34. Fellows’ Case Files: The Ohio State University College of Medicine

Welcome back to Pulm PEEPs Fellows’ Case Files series. We are traveling to the midwest to visit The Ohio State University College of Medicine and hear about another great pulmonary case.

Meet Our Guests

Kashi Goyal is a second-year Pulmonary and Critical Care Fellow at The Ohio State University Wexner Medical Center. She obtained her MD at OSU, and then completed her Internal Medicine residency at Beth Israel Deaconess Medical Center. She worked as a hospitalist and educator before going back to fellowship and remains passionate about medical education.

Lynn Fussner is an Associate Professor of Internal Medicine at OSU and has been there since completing her fellowship and Post-doctorate at Mayo Clinic. In addition to her clinical work in the multidisciplinary vasculitis clinic, she is a translational researcher with a focus on inflammatory pulmonary disorders and vasculitis.

Avi Cooper is an Assistant Professor of Medicine at Ohio State University College of Medicine and the Program Director of the Pulmonary and Critical Care Fellowship. He is an Associate Editor at the Journal of Graduate Medical Education. Last but not least, he co-hosts the Curious Clinician Podcast, one of the most popular medical education podcasts.

Patient Presentation

Key Learning Points

**Spoilers Ahead** If you want to think through the case on your own we advise listening to the episode first before looking at these points.

  • The three most common causes of cough in adults in the USA are cough variant asthma, GERD, and post-nasal drip
  • A post-viral cough can last for 8-12 weeks and still be within normal
  • Sinus symptoms in a chronic cough can just be sinusitis and post-nasal drip, but should consider eosinophilic granulomatosis with polyangiitis (EGPA), aspirin exacerbated respiratory disease (AERD), cystic fibrosis, or ciliary dyskinesia.
  • Examination of a wheeze
    • Fixed sound vs variable
    • Pitch: larger central airways vs lower peripheral airways
    • Is it throughout the cycle or at a certain phase?
    • Ask the patient to cough before listening and ask them to breathe out through their mouth
  • Approach to eosinophilia in a patient with cough and dyspnea
    •  Multi-system involvement vs lungs
      • Multi-system involvement
        • Vasculitis
        • Parasitic infection
        • Hematologic malignancy
        • Medication side effect
        • Primary hypereosinophilic syndromes
      • Within the lungs:
        • Parenchymal disease
          • Loeffler’s syndrome
          • Eosinophilic pneumonia
        • Airway disease
          • Asthma
          • ABPA
  • If you have a high suspicion for airways disease, PFTs should be requested with bronchodilator testing regardless of the degree of obstruction on baseline spirometry
  • Asthma alone should not cause ground glass opacities, so if see these in a patient with asthma we think about:
    • Infection, especially atypical infections
    • EGPA
    • Vasculitis with DAH
    • ABPA
    • Hypogammaglobulinemia or other immunodeficiency
  • EGPA diagnosis
    • ANCA testing is only positive in 60% of patients with EGPA so a negative test doesn’t rule it out by any means
    • It is easiest to make a diagnosis when there is a clear small vessel manifestation
      • Alveolar hemorrhage
      • Mononeuritis multiplex
      • Glomerulonephritis
    • Many patients with asthma, nasal polyposis, and high peripheral eosinophilia have EGPA but don’t have a clear small vessel feature of vasculitis or a positive ANCA
      • These patients typically have eosiniophilia a lot higher than when thinking about allergic phenotype asthma alone. As a rule of thumb, at least an absolute eosinophil count > 1000

References and Further Reading

  1. Carr TF, Zeki AA, Kraft M. Eosinophilic and Noneosinophilic Asthma. Am J Respir Crit Care Med. 2018;197(1):22-37. doi:10.1164/rccm.201611-2232PP
  2. Cottin V. Eosinophilic Lung Diseases. Clin Chest Med. 2016;37(3):535-556. doi:10.1016/j.ccm.2016.04.015
  3. Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis. Ann Rheum Dis. 2022;81(3):309-314. doi:10.1136/annrheumdis-2021-221794
  4. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. New England Journal of Medicine. 2017;376(20):1921-1932. doi:10.1056/NEJMoa1702079

33. Lung and Diaphragm Protective Ventilation Roundtable

Today the PulmPEEPs are discussing Lung and Diaphragm Protective Ventilation with two experts in the field. We are joined by Dr. Jose Dianti and Dr. Ewan Goligher.

Meet Our Guests

Dr. Jose Dianti is a clinical and research fellow at the University of Toronto and University Health Network. He completed his residency in Critical Care and worked as a critical care attending previously at the Hospital Italiano in Buenos Aires, Argentina. He is particularly interested in ventilator induced lung injury and personalized ventilation strategies. Dr. Ewan Goligher is an Assistant Professor at the University of Toronto and University Health Network, and is a world renowned researcher in the mechanisms of ventilator induced lung and diaphragm injury.

32. VV-ECMO Roundtable

For the first Pulm PEEPs episode of 2023, we are starting off with a bang and a Roundtable discussion about venovenous extracorporeal membrane oxygenation (VV-ECMO). VV-ECMO has been increasing in use in the intensive care unit for patients with severe respiratory failure, especially during the COVID-19 pandemic. We are joined by experts in the field, Cara Agerstrand, Eddy Fan, and Nida Qadir, to discuss the basics of how ECMO works, physiologic goals, when to use ECMO for patients with ARDS, and much more. Let us know your thoughts and stay tuned for more great content in 2023.

Meet Our Guests

Cara Agerstrand is an Associate Professor of Medicine at Columbia University Irving Medical Center / NewYork-Presbyterian Hospital, where she is also the Director of the Medical ECMO Program. She is an international renown ECMO expert and is the current Conference Chair for the Extracorporeal Life Support Organization (or ELSO). Finally, she is a lauded educator and has received the American College of Chest Physicians Distinguished Educator Award.

Eddy Fan is an Associate Professor at the University of Toronto, and the University Health Network / Mount Sinai Hospital. He is also the Director of Critical Research and the Medical Director of the Extracorporeal Life Support Program. He has literally 100s of publications about ARDS, ECMO, and critical care, chairs the ELSO Research Committee, and spearheads multiple international collaborative studies.

Nida Qadir is an Associate Professor at the University of California Los Angeles and is an Associate Director of the MICU, as well as the co-director of the Post-ICU Recovery Clinic. Nida is also on the Critical Care Editorial Board for CHEST and is a highly regarded pulmonary and critical care educator.

Key Learning Points

VV- ECMO Basic Components and Core Physiology

Oxygenation Delivery on VV-ECMO

Carbon Dioxide Removal on VV-ECMO

Flows and Line Pressures on VV-ECMO

ECMO for ARDS

  • Should be considered after conventional therapies have failed (including ventilator optimization and proning)
  • Allows for ultra-lung protective ventilation
  • Lung rest means settings that minimize ventilator-induced lung injury
  • EOLIA Trial (see below) shows that ECMO can be delivered safely, and likely has a benefit in severe ARDS, although the magnitude of that benefit remains uncertain. A Bayesian re-analysis showed a high likelihood of benefit even if skeptical of ECMO

ECMO For Bridge to Lung Transplant

  • Allows for patients to maintain gas exchange while awaiting transplant
  • Ideally done with patient extubated
  • Can allow for patients to maintain nutrition and mobility while awaiting transplant

References and Further Reading

  1. Brodie D, Bacchetta M. Extracorporeal Membrane Oxygenation for ARDS in Adults. N Engl J Med. 2011;365(20):1905-1914. doi:10.1056/NEJMct1103720
  2. Munshi L, Brodie D, Fan E. Extracorporeal Support for Acute Respiratory Distress Syndrome in Adults. NEJM Evidence. 2022;1(10):EVIDra2200128. doi:10.1056/EVIDra2200128
  3. Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2018;378(21):1965-1975. doi:10.1056/NEJMoa1800385
  4. Goligher EC, Tomlinson G, Hajage D, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial. JAMA. 2018;320(21):2251-2259. doi:10.1001/jama.2018.14276
  5. Erdeneochir E, Strunina S. Analysis of blood flow in extracorporeal membrane oxygenation circuit. Published online 2017.
  6. Schmidt M, Pham T, Arcadipane A, et al. Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort. Am J Respir Crit Care Med. 2019;200(8):1002-1012. doi:10.1164/rccm.201806-1094OC
  7. Tonna JE, Abrams D, Brodie D, et al. Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO). ASAIO Journal. 2021;67(6):601-610. doi:10.1097/MAT.0000000000001432
  8. Hayanga JWA, Hayanga HK, Holmes SD, et al. Mechanical ventilation and extracorporeal membrane oxygenation as a bridge to lung transplantation: Closing the gap. J Heart Lung Transplant. 2019;38(10):1104-1111. doi:10.1016/j.healun.2019.06.026

31. Last Night in the ICU

Today we have a Pulm PEEPs special episode! Dave and Kristina chat post-call about their respective nights in the ICU. Hear about clinical reasoning on the fly, some crucial learning points, insights on procedural troubleshooting, and about the value of end-of-life discussions. The post-call brain fog and jokes only add to the learning fun!

References and Further Reading

Stein PD, Yaekoub AY, Matta F, Kleerekoper M. Fat embolism syndrome. Am J Med Sci. 2008 Dec;336(6):472-7. doi: 10.1097/MAJ.0b013e318172f5d2. PMID: 19092320.

Kainoh T, Iriyama H, Komori A, Saitoh D, Naito T, Abe T. Risk Factors of Fat Embolism Syndrome After Trauma: A Nested Case-Control Study With the Use of a Nationwide Trauma Registry in Japan. Chest. 2021 Mar;159(3):1064-1071. doi: 10.1016/j.chest.2020.09.268. Epub 2020 Oct 13. PMID: 33058815.

Lara AR, Schwarz MI. Diffuse alveolar hemorrhage. Chest. 2010 May;137(5):1164-71. doi: 10.1378/chest.08-2084. PMID: 20442117.

30. Fellows’ Case Files: University of Mississippi Medical Center

We’re excited to be back with another episode in our Pulm PEEPs Fellows’ Case Files series! This is a particularly exciting case since it is our first episode where some intrepid fellows reached out to us with an interesting case they had encountered. If you have a great case, please let us know and you can follow in their footsteps! Pack your bags, and let’s head to Mississippi to learn about another great pulmonary and critical care case.

Meet our Guests

Meredith Sloan is a pulmonary and critical care fellow at the University of Mississippi. She completed her medical school at the Medical University of South Carolina College of Medicine, and her residency at the University of Mississippi.

Kevin Kinloch is a senior fellow at the University of Mississippi Medical Center where he also completed his internal medicine residency. He completed medical school at Meharry Medical College.

Jessie Harvey is an Associate professor of Medicine at the University of Mississippi and is the Pulmonary and Critical Care Program Director. She is also the Director of the MICU, and has been at MMC since medical school. She is a dedicated educator and leads the POCUS curriculum for IM residents and PCCM fellows

Patient Presentation

A 65-year-old man presented to the ED with worsening hemoptysis over the last several days after a recent lung biopsy. The patient is an active smoker with at least a 50-pack-year history, and he had been having a cough with small-volume hemoptysis. He ultimately had a chest CT that revealed a large LUL mass (10.3 x 6.4 cm). Given this suspicious mass, three days prior to his ED presentation, he was taken for bronchoscopy with BAL, transbronchial biopsies, endobronchial biopsy, EBUS guided TBNA of 11L, along with TBNA, brushing and radial EBUS TBNA of his left upper lobe mass.

Key Learning Points

**Spoilers Ahead** If you want to think through the case on your own we advise listening to the episode first before looking at these points.

Staging procedures for masses

  • Enough tissue so we can make a diagnosis and do molecular testing
  • Highest staging when getting your biopsy

POCUS for respiratory failure

  • Absence of lung slidings
    • Especially post procedure
  • The presence of a new pleural effusion after a procedure could indicate hemothorax
    • Hematocrit sign – an echogenic layering of material in an effusion
  • New B-lines, especially if prior there were only A-lines
    • Cardiogenic or non-cardiogenic pulmonary edema, alveolar hemorrhage, or infection
  • Diaphragmatic function
    • Excursion
    • Diaphragm thickness

References and Further Reading

1.Scorsetti M, Leo F, Trama A, D’Angelillo R, Serpico D, Maerelli M, Zucali P, Gatta G, Garassino MC. Thymoma and thymic carcinomas. Critical Reviews in Oncology/Hematology. 2016; 99:332-350.

2. Singh TD, Wijdicks EFM. Neuromuscular respiratory failure. Neurol Clin 2021; 39:333-353.

29. Long COVID Roundtable

This week on Pulm PEEPs, Dave and Kristina are joined by Jason Maley and Ann Parker, two pulmonary and critical care physicians who are leaders in treating patients with Long COVID, or Post-Acute Sequelae of SARS-CoV-2. Both of them help run the Long COVID clinics at their respective institutions and are part of broader consortiums dedicated to patient care. They also both participate in research to improve outcomes for patients with Long COVID and Post-Intensive Care Syndrome. In this conversation, we cover the diagnosis of Long COVID, common symptoms, abnormal test findings, possible mechanisms of disease, the impacts of variants and vaccines, treatments, and the natural history of this condition. We hope this will be helpful for providers, patients, and family members.

Meet Our Guests

Jason Maley is an Assistant Professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. He is the Director of the BIDMC Critical Illness and COVID-19 Survivorship Program, and the Co-Chair of the American Academy of Physical Medicine and Rehabilitation Postacute Sequeleae of SARS-CoV-2 infection (PASC) initiative. He is NIH funded to study post-COVID patients.

Ann Parker is an Assistant Professor of Medicine at Johns Hopkins and is the Co-Director of the Johns Hopkins Post-Acute COVID-19 team. She is NIH funded with her research focusing on survivors of respiratory failure and critical illness.

Key Learning Points

Long COVID or Post-Acute Sequelae of SARS-CoV-2 or Post-COVID condition

  • Long COVID was first described this way by patients so this is the common nomenclature that is used. It is also referred to as Post-Acute Sequelae of SARS-CoV-2 or Post-COVID condition
  • Defined by patients that have not returned to their baseline health 3 months after their acute episode of COVID-19
  • Major organizations in describing this disease and doing research are:
    • World Health Organization
    • Multiple patient-led organizations
    • CDC – INSPIRE
    • NIH – RECOVER

Post-COVID Clinic

  • Seeing patients across the spectrum of illness. Not all patients had to be critically ill or hospitalized
    • The standard patient has changed over time and now the vast majority had a mild initial illness, but afterward had unusual and persistent symptoms
  • Patients are generally referred by their PCP or self-referred
  • The criteria for being seen in clinic are very loose to make sure patients are not excluded
    • Many patients do not have a confirmed case of COVID since patients early in the pandemic often did not have a positive test available, and now many people are testing positive at home
  • Initial records review to make sure that can help patients
  • Standardized questionnaires
    • Screening for physical impairment, mental health impairment, and cognitive impairment
  • Rehabilitation and multi-disciplinary based approach
  • It is extremely important to be aware of the bias in patient populations in Post-COVID clinics
    • The population that can make it to clinic may not, and does not, represent all patients who have had COVID or have Long COVID. Patients may be limited in their ability to get to clinic based on their physical condition, financial resources, location, support, and language barriers.

Overlap of Long COVID and PICS

  • These conditions are very similar and certainly have a lot of overlap
  • For patients coming out of the ICU, screening should start with looking for known PICS symptoms.
    • These domains are mental health, physical impairment, and cognitive function
  • There may be some unique aspects, such as:
    • Severe persistent fatigue
    • Extreme changes in taste and smell

Common symptoms

  • Many symptoms are complex and multifactorial
  • Neuropsycholgoicl impairment – termed “brain fog”
    • Difficulty with concentration, and cognition
  • Anxiety
  • Depression
  • Persistent shortness of breath
    • Dyspnea can be reported even with just talking for long periods of time
    • “Deep breaths are just not satisfying”
  • Cough
  • Chest pain
  • Dysautonomia
    • Palpitations, dizziness, orthostasis
  • Fatigue
  • Post-exertional malaise
  • Cognitive blunting or “brain fog”
  • Changes in sleep
  • Headaches

Common findings on testing in patients with Long COVID

  • Shortness of breath
    • Some may have impaired diffusion (low DLCO) on PFTs
    • However, often patients have normal or near-normal PFTs
    • 10 – 20 % have air trapping on inspiratory/expiratory chest CTs that could indicate bronchiolitis
    • One study showed that CPETs showed impaired oxygen extraction
      • Preserved cardiac output to exercise and no evidence of deconditioning
      • This study indicated an issue at the peripheral level (ex: vascular, mitochondrial) with oxygen extraction.

Variants

  • It is very difficult to say if variants differ in rates of Long COVID given that often patients do not get sequencing to know the variant and because there is overlap in the timing of variants
  • Further testing will continue on this going forward

Vaccines

  • Reduced risk of Long COVID with vaccination
    • Boosting further decreases the risk compared to just the initial vaccination
  • There is a variable response to getting vaccinated if a patient has Long COVID
    • Most patients tolerate it well and some patients have relief of symptoms
    • There are some patients who can develop worsened Long COVID symptoms

References and further reading

  1. Chippa V, Aleem A, Anjum F. Post Acute Coronavirus (COVID-19) Syndrome. In: StatPearls. StatPearls Publishing; 2022. Accessed November 14, 2022. http://www.ncbi.nlm.nih.gov/books/NBK570608/
  2. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid—mechanisms, risk factors, and management. BMJ. 2021;374:n1648. doi:10.1136/bmj.n1648
  3. Durstenfeld MS, Sun K, Tahir P, et al. Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis. JAMA Network Open. 2022;5(10):e2236057. doi:10.1001/jamanetworkopen.2022.36057
  4. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-615. doi:10.1038/s41591-021-01283-z
  5. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. doi:10.1016/S1473-3099(21)00703-9
  6. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y

28. Fellows’ Case Files: Harvard – MGH & BIDMC

Welcome back to our Pulm PEEPs Fellows’ Case Files series! We are joined this week by a fellow and the program director from the Harvard combined PCCM fellowship at Massachusettes General Hospital and Beth Israel Deaconess Medical Center. Listen in for a great learning case and let us know on Twitter, if you have a great case to share!

Meet our Guests

Brian Rosenberg is a third year fellow at the Harvard MGH/BI program. He completed his undergraduate degree at Harvard, received his MD  from Yale where he also got a PhD in cell biology, and then did his internal medicine residency at Columbia University Medical Center in NYC.

Asha is an Assistant Professor Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, and is the Program Director of the Harvard MGH/BI combined fellowship. She is also the Director of the Pulmonary Consult Service at BIDMC, was a Rabkin Fellow in Medical Education and has received multiple leadership and teaching awards

27. Live from CHEST 2022

We are thrilled today here at Pulm PEEPs to be coming to you live from the CHEST 2022 Annual Meeting. We are joined by three fantastic speakers, and CHEST leaders to discuss the highlights and events of the conference, and to share some great learning points along the way. The episode is being released immediately after recording this morning, Monday 10/17/22, so if you’re at the conference now make sure to listen for some extremely timely recommendations. If you’re not here in Nashville, we’ve highlighted some learning points that you can take away and some wisdom on how to maximize your conference experience for the next time!

Meet Our Guests

Subani Chandra is an Associate Professor at Columbia University. She is the Vice Chair of Medicine for Education and the internal medicine residency program director. She is also the incoming Chair of the Training and Transitions Committee at CHEST, and the chair of the CHEST Scientific Program Committee for CHEST 2022.

Matt Siuba is an Assistant Professor of Medicine and intensivist at the Cleveland Clinic, where he is the associate program director for the Critical Care Medicine fellowship. He founded and runs the website Zentensivist.com, and is well known as a fantastic educator both in person via many different online formats.

Todd Rice is an Associate Profess of Medicine at Vanderbilt University, where he is also the Medical Director of the ICU. In addition, he is the Vice President for Clinical Trial Innovation and Operations in the Vanderbilt Institute for Clinical and Translational Research. He is also a past president of The American Society of Parenteral and Enteral Nutrition, and most relevant to today, the Associate Editor of Critical Care for Chest.

26. A Case of AMS, Renal Failure, and Hemolysis

This week on Pulm PEEPs, we have another great case episode. We’re switching up the format a bit, and instead of introducing our guests in the beginning, we’ll bring them in consultants as we need to. Luckily, we’re joined by Pulm PEEPs Associated Editor Luke Hedrick to walk us through the case. Let us know your thoughts and if you have any other pearls to add!

Meet Our Guests

Rakhi Naik an Associate Professor of Medicine at Johns Hopkins Hospital and the Associate Director for the Hematology / Oncology Fellowship program. She also has a Masters in Health Sciences from the Johns Hopkins Bloomberg School of Public Health. She has expertise in an array of non-malignant hematology disorders and focuses specifically on sickle cell in her research. She is also an outstanding and dedicated educator and serves as the Chair of the American Society of Hematology Hematology-Focused Training Program Consortium to develop innovative training pathways for non-malignant heme.

Patient Presentation

A 60-year-old woman with a past medical history of hypertension, diabetes, stage 4 chronic kidney disease, COPD, HFpEF, chronic pain on methadone, hyperparathyroidism s/p parathyroidectomy that was c/b hypothyroidism now on thyroid hormone replacement, and a recent admission for nonconvulsive status epilepticus is brought to an outside hospital by EMS with encephalopathy and shaking. 

When EMS gets her to the other hospital her GCS was 5, so she was intubated for airway protection and started on fentanyl and midazolam drips. Details of labs and imaging are scarce, but we know that she had a CT head that was normal, a CXR with a report of pulmonary edema, and labs with a Cr of 2.4, serum bicarbonate of 14, and a pH from a VBG of 7.1 with pCO2 of 38.

Key Learning Points

*Spoilers ahead* The infographic below highlighting key points gives away the diagnosis in this case so if you want to work through the case on your own, we recommend listening to the episode first.

References and further reading

  1. George JN. Thrombotic Thrombocytopenic Purpura. New England Journal of Medicine. 2006;354(18):1927-1935. doi:10.1056/NEJMcp053024
  2. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846. doi:10.1182/blood-2016-10-709857
  3. Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers. 2017;3(1):1-17. doi:10.1038/nrdp.2017.20
  4. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. New England Journal of Medicine. 2019;380(4):335-346. doi:10.1056/NEJMoa1806311
  5. Sukumar S, Lämmle B, Cataland SR. Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management. J Clin Med. 2021;10(3):536. doi:10.3390/jcm10030536

25. ARDS Precision Medicine & Phenotypes Roundtable

We’re very excited this week on Pulm PEEPs to be resuming our Roundtable series. We are joined by two outstanding critical care doctors to discuss precision medicine in the ICU, specifically ARDS phenotypes. This is a topic of increasing clinical and research interest, and personalized medicine in the ICU will certainly change the landscape of how care is delivered in the coming years and decades. We are honing in on ARDS today and how phenotyping can influence future research and clinical care.

Meet Our Guests

Carolyn Calfee is a Professor of Medicine and Anesthesia at the University of California, San Francisco. She is a leader in the field of ARDS research and a pioneer in the field of ARDS phenotyping research. She has received numerous NIH grants and has literally 100s of publications on ARDS and other topics. She is also a previous ATS CC Assembly chair, and in 2022 received the ATS Recognition Award for Scientific Accomplishments.

Annette Esper is an Associate Professor of Medicine at Emory University School of Medicine. She works clinically in critical care and is the Medical Director of the stepdown Intensive Care Unit at Grady Memorial Hospital. In addition to her clinical activities, Annette does both clinical and translational research in ARDS, and was the Assembly Chair for the ATS Critical Care Assembly from 2021 – 2022.

Key Learning Points

Berlin Criteria of ARDS:

— Acute symptoms developing within 7 days of a known insult

— Bilateral airspace opacites on chest imaging

— Hypoxemia not fully explained by cardiogenic pulmonary edema

— P:F ratio < 300 on a PEEP of 5

Heterogeneity in ARDS

— ARDS has a broad definition so it is comprised of people with a wide range of disease characteristics and severity

— There is heterogeneity in clinical characteristics, but also underlying biological drivers of disease

— Heterogeneity stymies research efforts to identify effective therapies in ARDS

Phenotyping in ARDS

— There are many ways of phenotyping for critical illness and ARDS

1. Etiology. Examples: COVID vs non-COVID, pulmonary vs non-pulmonary, bacterial vs viral

2. Physiologic phenotypes: Severity (Berlin criteria P:F ratio); Compliance, Ventilatory ratio

3. Biological phenotypes: Different underlying drivers of disease

— The motivation for phenotyping is to find treatment-responsive subgroups within the broader heterogeneous subgroups

— Phenotyping embodies more than risk factors, because it includes information about the host response, not just predictors of outcome

Biomarkers in ARDS

— There is probably a role for biomarkers in ARDS clinically and in research

> Prognostication

> Identify who will be responsive to specific therapies

> May not be one biomarker, will likely be a panel

— What is the perfect ARDS biomarker?

> Specific: identify a group of patients that are at risk, or respond to therapies differently

> Easily measurable at the bedside

> Reliable

> Reproducible

— Challengers in identifying useful biomarkers

> Heterogeneity of disease

> Real world applicability. For example, can you get IL-6 back in real-time? Can you apply it consistently when labs have different testing techniques and scales?

> Temporal stability – how do biomarkers change over the time course of ARDS?

— Biomarkers of interest

> Inflammatory markers (IL-6, IL-8, TNF)

> sRAGE – Soluble receptor for advanced glycation end products

> Highest levels on type 1 alveolar epithelial cells

> Seems to be a marker of alveolar epithelial injuries

> Meta-genomic sequencing of patients in a real-time environment

Latent class analysis

— Clustering technique that, agnostic to outcomes, looks for existing groups within the data

— Ideally, identifies biologically distinct phenotypes that may have different prognoses or response to therapy

Omics in ARDS

— Existing risk scores are quite limited, so using biological data to distinguish patients seems promising.

— Unbiased approach to identifying subgroups to identify patients that behave similarly biologically

— Omics is really thinking about endotyping patients and identifying the biological processes that are driving phenotypes

Hypo and hyperinflammatory phenotypes in ARDS

— Described by LCA incorporating demographics, clinical data, labs, vital signs, 6-8 plasma protein biomarkers

— Importantly, the groups were identified agnostically to outcomes.

— Distinguished by:

> Inflammatory biomarkers (IL-6, IL-8, TNF 1)

> Acidosis

> Shock, vasopressor requirement, and multi-system organ failure

— Consistently across 8 different data sets

— Both RCTs and observational cohorts

— Hyperinflammatory phenotype has dramatically worse clinically outcomes (higher mortality, fewer VFD)

— The different phenotypes respond differently to therapies retrospectively in RCTs

— The phenotypes did respond differently to PEEP, fluids conservative therapy, and simvastatin.

— This was not seen universally (rosuvastatin did not have differential treatment response)

— Note: We don’t really know that inflammation is at the heart of the pathogenesis of what distinguishes these two groups. The “hypoinflammatory” phenotype still has elevated levels of inflammatory biomarkers compared to controls.

What is next?

— This is all just subgroup analysis.

— These hypotheses still need to be tested prospectively

— Need to be able to easily identify the phenotypes quickly and easily

— Working on biomarker-based and non-biomarker-based clinical classifications

Key Quote:

Dr. Calfee “My takeaway point would be, there is no one best or one right way to phenotype these patients. I think there are numerous different approaches that we’re probably going to be using over the years. But I would say that what we want to focus on is what has the potential to change outcomes for our patients and to really identify individual patients or groups of patients that respond differently to therapies. And I think if we can keep that goal in mind and start testing some of these hypotheses prospectively we’re going to make progress.”

References and links for further reading

  1. Sinha P, Calfee CS. Phenotypes in ARDS: Moving Towards Precision Medicine. Curr Opin Crit Care. 2019;25(1):12-20. doi:10.1097/MCC.0000000000000571
  2. Calfee CS, Delucchi KL, Sinha P, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018;6(9):691-698. doi:10.1016/S2213-2600(18)30177-2
  3. Matthay MA, Arabi YM, Siegel ER, et al. Phenotypes and personalized medicine in the acute respiratory distress syndrome. Intensive Care Med. 2020;46(12):2136-2152. doi:10.1007/s00134-020-06296-9
  4. Wilson JG, Calfee CS. ARDS Subphenotypes: Understanding a Heterogeneous Syndrome. Crit Care. 2020;24(1):102. doi:10.1186/s13054-020-2778-x
  5. Yang P, Esper AM, Martin GS. The Future of ARDS Biomarkers: Where Are the Gaps in Implementation of Precision Medicine? In: Vincent JL, ed. Annual Update in Intensive Care and Emergency Medicine 2020. Annual Update in Intensive Care and Emergency Medicine. Springer International Publishing; 2020:91-100. doi:10.1007/978-3-030-37323-8_7