, Lindsell CJ, Self WH, Rice TW,
generalizability and uncertainty on the effect of the Janz DR, Semler MW; PREPARE II Investigators and the
intervention on patients who were selected for Pragmatic Critical Care Research Group. Effect of Fluid
enrollment through alternative methods. Bolus Administration on Cardiovascular Collapse Among
2. It is unclear what component of the STAR program Critically Ill Patients Undergoing Tracheal Intubation: A
was most impactful and the specific action Randomized Clinical Trial. JAMA. 2022 Jul 19;328(3):270-
pathways that could have led to mortality and 279. doi: 10.1001/jama.2022.9792. PMID: 35707974; PMCID:
readmission prevention (e.g., illustrative cases of PMC9204618.
patients’ clinical course changed through the
program). EXPERIMENTAL AND EMERGING THERAPIES IN SEPSIS
3. While 30-day mortality and readmission are Hammond NE, Myburgh J, Seppelt I, Garside T, Vlok R,
important metrics, further research is needed to Mahendran S, Adigbli D, Finfer S, Gao Y, Goodman F,
understand the longer-term benefits of this type of Guyatt G, Santos JA, Venkatesh B, Yao L, Di Tanna GL,
program in sepsis survivors. Delaney A. Association Between Selective
Decontamination of the Digestive Tract and In-Hospital
Mortality in Intensive Care Unit Patients Receiving
OTHER ARTICLES OF INTEREST Mechanical Ventilation: A Systematic Review and Meta-
FLUID RESUSCITATION analysis. JAMA. 2022 Nov 15;328(19):1922-1934. doi:
Zampieri FG, Machado FR, Biondi RS, Freitas FGR, Veiga 10.1001/jama.2022.19709. PMID: 36286098; PMCID:
VC, Figueiredo RC, Lovato WJ, Amêndola CP, Serpa-Neto PMC9607997.
A, Paranhos JLR, Lúcio EA, Oliveira-Júnior LC, Lisboa TC,
Lacerda FH, Maia IS, Grion CMC, Assunção MSC, Manoel Fujii T, Salanti G, Belletti A, Bellomo R, Carr A, Furukawa
ALO, Corrêa TD, Guedes MAVA, Azevedo LCP, Miranda TA, TA, Luethi N, Luo Y, Putzu A, Sartini C, Tsujimoto Y, Udy
Damiani LP, Brandão da Silva N, Cavalcanti AB. AA, Yanase F, Young PJ. Effect of adjunctive vitamin C,
Association between Type of Fluid Received Prior to glucocorticoids, and vitamin B1 on longer-term
Enrollment, Type of Admission, and Effect of Balanced mortality in adults with sepsis or septic shock: a
Crystalloid in Critically Ill Adults: A Secondary systematic review and a component network meta-
Exploratory Analysis of the BaSICS Clinical Trial. Am J analysis. Intensive Care Med. 2022 Jan;48(1):16-24. doi:
Respir Crit Care Med. 2022 Jun 15;205(12):1419-1428. doi: 10.1007/s00134-021-06558-0. Epub 2021 Nov 9. PMID:
10.1164/rccm.202111-2484OC. PMID: 35349397. 34750650; PMCID: PMC8724116.

Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J,

Markiewicz A, Spiegelhoff K, Hipp LA, Canales B, Szabo A,
Heyland DK, Stoppe C, Zielonka J, Freed JK. High-Dose IV
Hydroxocobalamin (Vitamin B12) in Septic Shock: A
Double-Blind, Allocation-Concealed, Placebo-Controlled
Single-Center Pilot Randomized Controlled Trial (The
Intravenous Hydroxocobalamin in Septic Shock Trial).
Chest. 2023 Feb;163(2):303-312. doi:
10.1016/[Link].2022.09.021. Epub 2022 Sep 26. PMID:
36174744.

Sepsis 62
 Clinical Year in Review

SEPSIS PHENOTYPES Health Care Use, and Costs in Sepsis Survivors. Ann Am
Bhavani SV, Semler M, Qian ET, Verhoef PA, Robichaux C, Thorac Soc. 2023 Feb;20(2):279-288. doi:
Churpek MM, Coopersmith CM. Development and 10.1513/AnnalsATS.202203-195OC. PMID: 36251451.
validation of novel sepsis subphenotypes using
trajectories of vital signs. Intensive Care Med. 2022 OTHER TOPICS
Nov;48(11):1582-1592. doi: 10.1007/s00134-022-06890-z. Law AC, Bosch NA, Peterson D, Walkey AJ. Comparison of
Epub 2022 Sep 24. PMID: 36152041; PMCID: PMC9510534. Heart Rate After Phenylephrine vs Norepinephrine
Initiation in Patients With Septic Shock and Atrial
Benzoni NS, Carey KA, Bewley AF, Klaus J, Fuller BM, Fibrillation. Chest. 2022 Oct;162(4):796-803. doi:
Edelson DP, Churpek MM, Bhavani SV, Lyons PG. 10.1016/[Link].2022.04.147. Epub 2022 May 5. PMID:
Temperature Trajectory Subphenotypes in Oncology 35526604; PMCID: PMC9808602.
Patients with Neutropenia and Suspected Infection. Am
J Respir Crit Care Med. 2022 Nov 30. doi: Adams R, Henry KE, Sridharan A, Soleimani H, Zhan A,
10.1164/rccm.202205-0920OC. Epub ahead of print. PMID: Rawat N, Johnson L, Hager DN, Cosgrove SE, Markowski
36449534. A, Klein EY, Chen ES, Saheed MO, Henley M, Miranda S,
Houston K, Linton RC, Ahluwalia AR, Wu AW, Saria S.
Leventogiannis K, Kyriazopoulou E, Antonakos N, Kotsaki Prospective, multi-site study of patient outcomes after
A, Tsangaris I, Markopoulou D, Grondman I, Rovina N, implementation of the TREWS machine learning-based
Theodorou V, Antoniadou E, Koutsodimitropoulos I, early warning system for sepsis. Nat Med. 2022
Dalekos G, Vlachogianni G, Akinosoglou K, Koulouras V, Jul;28(7):1455-1460. doi: 10.1038/s41591-022-01894-0.
Komnos A, Kontopoulou T, Prekates A, Koutsoukou A, Epub 2022 Jul 21. PMID: 35864252.
van der Meer JWM, Dimopoulos G, Kyprianou M, Netea
MG, Giamarellos-Bourboulis EJ. Toward personalized Writing Committee for the REMAP-CAP Investigators;
immunotherapy in sepsis: The PROVIDE randomized Higgins AM, Berry LR, Lorenzi E, Murthy S, McQuilten Z,
clinical trial. Cell Rep Med. 2022 Nov 15;3(11):100817. doi: Mouncey PR, Al-Beidh F, Annane D, Arabi YM, Beane A,
10.1016/[Link].2022.100817. PMID: 36384100; PMCID: van Bentum-Puijk W, Bhimani Z, Bonten MJM, Bradbury
PMC9729870. CA, Brunkhorst FM, Burrell A, Buzgau A, Buxton M,
Charles WN, Cove M, Detry MA, Estcourt LJ, Fagbodun EO,
SEPSIS SURVIVORSHIP Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa
Kowalkowski MA, Rios A, McSweeney J, Murphy S, R, Hills T, Horvat CM, Huang DT, Ichihara N, Lamontagne
McWilliams A, Chou SH, Hetherington T, Rossman W, F, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP,
Taylor SP. Effect of a Transitional Care Intervention on McVerry BJ, Neal MD, Nichol AD, Parke RL, Parker JC,
Rehospitalization and Mortality after Sepsis: A 12-Month Parry-Billings K, Peters SEC, Reyes LF, Rowan KM, Saito
Follow-up of a Randomized Clinical Trial. Am J Respir H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW,
Crit Care Med. 2022 Sep 15;206(6):783-786. doi: Shankar-Hari M, Stronach LM, Turgeon AF, Turner AM,
10.1164/rccm.202203-0590LE. PMID: 35608544. van de Veerdonk FL, Zarychanski R, Green C, Lewis RJ,
Angus DC, McArthur CJ, Berry S, Derde LPG, Gordon AC,
Winkler D, Rose N, Freytag A, Sauter W, Spoden M, Webb SA, Lawler PR. Long-term (180-Day) Outcomes in
Schettler A, Wedekind L, Storch J, Ditscheid B, Critically Ill Patients With COVID-19 in the REMAP-CAP
Schlattmann P, Reinhart K, Günster C, Hartog CS, Randomized Clinical Trial. JAMA. 2023 Jan 3;329(1):39-51.
Fleischmann-Struzek C. The Effects of Postacute doi: 10.1001/jama.2022.23257. PMID: 36525245; PMCID:
Rehabilitation on Mortality, Chronic Care Dependency, PMC9857594.

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 Clinical Year in Review

Sleep
Cathy Goldstein, MD
University of Michigan
Neurology
Ann Arbor, MI

OBSTRUCTIVE SLEEP APNEA Foundation concerning research project strategies for

Berry RB, Abreu AR, Krishnan V, Quan SF, Strollo PJ Jr, potential grant funding. Further discussions within the
Malhotra RK. A transition to the American Academy of Hypopnea Scoring Rule Task Force focused on
Sleep Medicine–recommended hypopnea definition in developing advocacy initiatives among patient
adults: initiatives of the Hypopnea Scoring Rule Task stakeholder groups to change payer policy.
Force. J Clin Sleep Med. 2022;18(5):1419–1425.
Comments
Summary 1. The American Academy of Sleep Medicine
The American Academy of Sleep Medicine (AASM) continues to recommend the hypopnea
recommends that hypopneas be identified using a definition where >=30% reduction in airflow
definition that is based on a ≥ 30% decrease in airflow terminates in a >= 3% oxygen desaturation or
associated with a ≥ 3% reduction in oxygen saturation arousal (H3A); however, CMS still only
or an arousal (H3A) for diagnosis of obstructive sleep recognizes hypopneas, and the derived AHI,
apnea (OSA) in adults. This conflicts with the Centers for when airflow reduction of at least 30%
Medicare & Medicaid Services definition, which requires terminates in an at least 4% arousal (H4).
a ≥ 4% decrease in the oxygen saturation to identify a 2. In the coming scoring manual revision, the
hypopnea (H4) and does not acknowledge arousals. In AASM will use H3A to define hypopneas and the
2018, the AASM Board of Directors constituted a H4 definition will be optional.
Hypopnea Scoring Rule Task Force with a mandate to 3. Defining hypopneas with the H3A rule classifies
"create a strategy for adoption and implementation of symptomatic individuals as having OSA that
the AASM recommended adult hypopnea scoring would fallen into ‘normal’ AHI range with the H4
criteria among members, payers and device rule.
manufacturers." The task force initiated several 4. Polysomnogram reports should include
activities including a survey of AASM-accredited sleep quantification of hypopneas using the H3A rule.
facilities and discussions with polysomnography
software vendors. Survey results indicated that most
sleep facilities scored polysomnograms using only the OBSTRUCTIVE SLEEP APNEA
Centers for Medicare & Medicaid Services definition. Hajipour M, Baumann B, Azarbarzin A, Allen AH, Liu Y,
Vendors indicated that they could easily support dual Fels S, Goodfellow S, Singh A, Jen R, Ayas NT. Association
scoring. Informal testing among task force members' of alternative polysomnographic features with patient
sleep facilities confirmed there would be little outcomes in obstructive sleep apnea: a systematic
additional work if dual scoring was performed. The task review. Journal of Clinical Sleep Medicine. 2023 Feb
force convened several meetings, with the purpose of 1;19(2):225-42.
creating research recommendations to study the impact
on relevant clinical outcomes using the different
definitions of hypopnea. Based on the deliberations of Summary
the working group, the Hypopnea Scoring Rule Task Polysomnograms (PSGs) collect a plethora of
Force submitted recommendations to the AASM physiologic signals across the night. However, few of

Sleep 64
 Clinical Year in Review

these PSG data are incorporated into standard reports, 4. In regards to cognitive function and vigilance,
and hence, ultimately, under-utilized in clinical decision the following candidate predictive PSG metrics
making. Recently, there has been substantial interest were identified: 1. Pulse arrival time (PAT), 2.
regarding novel alternative PSG metrics that may help Odds Ratio Product, 3. Other EEG metrics, 4.
to predict obstructive sleep apnea (OSA)-related Spindle burst index, 5. EEG power, 6. Arousal
outcomes better than standard PSG metrics such as the duration, 7. Desaturation severity and
apnea-hypopnea index. Authors systematically reviewed obstructive severity, and 8. Apnea or hypopnea
the literature between 2000 and 2022 for studies that load
examined the use of alternative PSG metrics in the 5. The authors concluded that advanced analysis
context of OSA and their association with health of physiologically complex PSG data has
outcomes. provided promising novel, alternative metrics to
predict OSA-related complications and that
Of the 186 initial studies identified by the original these new indicators fall into the following
search, 31 were ultimately included in the final analysis. categories: hemodynamic-related, EEG-related,
Numerous metrics were identified that were desaturation indices, and respiratory event
significantly related to a broad range of outcomes. data.

Comments
1. OSA is associated with daytime sleepiness, INSOMNIA
reduced quality of life, motor vehicle crashes, De Crescenzo F, D'Alò GL, Ostinelli EG, et al. Comparative
occupational injuries, hypertension, cancer, effects of pharmacological interventions for the acute
cardiovascular disease, arrhythmias, kidney and long-term management of insomnia disorder in
disease, cognitive dysfunction, and mortality. adults: a systematic review and network meta-analysis.
However, the presence of OSA or severity as Lancet 2022; 400:170.
quantified by the AHI, does not reliably predict
adverse outcomes. Summary
2. Marked interest in identifying alternative or In this systematic review and network meta-analysis,
novel metrics derived from PSG that are authors aimed to estimate the comparative
relevant to outcomes to guide more patient- effectiveness of pharmacological treatments for the
specific risk stratification and treatment and acute and long-term treatment of adults with insomnia
inform population selection for RCTs. disorder.
3. In regards to Cardiovascular/metabolic
outcomes and mortality the following candidate They searched several sources from database inception
predictive PSG metrics were identified: 1. Heart to Nov 25, 2021, to identify published and unpublished
rate response to respiratory events, 2. Pulse randomised controlled trials and included studies
arrival time, 3. Pulse wave characteristics, 4. comparing pharmacological treatments or placebo as
Pulse rate variability/HRV, 5. Cardiopulmonary monotherapy for the treatment of adults with insomnia
coupling, 6. Odds Ratio Product, 7. EEG power, 8. disorder. Primary outcomes were efficacy (ie, quality of
Arousal burden, 9. Hypoxic burden, 10. sleep measured by any self-rated scale), treatment
Respiratory event desaturation transient area, discontinuation for any reason and due to side-effects
11. Oxygen desaturation rate, 12. Lung to finger specifically, and safety (ie, number of patients with at
circulation time, 13. Desaturation severity and least one adverse event) both for acute and long-term
obstructive severity, 14. Respiratory event treatment.
duration, and 15. Duty cycle and inspiratory flow
limitation. They included 170 trials (36 interventions and 47950
participants) and 154 doubleblind, randomised

Sleep 65
 Clinical Year in Review

controlled trials (30 interventions and 44089 conclusions. Many licensed drugs (including
participants) were eligible for the network metaanalysis. benzodiazepines, daridorexant, suvorexant, and
trazodone) can be effective in the acute treatment of
In terms of acute treatment, benzodiazepines, insomnia but are associated with poor tolerability, or
doxylamine, eszopiclone, lemborexant, seltorexant, information about long-term effects is not available.
zolpidem, and zopiclone were more efficacious than Melatonin, ramelteon, and non-licensed drugs did not
placebo (SMD range: 0·36–0·83 [CINeMA estimates of show overall material benefits. These results should
certainty: high to moderate]). Benzodiazepines, serve evidence-based clinical practice.
eszopiclone, zolpidem, and zopiclone were more
efficacious than melatonin, ramelteon, and zaleplon Comments
(SMD 0·27–0·71 [moderate to very low]). Intermediate- 1. Most RCTs of pharmacological treatment of
acting benzodiazepines, long-acting benzodiazepines, insomnia are short-term leading to medication
and eszopiclone had fewer discontinuations due to any approval only for acute settings.
cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; 2. This systematic review and meta-analysis of
moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52– publications on the acute and long-term
0·98; moderate], respectively). Zopiclone and zolpidem pharmacological treatment of insomnia used
caused more dropouts due to adverse events than did outcomes of self-rated quality of sleep
placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; (efficacy), discontinuation due to any cause
zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone (acceptability), discontinuation due to any
caused more dropouts than did eszopiclone (OR 1·82 adverse event (tolerability), and presence of at
[95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; least one adverse event (safety). Among the
low), and suvorexant (3·13 [1·47–6·67; low]). For the studied medications, lemborexant and
number of individuals with side-effects at study eszopiclone had the best profile in terms of
endpoint, benzodiazepines, eszopiclone, zolpidem, and efficacy, acceptability, and tolerability; however,
zopiclone were worse than placebo, doxepin, eszopiclone might cause substantial adverse
seltorexant, and zaleplon (OR range 1·27–2·78 [high to events and safety data on lemborexant were
very low]). inconclusive.

For long-term treatment, eszopiclone and lemborexant

were more effective than placebo (eszopiclone: SMD RESTLESS LEGS SYNDROME
0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41
Winkelman JW, Wipper B, Zackon J. Long-term Safety,
[0·04–0·78; very low]) and eszopiclone was more
Dose Stability, and Efficacy of Opioids for Patients With
effective than ramelteon (0.63 [0·16–1·10; very low]) and
Restless Legs Syndrome in the National RLS Opioid
zolpidem (0·60 [0·00–1·20; very low]). Compared with
Registry. Neurology. 2023 Jan 25.
ramelteon, eszopiclone and zolpidem had a lower rate
of all-cause discontinuations (eszopiclone: OR 0·43 [95%
Summary
CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very
low]); however, zolpidem was associated with a higher In this study, authors report the 2-year longitudinal
number of dropouts due to side-effects than placebo data in a sample of patients treated with opioids for
(OR 2·00 [95% CI 1·11–3·70; very low]). RLS in the community.
The National RLS Opioid Registry is an observational
Overall, eszopiclone and lemborexant had a favorable longitudinal study consisting of individuals taking a
profile, but eszopiclone might cause substantial prescribed opioid for diagnosed and confirmed RLS,
adverse events and safety data on lemborexant were most of whom experienced augmented symptoms from
inconclusive. Doxepin, seltorexant, and zaleplon were dopamine agonists. Information on opioid dosages, side
well tolerated, but data on efficacy and other important effects, past and current concomitant RLS treatments,
outcomes were scarce and do not allow firm RLS severity, psychiatric symptoms, and opioid abuse

Sleep 66
 Clinical Year in Review

risk factors was collected at Registry entry and every 6 opioids for RLS. The initial 2 years of data from
months thereafter. No feedback or intervention was N=448 patients were available.
provided by the study staff to local providers. 2. Most common side effects at 2 years were
constipation (47%), drowsiness/fatigue (23%),
Registry participants (n = 448) with 2-year longitudinal itching (19%), sweating (17%), and
data available were mostly White, female, older than 60 stimulation/wakefulness (9%).
years, and, at Registry entry, had been on opioids for a 3. 80% of those who stayed on opioids remained
median of 1–3 years at a mean morphine milligram on the same opioid at the 2 year time point and
equivalent (MME) of 38.4 (SD = 43.5). No change in RLS the median MME dose was the same at the 2-
severity in the overall cohort was observed over the 2- year time point compared to baseline Two-
year follow-up period. The median change in daily fifths of patients increased opioid dose (the
opioid dose from baseline to 2 years was 0 MME balance remained the same or decreased).
(interquartile range = 0–10). While 41.1% of participants 4. Almost all individuals with opioid daily dose
increased their dose during the follow-up period increases of >25 or 50 MME had one of the
(median increase = 10 MME), 58.9% decreased their dose following characteristics: switching opioid
or saw no change. Only 8% and 4% saw increases of >25 medication, discontinuation of nonopioid RLS
MME and >50 MME, respectively. Ninety-five percent of treatment medications, at least mild insomnia
those who increased opioid dose >25 or >50 MME had at baseline, a history of depression, male sex,
one of the following features: switching opioids, younger than 45 years, and opioid use for
discontinuation of nonopioid RLS treatment comorbid pain.
medications, at least mild insomnia at baseline, a 5. Of those who remained on opioids and
history of depression, male sex, younger than 45 years, completed 2-year surveys, IRLS, ISI, and PHQ-9
and opioid use for comorbid pain. scores did not change from baseline to 2 years.
However, almost a quarter remaining on
Low-dose opioid medications continue to adequately opioids fell into the severe RLS category at
control symptoms of refractory RLS over 2 years of baseline and the 2 year follow up.
follow-up in most of the participants. A minority of 6. Opioids used were methadone (50.9%),
patients did see larger dose increases, which were oxycodone (15.0%), hydrocodone (11.6%),
invariably associated with a limited number of factors, oxycontin (7.1), and tramadol (6.7%). IRLS scores
most notably changes in opioid and nonopioid RLS at 2 years were significantly lower for
medications and opioid use for a non-RLS condition. participants using methadone.
Continued longitudinal observations will provide insight
into the long-term safety and efficacy of opioid
treatment of severe, augmented RLS. CENTRAL DISORDERS OF HYPERSOMNOLENCE
Dauvilliers, Y., Arnulf, I., Foldvary-Schaefer, N., Morse, A.
This study provides Class IV evidence that opioid doses M., Šonka, K., Thorpy, M. J., Mignot, E., Chandler, P.,
increase in roughly 40% of patients, in most by small Parvataneni, R., Black, J., Sterkel, A., Chen, D.,
amounts, over a 2-year period when prescribed for Skobieranda, F., & Bogan, R. K. (2022). Safety and efficacy
adult refractory restless leg syndrome. of lower-sodium oxybate in adults with idiopathic
hypersomnia: a phase 3, placebo-controlled, double-
Comments blind, randomised withdrawal study. The Lancet.
1. The RLS National Opioid Registry collects Neurology, 21(1), 53–65. [Link]
longitudinal observational data on efficacy, 4422(21)00368-9
dosage changes, tolerability, RLS severity, and
sleep, mood, and anxiety symptoms in a
national sample of patients using prescribed

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 Clinical Year in Review

Summary adverse events included nausea (34 [22%] of 154),

Idiopathic hypersomnia is a central hypersomnolence headache (27 [18%] of 154), dizziness (19 [12%] of 154),
disorder mainly characterised by excessive daytime anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No
sleepiness, with prolonged night-time sleep and deaths were reported during the study.
pronounced sleep inertia. Until August, 2021, no
medication had regulatory approval for the treatment Lower-sodium oxybate treatment resulted in a clinically
of idiopathic hypersomnia. This study aimed to evaluate meaningful improvement in idiopathic hypersomnia
the safety and efficacy of lower-sodium oxybate in symptoms, with an overall safety profile consistent with
idiopathic hypersomnia. that reported for narcolepsy. Lower-sodium oxybate
was approved in August, 2021, by the US Food and Drug
This was a phase 3, multicentre (50 specialist sleep Administration for the treatment of idiopathic
centres; six EU countries and the USA), placebo- hypersomnia in adults.
controlled, double-blind, randomised withdrawal study.
Participants (aged 18-75 years) with idiopathic Comments
hypersomnia began lower-sodium oxybate treatment 1. Idiopathic hypersomnia is a disorder of
(oral solution once or twice nightly) in an open-label excessive daytime sleepiness without
titration and optimisation period (10-14 weeks), explanation and without the REM intrusion that
followed by a 2-week, open-label, stable-dose period. marks narcolepsy. Calcium, magnesium,
After these open-label periods, participants were potassium, and sodium oxybates (lower-sodium
randomised (1:1) to either placebo or lower-sodium oxybate, Xywav) is the first medication FDA
oxybate (individually optimised dose; range 2·5-9·0 approved to treat idiopathic hypersomnia
g/night) during a 2-week, double-blind, randomised 2. This was a placebo-controlled, double-blind,
withdrawal period. To maintain masking of treatment randomised withdrawal study looking at the
assignment, placebo and lower-sodium oxybate oral primary endpoint of Epworth sleepiness scale
solutions were matched in volume, appearance, and (ESS) change. From the standard dose period,
taste. The primary efficacy endpoint was change in those who were withdrawn to placebo had a
Epworth Sleepiness Scale (ESS) score from the end of worsening of mean ESS by 7.4 points; those
the stable-dose period to the end of the double-blind, randomized to remain on the active medication
randomised withdrawal period, Adverse events were had ESS scores that were unchanged from the
assessed in the safety population (defined as all stable dose period (mean ESS=7) (and improved
participants who took at least one dose of study from baseline, mean ESS= 15.7).
medication). 3. Treatment-emergent adverse events included
nausea (22%), headache (18%), dizziness (12%),
Between Nov 2018, and March 2020, 154 participants anxiety (11%), and vomiting (11%).17%
were enrolled and comprised the safety population. ESS discontinued participation in the study due to
scores decreased from a mean of 15·7 (SD 3·8) at treatment-emergent adverse events.
baseline to 6·1 (4·0) by the end of the stable-dose
period. After the open-label periods, 115 participants
were randomly assigned either placebo (n=59) or lower-
sodium oxybate (n=56) and comprised the modified
intention-to-treat population. During the double-blind,
randomised withdrawal period, ESS scores increased
(worsened) in participants randomly assigned to
placebo but remained stable in those assigned to
lower-sodium oxybate (least squares mean difference -
6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent

Sleep 68
 Clinical Year in Review

REM SLEEP BEHAVIOR DISORDER

Howell, M., Avidan, A. Y., Foldvary-Schaefer, N., Malkani, Comments
R. G., During, E. H., Roland, J. P., McCarter, S. J., Zak, R. S., 1. The AASM suggests that clinicians use
Carandang, G., Kazmi, U., & Ramar, K. (2023). clonazepam, immediate-release melatonin, or
Management of REM sleep behavior disorder: an pramipexole (vs no treatment) for the treatment
American Academy of Sleep Medicine clinical practice of isolated RBD in adults. (CONDITIONAL)
guideline. Journal of clinical sleep medicine : JCSM : 2. The AASM suggests that clinicians use
official publication of the American Academy of Sleep transdermal rivastigmine (vs no treatment) for
Medicine, 19(4), 759–768. the treatment of isolated RBD in adults with
[Link] mild cognitive impairment. (CONDITIONAL)
3. The AASM suggests that clinicians use
Summary clonazepam or immediate-release melatonin
This guideline established clinical practice (vs no treatment) for the treatment of
recommendations for the management of rapid eye secondary RBD due to medical condition in
movement sleep behavior disorder (RBD) in adults. adults. (CONDITIONAL)
4. The AASM suggests that clinicians use
The American Academy of Sleep Medicine (AASM) transdermal rivastigmine (vs no treatment) for
commissioned a task force of experts in sleep medicine the treatment of secondary RBD due to medical
to develop recommendations and assign strengths condition (Parkinson disease) in adults.
based on a systematic review of the literature and an (CONDITIONAL)
assessment of the evidence using Grading of 5. The AASM suggests that clinicians not use deep
Recommendations, Assessment, Development and brain stimulation (DBS; vs no treatment) for the
Evaluation methodology. The task force provided a treatment of secondary RBD due to medical
summary of the relevant literature and the certainty of condition in adults. (CONDITIONAL)
evidence, the balance of benefits and harms, patient 6. The AASM suggests that clinicians use drug
values and preferences, and resource use discontinuation (vs drug continuation) for the
considerations that support the recommendations. The treatment of drug-induced RBD in adults.
AASM Board of Directors approved the final six (CONDITIONAL)
recommendations, listed below.

The good practice statement is based on expert

consensus, and its implementation is necessary for the OTHER ARTICLES OF INTEREST
appropriate and effective management of patients with Obstructive Sleep Apnea
RBD: It is critically important to help patients maintain a Khan NN, Todem D, Bottu S, Badr MS, Olomu A. Impact
safe sleeping environment to prevent potentially of patient and family engagement in improving
injurious nocturnal behaviors. In particular, the removal continuous positive airway pressure adherence in
of bedside weapons, or objects that could inflict injury patients with obstructive sleep apnea: a randomized
if thrown or wielded against a bed partner, is of controlled trial. Journal of Clinical Sleep Medicine. 2022
paramount importance. Sharp furniture like nightstands Jan 1;18(1):181-91.
should be moved away or their edges and headboard
should be padded. To reduce the risk of injurious falls, Li Y, Richard KE, Schwartz AR, Zealear D, Lindsell CJ,
a soft carpet, rug, or mat should be placed next to the Budnick HA, Kent DT. Quantitative Effects of Ansa
bed. Patients with severe, uncontrolled RBD should be Cervicalis Stimulation in Obstructive Sleep Apnea.
recommended to sleep separately from their partners, American Journal of Respiratory and Critical Care
or at the minimum, to place a pillow between Medicine. 2023 Jan 19(ja).
themselves and their partners.

Sleep 69
 Clinical Year in Review

Das AM, Chang JL, Berneking M, et al. Enhancing public Insomnia

health and safety by diagnosing and treating Zhao, J. L., Cross, N., Yao, C. W., Carrier, J., Postuma, R. B.,
obstructive sleep apnea in the transportation industry: Gosselin, N., Kakinami, L., & Dang-Vu, T. T. (2022).
an American Academy of Sleep Medicine position Insomnia disorder increases the risk of subjective
statement. J Clin Sleep Med 2022; 18:2467. memory decline in middle-aged and older adults: a
longitudinal analysis of the Canadian Longitudinal
Georgoulis M, Yiannakouris N, Kechribari I, et al. Dose- Study on Aging. Sleep, 45(11), zsac176.
response relationship between weight loss and [Link]
improvements in obstructive sleep apnea severity after
a diet/lifestyle interventions: secondary analyses of the Bushnell GA, Gerhard T, Keyes K, Hasin D, Cerdá M,
"MIMOSA" randomized clinical trial. J Clin Sleep Med Olfson M. Association of Benzodiazepine Treatment for
2022; 18:1251. Sleep Disorders With Drug Overdose Risk Among Young
People. JAMA Netw Open. 2022 Nov 1;5(11):e2243215. doi:
Lechat B, Appleton S, Melaku YA, Hansen K, McEvoy RD, 10.1001/jamanetworkopen.2022.43215. PMID: 36413369;
Adams R, Catcheside P, Lack L, Eckert DJ, Sweetman A. PMCID: PMC9682430.
Comorbid insomnia and sleep apnoea is associated CRSWD
with all-cause mortality. European Respiratory Journal.
Yip, T., Wang, Y., Xie, M., Ip, P. S., Fowle, J., & Buckhalt, J.
2022 Jul 1;60(1).
(2022). School Start Times, Sleep, and Youth Outcomes:
A Meta-analysis. Pediatrics, 149(6), e2021054068.
[Link]

Technology
Bakker JP, Ross M, Cerny A, Vasko R, Shaw E, Kuna S,
Magalang UJ, Punjabi NM, Anderer P. Scoring sleep with
artificial intelligence enables quantification of sleep
stage ambiguity: hypnodensity based on multiple expert
scorers and auto-scoring. Sleep. 2023 Feb;46(2):zsac154.

Sleep 70
 Clinical Year in Review

LUNG TRANSPLANTS
Sean Agbor-Enoh, MD, PhD
National Heart, Lung, and Blood Institute & Johns Hopkins Hospital
Medicine, Division of Intramural research
Bethesda, Maryland

ARE WE DONE HERE? INEQUITIES OF THE LUNG

ALLOCATION SCORE SYSTEM AND TIME TO MOVE ON
Kolaitis NA, Chen H, Calabrese DR, Kumar K, Obata J, Comments
Bach C, Golden JA, Simon MA, Kukreja J, Hays SR, Leard 1. This article addresses the question: does applying a
LE, Singer JP, De Marco T. The Lung Allocation Score single allocation system, such as the LAS, for
Remains Inequitable for Patients with Pulmonary patients with vastly different disease conditions
Arterial Hypertension, Even after the 2015 Revision. Am J often bring inequities?
Respir Crit Care Med. 2023 Feb 1;207(3):300-311. doi: 2. This work points out that even with revisions, the
10.1164/rccm.202201-0217OC. PMID: 36094471 LAS system continues to show inequities.
3. Unfortunately, the LAS system also struggles in its
Summary primary mission as a predictor of pre- and post-
Before March 2023, donor lungs in the United States transplant outcomes for patients listed for lung
were allocated via a system called the lung allocation transplantation.
score (LAS). LAS prioritizes patients for transplantation 4. The LAS has since been replaced by a new system,
based on an estimated risk of waitlist death and post- the composite allocation score (CAS), a scoring
transplant survival. Unfortunately, LAS creates multiple system that utilizes recipient medical information
inequities. This work examines the inequities of the LAS and facts from potential donors to determine
for patients with pulmonary arterial hypertension (PAH), allocation priorities.
a subgroup of patients where the LAS fails to capture 5. It remains unclear how allocation inequities will be
the impact of their pulmonary vascular disease on pre- impacted by the CAS, which was implemented in
and post-transplant outcomes. In 2015, the LAS system March 2023.
was revised to better reflect disease severity in PAH.
This manuscript utilizes national registry data to
estimate the benefit of the 2015 LAS revision. MANIPULATE THE DONOR LUNG BIOLOGY IN THE
RECIPIENTS’ FAVOR BEFORE TRANSPLANTATION
The study included about ~40,000 participants, half Miyamoto E, Takahagi A, Ohsumi A, Martinu T, Hwang D,
registered before the 2015 revision and half after. Boonstra KM, Joe B, Umana JM, Bei KF, Vosoughi D, Liu M,
Before the 2015 revisions, PAH demonstrated the Cypel M, Keshavjee S, Juvet SC. Ex vivo delivery of
highest risk of death and lowest likelihood of transplant regulatory T-cells for control of alloimmune priming in
compared to any other patient group. With the 2015 the donor lung. Eur Respir J. 2022 Apr 14;59(4):2100798.
revision, the LAS increased 14.2 points in the 100-point doi: 10.1183/13993003.00798-2021. Print 2022 Apr. PMID:
scale for PAH patients, without a significant change in 34475226
the LAS for other patient groups. Although inequities
improved, they nonetheless persisted. Specifically, PAH Summary
is now tied with pulmonary fibrosis for the highest risk Lung transplantation has the poorest survival of any
of waitlist death, while together with chronic allotransplant, partly resulting from a high degree of
obstructive pulmonary disease patients had the lowest hyperinflammation and allograft injury that starts from
likelihood of transplantation. implantation. Could one manipulate the donor lung to
reduce allograft inflammation prior to transplantation?

Lung Transplants 71
 Clinical Year in Review

Using an animal model, the investigator isolated, LUNG ALLOGRAFT MICROBIOME CHANGE QUICKLY AFTER
expanded in vitro, and fluorescently labelled IMPLANTATION AND PREDICT THE DEVELOPMENT OF
immunomodulating polyclonal regulatory T cells (Tregs). PRIMARY GRAFT DYSFUNCTION
Ex vivo lung perfusion (EVLP) was utilized to deliver the John E McGinniss, Samantha A Whiteside, Rebecca A
recipient’s Tregs into the donor lung prior to Deek, Aurea Simon-Soro, Jevon Graham-Wooten,
transplantation. Florescent labelling allowed the Michelle Oyster, Melanie D Brown, Edward Cantu, Joshua
tracking of the Tregs in the EVLP perfusate and M Diamond, Hongzhe Li, Jason D Christie, Frederic D
transplanted donor lung. Bushman, Ronald G Collman. The Lung Allograft
Microbiome Associates with Pepsin, Inflammation, and
Tregs entered the donor lung in a dose-dependent Primary Graft Dysfunction. Am J Respir Crit Care Med.
manner and resided in the donor lung until Day 7 post- 2022 Dec 15;206(12):1508-1521. doi: 10.1164/rccm.202112-
transplantation. Interestingly, Tregs maintained their 2786OC.
immunomodulating function based on the expression
of cell surface markers. Tregs also inhibited expansion Summary
of “bad players” such as CD3+ T cells. However, the
This manuscript goal is to answer the question of
polyclonal Tregs did not reduce lung injury scores.
whether the donor lung carries a baggage of microbiota
Infusion of Tregs also did not change lung physiology
that influences the post-transplant recipient allograft
parameters. In a human model, after EVLP perfusion,
microbiome and contributes to poor outcomes. The
Tregs entered the human lung graft and maintained
investigators collected donor bronchoalveolar lavage
their immunomodulating cell-surface markers. Taken
(BAL) at organ procurement. Recipient BAL was
together, this study demonstrates that the lung allograft
collected within one hour of implantation. BAL from
can be conditioned prior to transplantation.
healthy controls was also collected. The BAL
microbiome was determined using the 16S method.
Comments
Cytokine and pepsin, a gastric content biomarker, were
1. Reducing lung allograft inflammation with EVLP has measured for recipient BAL, but not for donor BAL given
potential as a preconditioning strategy, which may the limited material. Recipients were stratified for
reduce post-transplant allograft injury and primary graft dysfunction (PGD), a severe post-
downstream complications. transplant complication. Study measures were
2. This proof-of-concept study demonstrates that one compared between severe PGD and no PGD groups.
can indeed manipulate the donor organ without
compromising lung function. In total, 139 recipients were included: 109 with matched
3. While Tregs maintained their immunomodulating donor/recipient BAL samples. Donor microbiome was
functions, there was no reduction of lung injury different from healthy controls. Within one hour of
expected since the Tregs used were polyclonal and implantation, allograft microbiome changed into
not primed to identify donor antigens. oropharyngeal microbiota that was either Prevotella or
4. Fortunately, there are novel strategies available to Streptococcus predominant. Prevotella abundant
better prime Tregs to identify donor antigens and to microbiota correlated with the risk of severe PGD and
suppress alloimmunity without suppressing Treg high levels of BAL pepsin levels and pro-inflammatory
function. innate immune cytokines. On the other hand,
5. With these tools in hand, this manuscript helps lay Streptococcus abundance correlated with a low risk of
the foundation for a new era of pre-transplant PGD and low levels of BAL pepsin or inflammatory
organ manipulation to improve its survival in the cytokines.
immunologically hostile recipient environment.

Lung Transplants 72
 Clinical Year in Review

Comments multicenter cohort of 175 recipients with routine

1. This is one of very first studies to examine donor ddcfDNA testing instead of surveillance bronchoscopy.
lung microbiota and its relationship to peri- Levels of ddcfDNA ≥1.0% served as a “danger signal” to
transplant microbiota and outcomes. trigger for bronchoscopy and other work-up. Levels of
2. The study demonstrate that lung allograft 0.5% - <1% served as a “warning signal” for closer
microbiota drastically changed to primarily monitoring with additional ddcfDNA testing. Levels of
oropharyngeal microbiome within only one hour of <0.5% represented quiescent state. This ddcfDNA
implantation. approach avoided 83% of bronchoscopies and
3. The oropharyngeal microbiome correlates with demonstrated excellent sensitivity and negative
gastric content, implicating micro-aspiration as a predictive value for detecting acute rejection and/or
primary source of allograft microbiome in the peri- infection. However, the specificity to distinguish acute
transplant period. rejection and infection was poor. The accompanying
4. The strong association with peri-transplant editorial concluded that “the real-world data …suggest
inflammation and PGD would suggest that allograft that a new era of lung transplant care, born of the
microbiome is either a driving force or a biomarker genomic revolution, is dawning.”
of peri-transplant inflammation.
5. Perhaps one can someday manipulate allograft Comments
microbiome to reduce the risk of PGD. 1. The designation of bronchoscopy plus
histopathology as “gold standard” potentially
delays the development of novel monitoring
COULD THIS BE THE ALTERNATIVE TO SURVEILLANCE strategies since this approach demonstrates low
BRONCHOSCOPY THAT WE HAVE BEEN LOOKING FOR? performance to detect acute rejection.
Keller M, Sun J, Mutebi C, Shah P, Levine D, Aryal S, 2. An ideal alternative to bronchoscopy should be
Iacono A, Timofte I, Mathew J, Varghese A, Giner C, sensitive, non-invasive, and broadly applicable to
Agbor-Enoh S. Donor-derived cell-free DNA as a monitor the most common acute complications of
composite marker of acute lung allograft dysfunction in lung transplantation, infection, and acute rejection.
clinical care. J Heart Lung Transplant. 2022 Apr;41(4):458- 3. This work builds on a foundation of observational
466. doi: 10.1016/[Link].2021.12.009. Epub 2021 Dec 26. studies to propose real-life clinical application and
PMID: 35063338. performance of ddcfDNA to detect both infection
and rejection.
Summary 4. In fact, ddcfDNA detects acute rejection earlier than
the “gold standard,” potentially opening a window
Bronchoscopy plus histopathology remains the “gold
to intervene early before irreversible allograft
standard” to monitor for lung allograft rejection.
dysfunction sets in.
However, this invasive approach has low sensitivity and
5. While a randomized control trial is needed to
high interobserver variability. Alternative approaches to
establish the benefit of ddcfDNA, it is worth noting
bronchoscopy have been proposed but none have
that bronchoscopy has never been tested in a trial
progressed beyond observational studies. Forced by the
and its designation as “gold standard” continues to
SARS-COV-2 pandemic to reduce in-hospital patient
be questioned.
contact, this work presents the first real-world
experience of substituting surveillance bronchoscopy
with a commercial blood test, donor-derived cell-free
DNA (ddcfDNA).

The investigators first validated the commercial

ddcfDNA test against their in-lab test. Building on
observational study findings, they monitored a

Lung Transplants 73
 Clinical Year in Review

COVID-19 VACCINATION: THORACIC TRANSPLANT 3. Of note, these patients were maintained on

PATIENTS SHOW POOR RESPONSE mycophenolate mofetil, which has been shown to
Gerovasili V, Shah A, Singanayagam A, George PM, reduce SARS-COV-2 serologic response.
Njafuh R, Prendecki M, Carby M, Willicombe M, Kelleher 4. The study was further limited by a lack of data on
P, Reed A. Impaired Humoral and Cellular Responses to neutralizing antibodies and clinical outcomes.
COVID-19 Vaccine in Heart and Lung Transplant 5. Nonetheless, the low response to SARS-COV-2
Recipients. Am J Respir Crit Care Med. 2022 Jun vaccine calls for development of novel strategies to
15;205(12):1476-1479. doi: 10.1164/rccm.202109-2026LE. improve vaccination response in these highly
PMID: 35333143 immunosuppressed patients.

Summary
FINALLY, A FRAILITY SCORE TAILORED FOR LUNG
COVID-19 has devastating outcomes in thoracic
TRANSPLANT PATIENTS
transplant patients, who are maintained on multiple
and high dose immunosuppression drugs. These agents Singer JP, Christie JD, Diamond JM, Anderson MA,
may blunt recipients’ response to COVID vaccination. Benvenuto LA, Gao Y, Arcasoy SM, Lederer DJ, Calabrese
This study examined both humoral and cellular immune D, Wang P, Hays SR, Kukreja J, Venado A, Kolaitis NA,
response to two SARS-COV-2 vaccines in a cohort of Leard LE, Shah RJ, Kleinhenz ME, Golden J, Betancourt L,
heart and lung transplant patients. Healthcare workers Oyster M, Zaleski D, Adler J, Kalman L, Balar P, Patel S,
were recruited as controls. Participants received two Medikonda N, Koons B, Tevald M, Covinsky KE,
doses of COVID-19 vaccines. After the second vaccine Greenland JR, Katz PK. Development of the Lung
dose, humoral response was checked using an ELISA Transplant Frailty Scale (LT-FS). J Heart Lung Transplant.
approach to detect antibodies to SARS-COV-2. T-cell 2023 Feb 20: S1053-2498(23)00049-9. doi:
response was tested using ELISPOT. Humoral and T-cell 10.1016/[Link].2023.02.006. Online ahead of print.
response was compared between transplant patients PMID: 36925382
and healthcare workers.
Summary
Only 26% of the 58 thoracic transplant recipients Frailty is an important risk factor of early mortality in
demonstrated a positive humoral response to SARS- lung transplantation and other diseases. However,
COV-2 vaccination. Further, responders manifested low existing frailty scales are less suitable for lung
antibody titer. T-cell response was only detected in 21% transplant recipients since the scales were developed
of transplant recipients, and only 7% of transplant decades ago for community dwelling older adults. This
recipients showed both T-cell and humoral responses. multicenter study developed and tested a lung
The type of SARS-COV-2 vaccine mattered, with transplant frailty scale (LT-FS) in a multicenter cohort of
BNT162b2 showing greater response compared to lung transplant recipients. The study measured multiple
ChAdOx1. In contrast, 100% and 91% of healthcare biometric, functional and serum biomarkers that have
workers showed positive humoral and T-cell responses, been implicated in frailty. The measures were
respectively. incorporated into a well validated 4-step approach for
scale development. The approach began with individual
Comments frailty domain measures and ended with
1. Despite the small sample size, the low rate of SARS- multidimensional frailty scales. The construct and
COV-2 vaccine response is consistent with other predictive validity of these scales was compared to two
studies and clinical experience in lung existing frailty scales: - Short Physical Performance
transplantation. Battery (SPPB) and Fried Frailty Phenotype scales (FFP).
2. This study examines both humoral and T-cell
responses, providing a more complete immune The novel LT-FS demonstrated better performance
profile compared to other studies. compared to SPPB and FFP. Specifically, in the cohort of

Lung Transplants 74
 Clinical Year in Review

342 lung transplant candidates, LT-FS predicted waitlist Huang HJ, Schechtman K, Askar M, Bernadt C, Mittler B,
delisting and pre-transplant mortality better than SPPB Dore P, Witt C, Byers D, Vazquez-Guillamet R, Halverson
and FFP. Addition of body composition to LT-FS L, Nava R, Puri V, Gelman A, Kreisel D, Hachem RR. A
improved the predictive performance for both waitlist pilot randomized controlled trial of de novo belatacept-
delisting and pre-transplant mortality. Finally, pre- based immunosuppression following anti-thymocyte
transplant LT-FS-body composition scale was globulin induction in lung transplantation. Am J
associated with post-transplant survival; SPPB and FFP Transplant. 2022 Jul;22(7):1884-1892. doi:
demonstrated no association to post-transplant 10.1111/ajt.17028. Epub 2022 Mar 22. PMID: 35286760
survival.
Pierre H. H. Schneeberger, Chen Yang Kevin Zhang,
Comments Jessica Santilli, Bo Chen, Wei Xu, Youngho Lee, Zonelle
1. The LT-FS is an updated and disease-specific frailty Wijesinha, Elaine Reguera-Nuñez, Noelle Yee, Musawir
scale applicable to lung transplant candidates. Ahmed, Kristen Boonstra, Rayoun Ramendra, Courtney
2. The LT-FS demonstrated excellent predictive W. Frankel, Scott M. Palmer, Jamie L. Todd, Tereza
performance for both pre- and post-transplant Martinu, Bryan Coburn. Lung Allograft Microbiome
survival. Association with Gastroesophageal Reflux,
3. The finding of this study implicates frailty as an Inflammation, and Allograft Dysfunction. Am J Respir Crit
important risk in lung transplantation and joins the Care Med. 2022 Dec 15;206(12):1495-1507. doi:
growing international call to include frailty as part 10.1164/rccm.202110-2413OC.
of pre-transplant candidate evaluation.
4. Validating the LT-FS in other lung transplant Snyder ME, Moghbeli K, Bondonese A, Craig A, Popescu I,
cohorts is important and may lead to broader Fan L, Tabib T, Lafyatis R, Chen K, Trejo Bittar HE,
clinical utility and incorporation of frailty measures Lendermon E, Pilewski J, Johnson B, Kilaru S, Zhang Y,
into lung transplant candidate selection algorithm. Sanchez PG, Alder JK, Sims PA, McDyer JF. Modulation of
tissue resident memory T cells by glucocorticoids after
OTHER ARTICLES OF INTEREST acute cellular rejection in lung transplantation. J Exp
Med. 2022 Apr 4;219(4): e20212059. doi:
Dauriat G, Beaumont L, Luong Nguyen LB, Renaud Picard
10.1084/jem.20212059. Epub 2022 Mar 14. PMID: 35285873
B, Penhouet M, Coiffard B, Salpin M, Demant X, Saint
Raymond C, Carlier N, Messika J, Reynaud Gaubert M,
Verleden GM, Vos R, Godinas L, Verleden SE, Van
Danner I, Gallais F, Roux A, Le Pavec J. Efficacy of three
Raemdonck DE, Ceulemans LJ. Natural decline in
COVID-19 vaccine doses in lung transplant recipients: a
pulmonary function following bilateral lung
multicentre cohort study. Eur Respir J. 2023 Jan
transplantation: a single-centre study. Eur Respir J. 2022
19;61(1):2200502. doi: 10.1183/13993003.00502-2022. Print
Oct 13;60(4):2200633. doi: 10.1183/13993003.00633-2022.
2023 Jan. PMID: 36265877
Print 2022 Oct. PMID: 36229067
Brahmbhatt JM, Hee Wai T, Goss CH, Lease ED, Merlo CA,
Wang A, Ribeiro RVP, Ali A, Brambate E, Abdelnour-
Kapnadak SG, Ramos KJ. The lung allocation score and
Berchtold E, Michaelsen V, Zhang Y, Rahfeld P, Moon H,
other available models lack predictive accuracy for
Gokhale H, Gazzalle A, Pal P, Liu M, Waddell TK, Cserti-
post-lung transplant survival. J Heart Lung Transplant.
Gazdewich C, Tinckam K, Kizhakkedathu JN, West L,
2022 Aug;41(8):1063-1074. doi:
Keshavjee S, Withers SG, Cypel M. Ex vivo enzymatic
10.1016/[Link].2022.05.008. Epub 2022 May 20. PMID:
treatment converts blood type A donor lungs into
35690561; PMCID: PMC9329266.
universal blood type lungs. Sci Transl Med. 2022 Feb
16;14(632):eabm7190. doi: 10.1126/scitranslmed.abm7190.
Epub 2022 Feb 16.

Lung Transplants 75
 Clinical Year in Review

Calabrese DR, Aminian E, Mallavia B, Liu F, Cleary SJ, Liu Z, Liao F, Zhu J, Zhou D, Heo GS, Leuhmann HP,
Aguilar OA, Wang P, Singer JP, Hays SR, Golden JA, Scozzi D, Parks A, Hachem R, Byers DE, Tague LK,
Kukreja J, Dugger D, Nakamura M, Lanier LL, Looney MR, Kulkarni HS, Cano M, Wong BW, Li W, Huang HJ, Krupnick
Greenland JR. Natural killer cells activated through AS, Kreisel D, Liu Y, Gelman AE. Reprogramming alveolar
NKG2D mediate lung ischemia-reperfusion injury. J Clin macrophage responses to TGF-β reveals CCR2+
Invest. 2021 Feb 1;131(3):e137047. doi: 10.1172/JCI137047. monocyte activity that promotes bronchiolitis
PMID: 33290276. obliterans syndrome. J Clin Invest. 2022 Oct
3;132(19):e159229. doi: 10.1172/JCI159229. PMID: 36189800.
Bansal S, Arjuna A, Perincheri S, Poulson C, Bremner RM,
Smith MA, Tokman S, Mohanakumar T. Restrictive Todd JL, Weber JM, Kelly FL, Neely ML, Nagler A, Carmack
allograft syndrome vs bronchiolitis obliterans D, Frankel CW, Brass DM, Belperio JA, Budev MM, Hartwig
syndrome: Immunological and molecular MG, Martinu T, Reynolds JM, Shah PD, Singer LG, Snyder
characterization of circulating exosomes. J Heart Lung LD, Weigt SS, Palmer SM. Early posttransplant
Transplant. 2022 Jan;41(1):24-33. doi: reductions in club cell secretory protein associate with
10.1016/[Link].2021.09.001. Epub 2021 Sep 10. PMID: future risk for chronic allograft dysfunction in lung
34602310. recipients: results from a multicenter study. J Heart
Lung Transplant. 2023 Feb 28:S1053-2498(23)01547-4. doi:
Halloran K, Mackova M, Parkes MD, Hirji A, Weinkauf J, 10.1016/[Link].2023.02.1495. Online ahead of print.
Timofte IL, Snell GI, Westall GP, Lischke R, Zajacova A, PMID: 36941179
Havlin J, Hachem R, Kreisel D, Levine D, Kubisa B,
Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Shino MY, Todd JL, Neely ML, Kirchner J, Frankel CW,
Halloran PF. The molecular features of chronic lung Snyder LD, Pavlisko EN, Fishbein GA, Schaenman JM,
allograft dysfunction in lung transplant airway mucosa. Mason K, Kesler K, Martinu T, Singer LG, Tsuang W, Budev
J Heart Lung Transplant. 2022 Dec;41(12):1689-1699. doi: M, Shah PD, Reynolds JM, Williams N, Robien MA, Palmer
10.1016/[Link].2022.08.014. Epub 2022 Aug 27. PMID: SM, Weigt SS, Belperio JA. Plasma CXCL9 and CXCL10 at
36163162 allograft injury predict chronic lung allograft
dysfunction. Am J Transplant. 2022 Sep;22(9):2169-2179.
Sweet SC, Armstrong B, Blatter J, Chin H, Conrad C, doi: 10.1111/ajt.17108. Epub 2022 Jun 15. PMID: 35634722.
Goldfarb S, Hayes D Jr, Heeger PS, Lyou V, Melicoff-
Portillo E, Mohanakumar T, Odim J, Ravichandran R, Ghadimi K, Cappiello J, Cooter-Wright M, Haney JC,
Schecter M, Storch GA, Visner G, Williams NM, Danziger- Reynolds JM, Bottiger BA, Klapper JA, Levy JH, Hartwig
Isakov L. CTOTC-08: A multicenter randomized MG; INSPIRE-FLO Investigators. Inhaled Pulmonary
controlled trial of rituximab induction to reduce Vasodilator Therapy in Adult Lung Transplant: A
antibody development and improve outcomes in Randomized Clinical Trial. JAMA Surg. 2022 Jan
pediatric lung transplant recipients. Am J Transplant. 1;157(1):e215856. doi: 10.1001/jamasurg.2021.5856. Epub
2022 Jan;22(1):230-244. doi: 10.1111/ajt.16862. Epub 2021 2022 Jan 12. PMID: 34787647
Nov 5. PMID: 34599540.

Lung Transplants 76
 Clinical Year in Review

Medical Education
Juliana Ferreira, MD, PhD, ATSF
University of Sao Paulo, Brazil
Heart Institute, Division of Pulmonology
Sao Paulo, Brazil

DIVERSITY, EQUITY AND INCLUSION health inequity and reveals a nearly unanimous
Banerjee D, Nassikas NJ, Singh P, Andrea SB, Zhang AY, belief that racism is present in medicine and
Aswad Y, Singh N, Walsh SR, Cox-Flaherty K, Carter EJ, impacts patient care.
Sharkey KM. Feasibility of an Antiracism Curriculum in 2. The delivery format, based on one-hour interactive
an Academic Pulmonary, Critical Care, and Sleep sessions with small group discussions over the
Medicine Division. ATS Sch. 2022 Sep 30;3(3):433-448. course of a year contributed to feasibility and
increased effectiveness
Summary 3. The authors credit the successful implementation
to several factors, including scheduling at a
This was a pre- and post pilot study in which the
preexisting didactic timeslot, no need for additional
authors piloted a year-long antiracism curriculum
funding, prior interest in having a curriculum on
focusing on individual, institutional, and systemic
antiracism, and leadership role-modeling.
racism in a PCCSM division in a large tertiary center.
4. The absence of significant change in knowledge-
Participants - 41 division faculty members and 12
based items and attitudes post-curriculum needs to
fellows - were invited to attend training sessions and
be addressed to increase sustainability and
complete an electronic survey pre and post-curriculum.
implementation in other institutions.
The curriculum consisted of 13 1-hour virtual workshops
5. Limitations include a single center design, few
over the course of the academic year scheduled during
knowledge-based questions to measure the efficacy
an existing didactic timeslot. A total of 27 faculty
of the curriculum, and lack of inclusion of other
members and 11 fellows responded to the pre-
healthcare workers.
curriculum survey (response rate 72%) and 28
completed both pre- and post-curriculum surveys. Most
participants acknowledged that racism occurs in
CLINICIAN WELL-BEING AND BURNOUT
medicine and has consequences for providers and
patients, and 28 (74%) reported wanting a structured Leitman IM, Muller D, Miller S, Hanss BG, Catron TF,
curriculum. The mean attendance for the curriculum Cooper WO, Filizola M. Implementation of an Online
was 28 users, with median attendance of 6 of the 13 Reporting System to Identify Unprofessional Behaviors
sessions (IQR 4–9). The belief that discrimination exists and Mistreatment Directed at Trainees at an Academic
in Medicine (95% of respondents) and impacts health Medical Center. JAMA Netw Open. 2022 Dec
outcomes (83%), did not change with training. In the 1;5(12):e2244661.
post-curriculum survey, 14% fewer respondents wanted
a continued structured antiracism curriculum. There Summary
was a weak positive change in perceived knowledge and This study describes the design and implementation of
comfort with talking about race and being actively an unprofessional behavior reporting tool and policies
involved in advancing racial equity. to review and handle incidents while providing
confidentiality and protecting trainees from retaliation
Comments at a large academic medical center. Participants
1. This study highlights a high level of interest among included 2900 faculty, 600 medical students, more than
fellows and faculty in an antiracist curriculum, in 1000 graduate students and postdocs, and 2600
accordance with the ACGME's call for education on residents and fellows. In approximately two years,

Medical Education 77
 Clinical Year in Review

trainees submitted 173 reports of unprofessional

interactions, 60 (35%) were from medical students and Summary
96 (56%) were from residents and fellows. Most negative This was a prospective observational study of a
reports described behaviors by faculty (61%). The most longitudinal POCUS training program for pulmonary and
common negative feedback reported was publicly critical care medicine (PCCM) fellows at an academic
embarrassment or humiliation (55%), offensive remarks center. Before the study, ultrasound skills were taught
related to gender, sexual orientation, national origin, informally only on inpatient teaching rounds. The
race, color, religion (33%) and denied opportunities for curriculum consisted of 6 didactic lectures and 2
training or rewards on the basis of membership in a hands-on skills sessions. Training was repeated at 6
protected group (9%). Most (94%) reports were handled and 18 months, and monthly practice sessions were
by a single discussion with the subject of the report and also offered. Participants were assessed before and
10 (6%) were escalated to written warning or after each training session, and at 12 months with
modification of faculty duties. Fourteen reported faculty written examinations and a hands-on skills assessment.
(8%) were referred for a physician wellness evaluation. In addition, participants self-rated their confidence in
Following its implementation, most trainees have POCUS skills. Twenty-two fellows participated and were
become aware of the process and those who expressed followed for 18 months. Participants were grouped by
their concerns through the online system reported their training levels (first-, second-, and third-year
satisfaction with the results. fellows), and all training levels improved their
knowledge, confidence and POCUS skills after the
Comments course, with first-year fellows having the greatest
1. The majority of the reports of mistreatment or increase. Improvements in POCUS knowledge,
unprofessional behavior are from residents and confidence, and skills compared to baseline were
fellows, most often directed to faculty. retained after 12 months. At 18 months, knowledge was
2. Although 90% of faculty did not receive any reports, maintained while confidence continued to increase.
20 faculty (less than 1%) accounted for half of the Knowledge and skills scores were significantly higher
reports. among fellows exposed to 1 year of formal training
3. Endorsement from the leadership combined with compared with fellows exposed to 1 year of informal
trainee representation in every step of training, while confidence was similar for these groups.
development and implementation played a
significant role to successful implementation Comments
4. The reporting system was implemented in a single 1. A formal POCUS curriculum led to greater increases
large urban academic center, with considerable in knowledge and skills compared to informal
investment of time and resources, and may not be training and supports the incorporation of formal
generalizable to other institutions curriculum into a PCCM fellowship programs
5. The authors acknowledge a persisting perception 2. Knowledge, skills and confidence gains were high,
among trainees, especially graduate students and and retained after 12 months
postdocs, that reporting mistreatment and 3. First year fellows benefitted the most from the
unprofessional behavior may not be safe due to a training, but repetition at 18 months was
belief that no action will be taken, and fear of considered important to maximize retention and
retaliation. increase confidence
4. Limitations include the small sample size and
CLINICAL TRAINING single-center design
Young AC, Butts C, deBoisblanc BP, Tejedor RS, Kantrow
SP, Lammi MR. Implementation of a Longitudinal Critical
Care Fellowship Ultrasound Curriculum. ATS Sch. 2022
Jan 28;3(1):125-134.

Medical Education 78
 Clinical Year in Review

ASSESSMENT 3. Consistent underconfidence in self-assessment can

Schultz K, McGregor T, Pincock R, Nichols K, Jain S, Pariag lead to residents restricting their practice, overuse
J. Discrepancies Between Preceptor and Resident of resources and increased anxiety among trainees.
Performance Assessment: Using an Electronic Formative 4. There were only a few residents who significantly or
Assessment Tool to Improve Residents' Self-Assessment repeatedly overcalled their performance but
Skills. Acad Med. 2022 May 1;97(5):669-673. identifying such cases provides an opportunity for
discussing discrepancies and working towards
Summary better self-assessment to decrease risks to patient
safety.
This Family Medicine residency program in Canada
5. The study did not include associations between
implemented a system to provide formative and
self-assessment discrepancies with need for
summative assessments using electronic field notes
resident remediation or patient safety outcomes.
that document a resident’s performance in clinical
encounters and summarize the preceptor’s feedback
FACULTY DEVELOPMENT
given about his or her performance during that
encounter. Field notes are initiated by the resident and Viglianti EM, Admon AJ, Carlton EF, Denstaedt SJ, Valley
also capture self-assessment of competence for that TS, Costa DK, Cooke CR, Dickson R, Iwashyna TJ, Prescott
particular knowledge or skill at one of the 4 levels: HC. Development and Retention of Early-Career
flagged (concerning behavior), needing close Clinician-Scientists through a Novel Peer Mentorship
supervision, minimal/reactive supervision, or Program: Multidisciplinary Intensive Care Research
supervision for refinement only. Fields notes are then Workgroup. ATS Sch. 2022 Oct 4;3(4):588-597.
reviewed by the preceptor and modified as needed
before submission. A software identified field notes Summary
where the level of competence was discordant between This study describes the creation, implementation and
resident self-assessment and preceptor's assessment. results of a multidisciplinary and interprofessional
From 2011–2019, 11,429 field notes were submitted by peer-mentoring group for early-career researcher
1120 residents, with 3200 (28%) showing discordance focused on critical care in an academic center. The
between residents’ and preceptors’ performance group has a formal structure, mission statement,
assessments. Residents assessed their performance as application process and clear expectations for
less competent (undercalled) than their preceptor 73% participation. The group meets for 90 minutes twice a
of the time and overcalled it in 27% of discordant notes. month and starts with accountability rounds, in which
Only six residents overcalled performance to a each member identifies two research goals to
dangerous extent (2 or 3 levels of supervision higher accomplish by the next meeting, followed by two 30-
than what their supervisors) and 26 repeatedly (greater minute presentations of work in progress for group
than 5 times) overcalled their level of performance by 1 feedback. The group has been meeting regularly since
supervisory level. 2015 despite the expected turnover (members graduate
when they obtain independent funding). Out of the 30
Comments members of the group, 15 are active members, 8 have
1. This study reveals a high rate of discordance graduated, and 7 are former members. Almost all (29
between resident self-assessment and preceptor out of 30) continue to pursue careers in academic
assessment, with residents more often undercalling medicine, and all 30 individuals remain actively
their performance. involved in research. Satisfaction was measured with
2. The findings highlight the need to include an anonymous survey (22 responses out of 26 sent).
deliberate curriculum to foster self-assessment as a Most members felt MICReW created an environment
critical skill in competency-based medical that fostered diverse thoughts (95%, n=21/22),
education constructive feedback (91%, n=20/22), provided them
with a supportive environment (91%, n=20/22), and

Medical Education 79
 Clinical Year in Review

benefitted them personally in their academic research CLINICIAN WELL-BEING AND BURNOUT
careers (95%, n=21/22). Fainstad T, Mann A, Suresh K, Shah P, Dieujuste N,
Thurmon K, Jones CD. Effect of a Novel Online Group-
Comments Coaching Program to Reduce Burnout in Female
1. This peer-mentoring group has been sustainable for Resident Physicians: A Randomized Clinical Trial. JAMA
several years and half of its members have Netw Open. 2022 May 2;5(5):e2210752. Erratum in: JAMA
obtained independent funding after participation in Netw Open. 2022 Jun 1;5(6):e2220348.
the group
2. Participation in the program was associated with Feingold JH, Kaplan CA, Hart A, Waldman R, Kronman H,
high retention rate of early-career researchers in Brody J, Hargrove J, Hurtado A, Simon AB. We Get by
academia With a Little Help From Our PEERS: The Practice
3. The study design and risk of selection bias do not Enhancement, Engagement, Resilience, and Support
allow for an accurate assessment of the program's Program for Building Community and Well-Being in
direct impact on retention and career success. Medical Education. Acad Med. 2022 Jun 1;97(6):858-862.
4. Peer-mentoring complemented traditional
mentorship needs for early-career scientists and O'Marr JM, Chan SM, Crawford L, Wong AH, Samuels E,
provided an environment rated as supportive and Boatright D. Perceptions on Burnout and the Medical
beneficial to academic careers of its members School Learning Environment of Medical Students Who
Are Underrepresented in Medicine. JAMA Netw Open.
2022 Feb 1;5(2):e220115.
OTHER ARTICLES OF INTEREST

CLINICAL TRAINING
DIVERSITY, EQUITY AND INCLUSION
Santhosh L, Rojas JC, Garcia B, Thomashow M, Lyons PG.
Ravenna PA, Wheat S, El Rayess F, McCrea L 2nd,
Cocreating the ICU-PAUSE Tool for Intensive Care Unit-
Martonffy AI, Marshall C, Tepperberg S, Friedman RSC,
Ward Transitions. ATS Sch. 2022 Apr 5;3(2):312-323.
Barr WB. Diversity, Equity, and Inclusion Milestones:
Creation of a Tool to Evaluate Graduate Medical
Krumm IR, Miles MC, Clay A, Carlos Ii WG, Adamson R.
Education Programs. J Grad Med Educ. 2022
Making Effective Educational Videos for Clinical
Apr;14(2):166-170.
Teaching. Chest. 2022 Mar;161(3):764-772.
Olson EM, Kennedy CC, Kelm DJ. Assessment of Gender
Berens M, Becker T, Anders S, Sam AH, Raupach T.
Parity: Leadership Representation in Pulmonary and
Effects of Elaboration and Instructor Feedback on
Critical Care Medicine. J Womens Health (Larchmt). 2022
Retention of Clinical Reasoning Competence Among
Mar;31(3):439-446.
Undergraduate Medical Students: A Randomized
Crossover Trial. JAMA Netw Open. 2022 Dec
Santhosh L, Rojek AE, Yim JWL, Lisker S, Wang K, Dy M,
1;5(12):e2245491.
Sarkar U. Analysis of Narrative Text in Evaluations of
Continuing Medical Education Faculty by Gender. JAMA
Camac E, Stewart N, Santhosh L, Carlos WG, Denson JL,
Netw Open. 2022 Aug 1;5(8):e2227948.
Heath J. Best Practices for Remediation in Pulmonary
and Critical Care Medicine Fellowship Training. ATS Sch.
Boatright D, London M, Soriano AJ, Westervelt M,
2022 Aug 31;3(3):485-500.
Sanchez S, Gonzalo JD, McDade W, Fancher TL. Strategies
and Best Practices to Improve Diversity, Equity, and
ASSESSMENT
Inclusion Among US Graduate Medical Education
Hayashi FK, Sousa MLA, Garcia MVF, Macedo BR, Ferreira
Programs. JAMA Netw Open. 2023 Feb 1;6(2):e2255110.
JC. Simulation-based Assessment to Measure

Medical Education 80
 Clinical Year in Review

Proficiency in Mechanical Ventilation among Residents. Residency Assessments. JAMA Netw Open. 2022 Dec
ATS Sch. 2022 Jun 30;3(2):204-219. 1;5(12):e2247649.

King AJ, Kahn JM, Brant EB, Cooper GF, Mowery DL. Initial
Development of an Automated Platform for Assessing FACULTY DEVELOPMENT
Trainee Performance on Case Presentations. ATS Sch. Kalynych C, Edwards L, West D, Snodgrass C, Zenni E.
2022 Sep 23;3(4):548-560. Tuesday's Teaching Tips-Evaluation and Feedback: A
Spaced Education Strategy for Faculty Development.
Waechter J, Allen J, Lee CH, Zwaan L. Development and MedEdPORTAL. 2022 Nov 22;18:11281.
Pilot Testing of a Data-Rich Clinical Reasoning Training
and Assessment Tool. Acad Med. 2022 Oct 1;97(10):1484- Weber-Main AM, Thomas-Pollei KA, Grabowski J, Steer CJ,
1488. Thuras PD, Kushner MG. The Proposal Preparation
Program: A Group Mentoring, Faculty Development
Boatright D, Anderson N, Kim JG, Holmboe ES, McDade Model to Facilitate the Submission and Funding of NIH
WA, Fancher T, Gross CP, Chaudhry S, Nguyen M, Grant Applications. Acad Med. 2022 Jan 1;97(1):53-61.
Nguemeni Tiako MJ, Colson E, Xu Y, Li F, Dziura JD, Saha
S. Racial and Ethnic Differences in Internal Medicine

Medical Education 81
 Clinical Year in Review

Health Equity
Deepshikha Charan Ashana, MD, MBA, MS
Duke University
Department of Medicine
Durham, NC

SPIROMETRY RACE CORRECTION race/ethnicity in spirometry reference equations should

Elmaleh-Sachs A, Balte P, Oelsner EC, Allen NB, Baugh A, be reconsidered.
Bertoni AG, Hankinson JL, Pankow J, Post WS, Schwartz
JE, Smith BM, Watson K, Barr RG. Race/Ethnicity,
Spirometry Reference Equations, and Prediction of Comments
Incident Clinical Events: The Multi-Ethnic Study of 1. Population-based, multi-ethnic prospective cohort
Atherosclerosis (MESA) Lung Study. Am J Respir Crit Care study of incident (validated) chronic lower
Med. 2022 Mar 15;205(6):700-710. doi: respiratory disease (CLRD) events and all-cause
10.1164/rccm.202107-1612OC. PMID: 34913853. mortality with high follow-up.
2. No evidence that the currently recommended
Summary race/ethnicity-based spirometry reference
Normal values for FEV1 and FVC are currently calculated equations for FEV1 and FVC were of clinical benefit
using cross-sectional reference equations that include compared to currently available race/ethnicity-
terms for race/ethnicity, an approach that may neutral reference equations (GLI “Other”).
reinforce disparities and is of unclear clinical benefit. 3. Given the observed lack of clinical benefit and
Many clinical thresholds for disease diagnosis (e.g., known harm of race-based medicine, clinicians
blood pressure, lipids) are based upon their ability to should consider using race/ethnicity-neutral
predict incident clinical events. The authors used a alternatives.
similar approach to test the utility of race/ethnicity-
based spirometry reference equations for predicting
incident chronic lower respiratory disease (CLRD) events SPIROMETRY RACE CORRECTION
and mortality compared with race/ethnicity-neutral Baugh AD, Shiboski S, Hansel NN, Ortega V, Barjaktarevic
equations in the MESA Lung Study, a population-based, I, Barr RG, Bowler R, Comellas AP, Cooper CB, Couper D,
prospective cohort study. Standardized spirometry was Criner G, Curtis JL, Dransfield M, Ejike C, Han MK,
performed between 2004-2006. Predicted values for Hoffman E, Krishnan J, Krishnan JA, Mannino D, Paine R
spirometry were calculated using the guideline- 3rd, Parekh T, Peters S, Putcha N, Rennard S, Thakur N,
recommended GLI race/ethnicity-based equations and, Woodruff PG. Reconsidering the Utility of Race-Specific
alternatively, race/ethnicity-neutral equations without Lung Function Prediction Equations. Am J Respir Crit
terms for race/ethnicity (GLI “Other” equations). Care Med. 2022 Apr 1;205(7):819-829. doi:
Participants were followed through 2019. The mean age 10.1164/rccm.202105-1246OC. Erratum in: Am J Respir Crit
of 3,344 participants was 65 years, and self-reported Care Med. 2022 Jul 15;206(2):230. PMID: 34913855; PMCID:
race/ethnicity was 36% White, 25% Black, 23% Hispanic, PMC9836221.
and 17% Asian. There was no evidence that percentage
predicted FEV1 or FVC calculated using race/ethnicity- Summary
based equations improved the prediction of CLRD- In a cohort with and at risk for chronic obstructive
related events compared with those calculated using pulmonary disease (COPD), the authors assessed
race/ethnicity-neutral equations. Findings were similar whether lung function prediction equations applied in a
for mortality. The authors conclude that the inclusion of race-specific versus universal manner better modeled

Health Equity 82
 Clinical Year in Review

the relationship between FEV1, FVC, and other COPD neighborhood characteristics, racial demographics were
outcomes, including the COPD Assessment Test, St. significantly associated with trigger incidence. For each
George's Respiratory Questionnaire, computed 10 percent decrease in neighborhood proportion of
tomography percent emphysema, airway wall thickness, White residents, trigger incidence increased by 3.14
and 6-minute-walk test. Using race-specific equations, reports per thousand residents. These disparities
African American individuals were calculated to have persisted during the study period (2011-2021), and for
better lung function than non-Hispanic White mold, an established asthma trigger, racial disparities in
individuals (FEV1, 76.8% vs. 71.8% predicted; P = 0.02). reported exposure widened. The municipal response
Using universally applied equations, African American also demonstrated disparities: In neighborhoods with
individuals were calculated to have worse lung function. the fewest White residents compared to neighborhoods
Prediction errors from linear regression were less for with the most, adjusted models showed a 17 percent
universally applied equations compared with race- (3.51 days) slower median time until cases (tenant
specific equations when examining FEV1% predicted requests for inspections to the Inspectional Services
with the COPD Assessment Test (P < 0.01), St. George's Department) were closed, a 14 percent higher
Respiratory Questionnaire (P < 0.01), and airway wall probability of being flagged as overdue, and a 54.4
thickness (P < 0.01). This study suggests that race- percent lower probability of a repair. We found that in
specific lung function equations may underestimate Boston, current regulatory systems are insufficient to
COPD severity in African American individuals. address disparities in healthy housing. To reduce
asthma disparities, stronger inspectional standards and
Comments further enforcement policies to increase landlords’
1. African American individuals had lower percent accountability and support tenants’ rights to have
predicted FEV1 when using race-specific versus repairs made are essential.
universal equations.
2. The utility of FEV1 in predicting COPD severity and Comments
radiographic correlates of COPD was higher when 1. Asthma-inducing exposures to household triggers
using universally applied versus race-specific were different by race and class.
equations. 2. The median time to a definitive municipal response
3. Race-specific lung function equations may for addressing household triggers was longer in
underestimate COPD severity in African American neighborhoods with the fewest White residents
individuals. compared to neighborhoods with the most.
3. Given the established role of indoor air quality as a
key factor in development and severity of asthma,
PULMONARY HEALTH POLICY EVALUATION these findings demonstrate that urban housing
Lemire E, Samuels EA, Wang W, Haber A. Unequal markets and associated code enforcement systems
Housing Conditions And Code Enforcement Contribute continue to drive asthma disparities.
To Asthma Disparities In Boston, Massachusetts. Health 4. As a primary determinant of a range of health
Aff (Millwood). 2022 Apr;41(4):563-572. doi: outcomes, particularly respiratory health, the right
10.1377/hlthaff.2021.01403. PMID: 35377754. to healthy housing must be upheld by stronger
code enforcement and provision of high-quality
Summary public housing.
Housing quality is a primary determinant of asthma
disparities by race and class in the United States (US).
The authors assessed how housing code enforcement
systems in a US city addressed tenants’ reports of
asthma triggers (rodents, roaches, mold, and
insufficient heat). After adjustment for income and

Health Equity 83
 Clinical Year in Review

PULMONARY HEALTH POLICY EVALUATION BIASED DIAGNOSTIC HEURISTICS

Asare S, Majmundar A, Westmaas JL, Bandi P, Xue Z, Modra LJ, Higgins AM, Pilcher DV, Bailey MJ, Bellomo R.
Jemal A, Nargis N. Association of Cigarette Sales With Sex Differences in Mortality of ICU Patients According to
Comprehensive Menthol Flavor Ban in Massachusetts. Diagnosis-related Sex Balance. Am J Respir Crit Care
JAMA Intern Med. 2022 Feb 1;182(2):231-234. doi: Med. 2022 Dec 1;206(11):1353-1360. doi:
10.1001/jamainternmed.2021.7333. PMID: 34982100; 10.1164/rccm.202203-0539OC. PMID: 35849500; PMCID:
PMCID: PMC8728656. PMC9746862.

Summary Summary
In April 2021, the US Food and Drug Administration The authors examined the differences in hospital
announced its intention to ban menthol flavors from mortality of women and men admitted to adult ICUs in
cigarettes and cigars. Before this announcement, Australia and New Zealand. Between 2011 and 2020,
Massachusetts was the only state to implement a there were 1.45 million eligible ICU admissions (42.1%
statewide comprehensive flavor ban on tobacco women). There was no difference in the hospital
products in June 2020. The authors used a difference- mortality of women and men in the study population
in-differences design to examine temporal changes in overall, after adjustment for illness severity, admission
cigarette sales in Massachusetts before (January 2017 to diagnosis, time in hospital before ICU admission,
May 2020) and after (June 2020 to July 2021) the admission year and hospital site using a mixed effect
comprehensive flavor ban, in comparison with 27 states logistic regression model. However, there was
that did not enact similar bans. After the flavor ban, the substantial variation in the adjusted hospital mortality
adjusted 4-week sales of cigarettes in Massachusetts vs of women compared to men across diagnostic groups of
the comparison states decreased by 372.27 (95% CI, ICU patients. Among patients admitted following cardiac
−428.90 to −315.64; P < .001) packs per 1000 people for surgery, women were more likely to die than men
menthol cigarettes but increased by 120.25 (95%CI, (adjusted OR 1.63, 99% CI 1.45–1.82). Among patients
72.61-167.88; P < .001) packs per 1000 people for admitted with metabolic, renal or hematologic
nonflavored cigarettes. Overall, the adjusted 4-week disorders, men were more likely to die than women
sales of all cigarettes decreased by 282.65 (95%CI, (adjusted OR 0.87, 99% CI 0.81-0.94). There was an
−356.07 to −209.23; P < .001) packs per 1000 people in association between sex balance (% female patients)
Massachusetts vs the comparison states. within a diagnostic group and the mortality of women
compared to men with that same diagnosis. In
Comments diagnoses with more men, women were relatively more
1. Cigarettes are a leading cause of preventable death likely to die; in diagnoses with more women, men were
and disability. more likely to die – a finding that may be attributable to
2. In the United States, there are large socioeconomic clinician cognitive bias.
disparities in the prevalence of cigarette smoking.
3. This study used causal inference methods to Comments
evaluate the effect of a policy regulating the sale of 1. ICU admission diagnosis is important when
flavored tobacco products. considering sex differences in outcomes from
4. A state-wide ban on the sale of menthol flavored critical illness.
cigarettes and cigars led to a significant net 2. The most significant sex difference in mortality was
reduction in cigarette sales. in the cardiac surgery category (bypass graft and
5. Structural solutions are needed to mitigate health valvular heart surgery).
inequities and improve health. 3. Patients presenting with illnesses less common for
their sex tended to be sicker and more likely to die
than the opposite sex.

Health Equity 84
 Clinical Year in Review

4. This may represent a sex-based volume-outcome 2. Conducted a survey of 350 public and private health
relationship that is mediated by clinician cognitive facilities that queried the type of facility; hours of
bias, in which clinicians treat patients with illnesses operation; availability of inpatient beds, healthcare
expected for their sex more promptly or effectively. personnel, equipment, medications, vaccines; and
implementation of cold-chain protocols.
3. Used a consensus definition to identify facilities
GLOBAL MEDICAL OXYGEN SECURITY that were adequately resourced to manage severe
Simkovich SM, Underhill LJ, Kirby MA, Crocker ME, pediatric pneumonia, which comprised being open
Goodman D, McCracken JP, Thompson LM, Diaz-Artiga A, daily and having overnight beds, an available
Castañaza-Gonzalez A, Garg SS, Balakrishnan K, physician, a pulse oximeter, supplemental oxygen,
Thangavel G, Rosa G, Peel JL, Clasen TF, McCollum ED, respiratory support devices (i.e., non-invasive or
Checkley W; HAPIN Investigators. Resources and invasive mechanical ventilation), X-ray or
Geographic Access to Care for Severe Pediatric ultrasound capacity, and antibiotics.
Pneumonia in Four Resource-limited Settings. Am J 4. Of the facilities surveyed, 13% were adequately
Respir Crit Care Med. 2022 Jan 15;205(2):183-197. doi: resourced to manage severe pneumonia, 37% had
10.1164/rccm.202104-1013OC. PMID: 34662531; PMCID: pulse oximeters, and 44% had supplemental
PMC8787246. oxygen, and mean travel time to an adequately
resourced facility ranged from 31 to 99 minutes
Summary across sites.
5. This article demonstrates highlights an urgent need
Severe cases of pneumonia, such as those marked with
to ensure global medical oxygen security, and
clinical features of hypoxemia, carry the highest risk of
demonstrates the importance of mixed-methods
morbidity and mortality. Early diagnosis and treatment
and qualitative and research for understanding
of severe pneumonia are associated with reduced
mechanisms of health care inequities.
mortality. There are limited data on the geographic
accessibility of facilities that are adequately resourced
OTHER ARTICLES OF INTEREST
to care for severe pediatric pneumonia in low-and
middle-income countries. This is the first study to Agulnik A, Ferrara G, Puerto-Torres M, Gillipelli SR, Elish
characterize the geographic accessibility of adequately P, Muniz-Talavera H, Gonzalez-Ruiz A, Armenta M, Barra
resourced healthcare facilities to manage severe C, Diaz R, Hernandez C, Juárez Tobias S, de Jesus Loeza J,
pediatric pneumonia in low- and middle-income Mendez A, Montalvo E, Penafiel E, Pineda E, Graetz DE.
country settings. The authors found inconsistent levels Assessment of Barriers and Enablers to Implementation
of resources across facilities and significant of a Pediatric Early Warning System in Resource-Limited
heterogeneity in the availability of healthcare Settings. JAMA Netw Open. 2022 Mar 1;5(3):e221547. doi:
personnel, equipment, and medications in non-hospital 10.1001/jamanetworkopen.2022.1547. PMID: 35262714;
facilities. Although most of the population at each site PMCID: PMC8908074.
had access to a facility within 30 minutes of travel time,
few healthcare facilities were adequately resourced to Ashana DC, Jan A, Parish A, Johnson KS, Steinhauser K,
manage severe pneumonia. Expanding the availability Olsen MK, Cox CE. Interpersonal Perception: Family- and
of pulse oximetry devices to all facilities may be an Physician-reported Conflict in the Intensive Care Unit.
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them for care in a timely manner. 35622412.

Comments
1. Utilized the HAPIN (Household Air Pollution
Intervention Network) trial infrastructure with sites
in Guatemala, Peru, Rwanda, and India.

Health Equity 85
 Clinical Year in Review

Bastos LSL, Aguilar S, Rache B, Maçaira P, Baião F, Kim RY, Rendle KA, Mitra N, Saia CA, Neslund-Dudas C,
Cerbino-Neto J, Rocha R, Hamacher S, Ranzani OT, Bozza Greenlee RT, Burnett-Hartman AN, Honda SA, Simoff MJ,
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from inequity in COVID-19 vaccination: An ecological Vachani A. Socioeconomic Status as a Mediator of
analysis of nationwide data from Brazil. Lancet Reg Racial Disparity in Annual Lung Cancer Screening
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35991675; PMCID: PMC9381845. 36306485.

Cheng I, Yang J, Tseng C, Wu J, Shariff-Marco S, Park SL, Kitutu FE, Rahman AE, Graham H, King C, El Arifeen S,
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Lane-Fall MB, Halpern SD. Characterizing Equity of to US Preventive Services Task Force Screening
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environmental injustice and social determinants of 19 Vaccination And Narrower Disparities In US Cities
health on the role of air pollution in asthma and With Paid Sick Leave Compared To Those Without.
allergic disease in the United States. J Allergy Clin Health Aff (Millwood). 2022 Nov;41(11):1565-1574. doi:
Immunol. 2021 Nov;148(5):1089-1101.e5. doi: 10.1377/hlthaff.2022.00779. PMID: 36343316; PMCID:
10.1016/[Link].2021.09.018. PMID: 34743831. PMC9913883.

Fawzy A, Wu TD, Wang K, Robinson ML, Farha J, Bradke A, Schuyler AJ, Wenzel SE. Historical Redlining Impacts
Golden SH, Xu Y, Garibaldi BT. Racial and Ethnic Contemporary Environmental and Asthma-related
Discrepancy in Pulse Oximetry and Delayed Outcomes in Black Adults. Am J Respir Crit Care Med.
Identification of Treatment Eligibility Among Patients 2022 Oct 1;206(7):824-837. doi: 10.1164/rccm.202112-
With COVID-19. JAMA Intern Med. 2022 Jul 1;182(7):730-738. 2707OC. PMID: 35612914; PMCID: PMC9799280.
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PMCID: PMC9257583. Paoletti L, White ES, Palmer SM, Whelan TPM, Dilling DF;
Idiopathic Pulmonary Fibrosis Prospective Outcomes
Hauschildt, K. E. (2022). Whose Good Death? Valuation Registry investigators. Disparities in Lung Transplant
and Standardization as Mechanisms of Inequality in among Patients with Idiopathic Pulmonary Fibrosis: An
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Wei Y, Qiu X, Sabath MB, Yazdi MD, Yin K, Li L, Peralta AA,

Wang C, Koutrakis P, Zanobetti A, Dominici F, Schwartz
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Health Equity 87
 Clinical Year in Review

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis

Simone Visser, MBBS, BPharm, FRACP, PhD
Royal Prince Alfred Hospital
Adult Cystic Fibrosis and Bronchiectasis Service, Department of Respiratory Medicine
Sydney, Australia

REAL-WORLD EXPERIENCE WITH substantial in all subgroups. No new safety signals were
ELEXACAFTOR/IVACAFTOR/TEZACAFTOR MIRRORS observed.
CLINICAL TRIAL EVIDENCE
Nichols, DP, Paynter, AC, Heltshe SL, Donaldson SH,
Frederick CA, Freedman SD, Gelfond D, Hoffman, LR, Comments
Kelly A, Narkewicz MR, Pittman JE, Ratjen F, Rosenfeld M, 1. These data show improvements of a similar
Sagel SD, Schwarzenberg SJ, Singh PK, Solomon GM, magnitude to the RCTs in a real-world setting and
Stalvey MS, Clancy JP, Kirby S, Van Dalfsen, JM, Kloster provide confidence in the generalizability of the RCT
MH, Rowe SM, the Promise Study Group. Clinical findings in a broader population, especially those
effectiveness of elexacaftor/tezacaftor/ivacaftor in with very mild or severe disease who were excluded
people with cystic fibrosis a clinical trial. Am J Respir from the clinical trials.
Crit Care Med. 2022;205(5):529-39. 2. One third of patients had the maximum CFQ-R RD
score at 6 months, suggesting resolution of chronic
Summary respiratory symptoms in many patients on ETI.
In controlled clinical trials, the triple CFTR modulator 3. Despite encouragement to remain on usual therapy,
elexacaftor/tezacaftor/ivacaftor (ETI) resulted in by 6 months, the proportion using dornase alfa
dramatic improvements in FEV1, sweat chloride and decreased by 6%, hypertonic saline by 9.8%,
respiratory symptoms in people with cystic fibrosis azithromycin by 9.1%, and inhaled antibiotics by
(PwCF) and an F508del allele. ETI has the potential to 34%, showing the need for further evidence
treat the majority of PwCF and its use has become regarding safety of cessation of usual therapies.
widespread in many developed countries. The post- 4. Additional 18- and 30-month timepoints are
approval PROMISE study (Prospective Study to Evaluate planned and trial design includes several sub-
Biological and Clinical Effects of Significantly Corrected studies investigating the microbiological and real-
CFTR Function) is being conducted at multiple US sites world extrapulmonary effects of ETI.
and aims to investigate the effectiveness of ETI in a
real-world setting, out to 30 months. The primary REDUCING TREATMENT BURDEN IN THOSE ON CFTR
outcomes are change in sweat chloride and percent- MODULATORS – SAFE IN THE SHORT TERM?
predicted FEV1 (ppFEV1). This planned 6 month interim Mayer-Hamblett N, Ratjen F, Russell R, Donaldson SH,
analysis found that among 487 PwCF ≥12 years with ≥ 1 Riekert KA, Sawicki GS, Odem-Davis K, Young JK,
F508del allele, ppFEV1 improved 9.76% (95% CI 8.76 to Rosenbluth D, Taylor-Cousar JL, Goss CH, Retsch-Bogart
10.76), and sweat chloride decreased by 41.7mmol/L G, Clancy JP, Genatossio A, O'Sullivan BP, Berlinski A,
(95% CI, 43.8 to 39.6). Further, the cystic fibrosis Millard SL, Omlor G, Wyatt CA, Moffett K, Nichols DP,
questionnaire–revised respiratory domain (CFQ-R RD) Gifford AH; SIMPLIFY Study Group. Discontinuation
score improved 20.4 points (95% CI, 18.3 to 22.5, MCID 4). versus continuation of hypertonic saline or dornase
Prespecified subgroup analysis stratified by baseline alfa in modulator treated people with cystic fibrosis
CFTR modulator use (none – 49%; ivacaftor – 7%; dual (SIMPLIFY): results from two parallel, multicentre, open-
modulator – 44%) showed that improvements were label, randomised, controlled, non-inferiority trials.
most pronounced in modulator-naïve patients, but were Lancet Respir Med. 2022:S2213-2600(22)00434-9.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis 88

 Clinical Year in Review

4. The trial intentionally recruited a very adherent

Summary patient group, which does not reflect the real-world
Elexacaftor/tezacaftor/ivacaftor (ETI) substantially situation but strengthens the non-inferiority
restores CFTR protein function and improves findings of the study.
mucociliary clearance, thereby reducing sputum load. 5. This first, important study to examine
In PwCF on ETI, cessation of burdensome nebulized discontinuation of mucoactive treatment in the
therapies has been observed in real-world trials and CFTR modulator era shows that decreasing the
clinical practice, but whether it is safe to stop chronic burden of therapy by stopping either dornase alfa
therapies is unclear. The SIMPLIFY study aimed to or hypertonic saline appears safe in a population
assess the non-inferiority of ceasing either nebulized with mild disease, at least in the short term – the
hypertonic saline or dornase alfa in those on ETI. Two results of HERO-2 and CF STORM are awaited.
parallel, multicentre, open-label, randomised,
controlled trials were conducted at 80 US sites and
included 594 participants ≥12years, on stable therapy PHAGE THERAPY FOR TREATMENT-REFRACTORY
with ETI plus ≥3% hypertonic saline and/or dornase MYCOBACTERIAL INFECTIONS
alfa. Participants were randomly assigned to either Dedrick RM, Smith BE, Cristinziano M, Freeman KG,
continue or cease hypertonic saline or dornase alfa for Jacobs-Sera D, Belessis Y, Whitney Brown A, Cohen KA,
6 weeks. This non-inferiority trial examined whether Davidson RM, van Duin D, Gainey A, Garcia CB, Robert
there was more than a 3% difference in ppFEV1 between George CR, Haidar G, Ip W, Iredell J, Khatami A, Little JS,
groups (continue vs. cease) at 6 weeks. In the per Malmivaara K, McMullan BJ, Michalik DE, Moscatelli A,
protocol population, discontinuing treatment was non- Nick JA, Tupayachi Ortiz MG, Polenakovik HM, Robinson
inferior to continuing treatment in both the hypertonic PD, Skurnik M, Solomon DA, Soothill J, Spencer H, Wark
saline trial (between-group difference in ppFEV1 –0·32% P, Worth A, Schooley RT, Benson CA, Hatfull GF. Phage
[95% CI –1·25 to 0·60]) and dornase alfa trial (between- therapy of mycobacterium infections: compassionate
group difference in ppFEV1 0·35% [95% CI –0·45 to 1·14]). use of phages in 20 patients with drug-resistant
mycobacterial disease. Clin Infect Dis. 2023;76(1):103-112.
Comments
1. Although promising, generalizability to clinical Summary
practice is limited as the trial was of short duration In patients with CF and bronchiectasis, non-tuberculous
and the study population had near-normal lung mycobacterial (NTM) infection is increasingly common
function (mean ppFEV1 of 97%) and minimal and poses a significant treatment challenge due to
symptoms (mean CFQ-R RD >94, maximum possible intrinsic antibiotic resistance. Bacteriophage therapy is
score 100) at baseline. a novel treatment approach and case reports have
2. Lung clearance index at 2·5% of the starting gas suggested a good safety profile and microbiological
concentration (LCI2·5) which is a more sensitive efficacy. However, relatively few active lytic phages are
marker of lung function in people with mild disease available, the variation in phage susceptibility of
was measured in 27% of the study population and mycobacterial isolates necessitates phage
no significant between- group difference was found personalization, and the development of phage
at 6 weeks. resistance or phage-neutralizing antibodies is of
3. No serious adverse events were seen, however potential concern. Dedrick et al. present their
there were more respiratory adverse events in experience of compassionate phage therapy in 20
patients who discontinued mucoactive therapies patients with treatment-refractory NTM. Of 200
(~2-fold increase in those who discontinued mycobacterial isolates received from culture-positive
dornase alfa; ~1·5-fold in those who discontinued patients, lytic phage/s were identified for 55 patients.
hypertonic saline), particularly in the small Patients eligible for treatment were those >5yrs with
subgroup of patients with ppFEV1 below 70. NTM-pulmonary disease or disseminated disease, with

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis 89

 Clinical Year in Review

failure or intolerance of antimycobacterial therapy. Summary

Ultimately, 20 patients received phage therapy Inhaled antibiotics in patients with bronchiectasis have
(predominantly intravenously +_ aerosolized/topical) in been shown to provide a modest reduction in
combination with at least 2 appropriate exacerbation frequency in meta-analyses and are
antimycobacterial drugs for a planned duration of 6 recommended in international guidelines for select
months, although this was individualized depending on patients with frequent exacerbations. However,
clinical and microbiological response. Favourable individual RCT results have often not reached statistical
clinical or microbiological response was observed in 11 significance for the clinical endpoints. The TORNASOL
patients (of whom 5 had sustained negative (Tobramycin in Bronchiectasis Colonized With
mycobacterial cultures and 1 underwent successful lung Pseudomonas aeruginosa) study aimed to evaluate
transplantation); 5 had inconclusive results; 4 had no safety and efficacy of tobramycin inhalation solution
response. No phage-attributable adverse reactions were (TIS) in adults with bronchiectasis and chronic P.
noted. aeruginosa infection. This 16-week multicentre study
included 339 participants who received randomised
Comments treatment with either nebulized TIS or normal saline, for
1. Of the 20 patients offered treatment, 17 had M. 2 cycles of 28 days on/28 days off. The coprimary end
abscessus infection and 14 had underlying cystic points were change in P. aeruginosa density and
fibrosis. Quality-of-Life Bronchiectasis Respiratory Symptoms
2. A favourable response was defined as score (QoLB-RSS) on day 29, compared to baseline. On
mycobacterial smear and culture conversion to day 29, TIS significantly reduced P. aeruginosa density
negative in at least 1 relevant specimen and clinical (adjusted mean difference 1.74 log10 colony-forming
and/or radiographic improvement, or resolution of units/g; 95% CI 1.12-2.35) and improved QoLB-RSS
signs and symptoms of infection after at least 6–8 (adjusted mean difference 7.91; 95% CI 5.72-10.11) which
weeks of phage treatment. was statistically significant but fell short of the
3. No phage resistance was detected, even in 11 minimum clinically important difference of 8. TIS also
patients who received therapy with a single phage. resulted in improved sputum volume and purulence.
4. Neutralizing antibodies were identified in the sera Discontinuations due to adverse events were 6.2% and
of 8 patients after IV administration but did not 2.8% in the TIS and control groups. Serious adverse
always result in an unfavourable response. events were comparable across groups.
5. This large case series demonstrates the potential of
phage therapy for refractory NTM disease and Comments
highlights ongoing questions around 1. TORNASOL represents that largest clinical trial of
pharmacodynamics, tissue penetration, optimal nebulized tobramycin conducted, however again
dose and route of administration for phage therapy. does not provide definitive data around its clinical
endpoint.
2. Generalizability is limited - the trial population
NEBULIZED TOBRAMYCIN IN BRONCHIECTASIS were relatively younger Chinese patients with a
Guan WJ, Xu JF, Luo H, Xu XX, Song YL, Ma WL, Liang ZA, median of 2 exacerbations in the preceding 2 years
Liu XD, Zhang GJ, Zhang XJ, Li RK, Zhu SY, Zhang YJ, Cai XJ, i.e., not the frequent exacerbator phenotype that
Wei LP, Tian DB, Zhao H, Chen PY, Qu JM, Zhong NS; would usually be considered for inhaled antibiotic
TORNASOL Study Group. A double-blind randomized therapy.
placebo-controlled phase 3 trial of tobramycin 3. No differences in exacerbation frequency were seen
inhalation solution in adults with bronchiectasis with in the trial population within the short duration of
Pseudomonas aeruginosa infection. Chest. this trial.
2023;163(1):64-76.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis 90

 Clinical Year in Review

4. Tobramycin-resistant strains were isolated in 5.4% performed to delineate the effect of tiotropium
of the TIS groups vs 0% of the control group at day when used alone vs. in combination.
29. 3. The clinical relevance of a 58mL improvement in
FEV1 is uncertain; the MCID for FEV1 in COPD is
THE FIRST LARGE CLINICAL TRIAL OF INHALED 100mL however the MCID for FEV1 in bronchiectasis
BRONCHODILATOR IN BRONCHIECTASIS has not yet been determined.
Jayaram L, Vandal AC, Chang CL, Lewis C, Tong C, Tuffery 4. This is the first large RCT of bronchodilator in
C, Bell J, Fergusson W, Jeon G, Milne D, Jones S, Karalus patients with bronchiectasis and demonstrates that
N, Hotu S, Wong C. Tiotropium treatment for further studies are required to determine which
bronchiectasis: a randomised, placebo-controlled, phenotypes may benefit from tiotropium.
crossover trial. Eur Respir J. 2022;59(6):2102184.
BRONCHIECTASIS – IT’S NOT ALL ABOUT NEUTROPHILS
Summary Shoemark A, Shteinberg M, De Soyza A, Haworth CS,
The efficacy of bronchodilators in patients with Richardson H, Gao Y, Perea L, Dicker AJ, Goeminne PC,
bronchiectasis has not been studied in large clinical Cant E, Polverino E, Altenburg J, Keir HR, Loebinger MR,
trials and although they are commonly prescribed, the Blasi F, Welte T, Sibila O, Aliberti S, Chalmers JD.
routine use of bronchodilators is not supported by Characterization of eosinophilic bronchiectasis: a
current bronchiectasis treatment guidelines. The European multicohort study. Am J Respir Crit Care Med.
antimuscarinic agent tiotropium results in 2022;205(8):894-902.
bronchodilation and reduced submucosal gland
secretion, providing a rationale for its use in Summary
bronchiectasis. This randomized, double-blind, placebo- A subset of patients with bronchiectasis and sputum
controlled, crossover trial aimed to evaluate the effect eosinophilia has recently been recognised, but is not
of 6 months of inhaled tiotropium therapy on the rate well characterized. It is unclear whether blood and
of exacerbations. Ninety adults with bronchiectasis, sputum eosinophil counts are correlated and whether
airflow limitation and ≥1 exacerbation in the previous eosinophilia is useful prognostically in patients with
year were randomised. Smokers with a >20pack-year bronchiectasis. To answer these questions, the authors
history and/or those with a primary diagnosis of used data from 5 existing bronchiectasis cohorts, and
asthma were not eligible. Results for the primary excluded those with asthma and allergic
endpoint showed that tiotropium did not reduce bronchopulmonary aspergillosis. In 2 independent UK
exacerbations; exacerbation rate on tiotropium was cohorts (Dundee n=123, Newcastle n=112) a statistically
2.17/year vs. 2.27/year on placebo (rate ratio 0.96, 95% significant correlation between blood and sputum
CI 0.72–1.27). Tiotropium improved FEV1 by 58mL (95% CI eosinophil counts was found. Analysis of the sputum
23–92mL) but did not improve symptoms, 6-minute walk microbiome in a cohort of 198 patients from the UK,
distance, or change neutrophil or eosinophil counts in Spain and Italy showed that high blood eosinophil
blood or sputum. Tiotropium was well tolerated. counts (BEC) ≥300 cells/μl were associated with
Streptococcus and Pseudomonas-dominated
Comments microbiome profiles. Analysis of EMBARC FRIENDS
1. At baseline, participants had mild symptoms and a (Facilitating Research into Existing National Datasets,
normal/near normal exercise capacity, therefore n=951) cohort data showed no relationship between BEC
the results cannot be generalized to very breathless and exacerbations. However, when the presence of
bronchiectasis patients and it may be these infection was controlled (via post hoc analysis of data
patients who stand to benefit most. from the PROMIS- Inhaled Promixin in the Treatment of
2. Almost half of participants (47%) were on LABA or Non–Cystic Fibrosis Bronchiectasis trial– wherein all
LABA/ICS throughout the trial, however due to small patients had chronic Pseudomonas) BEC >100 cells/μl
numbers, subgroup analysis was not able to be was associated with shorter time to exacerbation (n =

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis 91

 Clinical Year in Review

144, BEC 100–299 cells/μl HR 2.38; 95% CI 1.33–4.25 and

BEC ≥300 cells/μl HR 3.99; 95% CI 2.20–7.85). Ramos KJ, Guimbellot JS, Valapour M, Bartlett LE, Wai TH,
Goss CH, Pilewski JM, Faro A, Diamond JM; CFLTC Study
Comments Group. Use of elexacaftor/tezacaftor/ivacaftor among
1. The correlation between blood and sputum cystic fibrosis lung transplant recipients. J Cyst Fibros.
eosinophil counts was weak to moderate (r=0.31; 2022;21(5):745-752.
P=0.0001) but of a similar strength to that which is
accepted in COPD and asthma cohorts, therefore Martin C, Reynaud-Gaubert M, Hamidfar R, Durieu I,
validating BEC as a surrogate of airway eosinophilia Murris-Espin M, Danner-Boucher I, Chiron R, Leroy S,
in bronchiectasis. Douvry B, Grenet D, Mely L, Ramel S, Montcouquiol S,
2. Across all the cohorts studied, eosinophilic Lemonnier L, Burnet E, Paillasseur JL, Da Silva J, Burgel
bronchiectasis (BEC 300 cells/μl) was relatively PR. Sustained effectiveness of elexacaftor-tezacaftor-
common, affecting ~20% of patients. ivacaftor in lung transplant candidates with cystic
3. After controlling for the confounder of infection, fibrosis. J Cyst Fibros. 2022;21(3):489-496.
high BEC predicted exacerbations, however whether
this would be true in patients without or with Szentpetery S, Foil K, Hendrix S, Gray S, Mingora C, Head
pathogens other than pseudomonas is unclear; B, Johnson D, Flume PA. A case report of CFTR
there is an incompletely understood interaction modulator administration via carrier mother to treat
between inflammation, patient microbiology and meconium ileus in a F508del homozygous fetus. J Cyst
outcomes. Fibros. 2022;21(4):721-724.
4. Eosinophilia may represent a therapeutic target in
bronchiectasis; the Phase 3 MAHALE Study CARDIOMETABOLIC RISK IN CF
(NCT05006573) will investigate the efficacy and Szentpetery S, Fernandez GS, Schechter MS, Jain R,
safety of benralizumab in patients with Flume PA, Fink AK. Obesity in Cystic fibrosis: prevalence,
bronchiectasis and eosinophilia and further trends and associated factors data from the US cystic
characterize bronchiectasis endotypes. fibrosis foundation patient registry. J Cyst Fibros.
2022;21(5):777-83.

OTHER ARTICLES OF INTEREST Petersen MC, Begnel L, Wallendorf M, Litvin M. Effect of

elexacaftor-tezacaftor-ivacaftor on body weight and
GENOTYPE-AGNOSTIC TREATMENTS FOR ALL PATIENTS
metabolic parameters in adults with cystic fibrosis. J
WITH CF
Cyst Fibros. 2022;21(2):265-71.
Amaral MD, Harrison PT. Development of novel
therapeutics for all individuals with CF (the future goes
MANAGEMENT OF CF PULMONARY EXACERBATIONS
on). J Cyst Fibros. 2023;22 Suppl 1:S45-S49.
VanDevanter DR, West NE, Sanders DB, Skalland M, Goss
CH, Flume PA, Heltshe SL. Antipseudomonal treatment
CFTR MODULATORS
decisions during CF exacerbation management. J Cyst
Southern, K. W., Castellani, C., Lammertyn, E., Smyth, A.,
Fibros. 2022;21(5):753-758.
VanDevanter, D., van Koningsbruggen-Rietschel, S.,
Barben, J., Bevan, A., Brokaar, E., Collins, S., Connett, G. J.,
Sanders DB, Khan U, Heltshe SL, Skalland M, West NE,
Daniels, T. W. V., Davies, J., Declercq, D., Gartner, S.,
VanDevanter DR, Goss CH, Flume PA; STOP2
Gramegna, A., Hamilton, N., Hauser, J., Kashirskaya, N.,
Investigators. Association of site of treatment with
Kessler, L., … Duff, A. (2023). Standards of care for CFTR
clinical outcomes following intravenous antimicrobial
variant-specific therapy (including modulators) for
treatment of a pulmonary exacerbation. J Cyst Fibros.
people with cystic fibrosis. Journal of cystic fibrosis :
2022;21(4):574-580.
official journal of the European Cystic Fibrosis Society,
22(1), 17–30. [Link]

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COVID-19 and CF Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq

Doumit M, Chuang S, Middleton P, Selvadurai H, Sivam S, A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M,
Ruseckaite R, Ahern S, Mallitt KA, Pacey V, Gray K, Jaffe A. Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A,
Clinical outcomes of adults and children with cystic Welland MJ, Williams E, Witkowska K, Wood SM. Genome
fibrosis during the COVID-19 pandemic. J Cyst Fibros. sequencing reveals underdiagnosis of primary ciliary
2022:S1569-1993(22)00685-3. dyskinesia in bronchiectasis. Eur Respir J.
2022;60(5):2200176.
NTM
Lange C, Böttger EC, Cambau E, Griffith DE, Guglielmetti Hannah WB, Seifert BA, Truty R, Zariwala MA, Ameel K,
L, van Ingen J, Knight SL, Marras TK, Olivier KN, Santin M, Zhao Y, Nykamp K, Gaston B. The global prevalence and
Stout JE, Tortoli E, Wagner D, Winthrop K, Daley CL; ethnic heterogeneity of primary ciliary dyskinesia gene
expert panel group for management recommendations variants: a genetic database analysis. Lancet Respir
in non-tuberculous mycobacterial pulmonary diseases. Med. 2022;10(5):459-468.
Consensus management recommendations for less
common non-tuberculous mycobacterial pulmonary ENDOTYPING & THE GUT-LUNG AXIS IN BRONCHIECTASIS
diseases. Lancet Infect Dis. 2022;22(7):e178-e190. Huang JT, Cant E, Keir HR, Barton AK, Kuzmanova E,
Shuttleworth M, Pollock J, Finch S, Polverino E, Bottier M,
PRIMARY CILIARY DYSKINESIA UNDER-DIAGNOSED Dicker AJ, Shoemark A, Chalmers JD. Endotyping chronic
Shoemark A, Griffin H, Wheway G, Hogg C, Lucas JS; obstructive pulmonary disease, bronchiectasis, and the
Genomics England Research Consortium; Camps C, "chronic obstructive pulmonary disease-bronchiectasis
Taylor J, Carroll M, Loebinger MR, Chalmers JD, Morris- association". Am J Respir Crit Care Med. 2022;206(4):417-
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