120. Pulm PEEPs & Irish Thoracic Society: Understanding Refractory Chronic Cough

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We’re excited today to launch our first episode in collaboration with the Irish Thoracic Society and their podcast series. The Irish Thoracic Society represents respiratory professionals throughout Ireland and is dedicated to championing excellence in the prevention, diagnosis, and clinical care of respiratory disease through its work in advocacy, education and research.

In today’s episode, we explore the complex and often overlooked world of refractory chronic cough — a condition that can significantly impact patients’ quality of life but is frequently misunderstood or underdiagnosed. With insights from leading respiratory specialists in Ireland and the United States, we discuss the latest thinking on diagnosis, management, and emerging treatments aimed at improving outcomes for patients and helping clinicians navigate this challenging area of respiratory medicine.

Joining us are renowned experts Professor Lorcan McGarvey and Professor Brendan Canning, both internationally recognised leaders in respiratory medicine and cough research. Together, they share their perspectives on the neurobiology of chronic cough, the considerable morbidity experienced by patients, and how clinicians can approach diagnostic investigations more effectively.

We also explore current treatment strategies and promising new therapies on the horizon as chronic cough increasingly gains recognition as a disease in its own right — rather than simply a symptom. Whether you’re a clinician, researcher, or simply interested in advances in respiratory medicine, this episode offers valuable insights into a condition that is finally receiving the attention it deserves.

Meet Our Co-Hosts


Marissa O’Callaghan is an Irish trained Respiratory fellow currently undertaking a post-doc fellow working in Erasmus MC Rotterdam in the Netherlands. She finished her Irish respiratory and Internal medicine training and Phd in 2025. Her areas of interest are interstitial and rare lung diseases. She enjoys clinical research, Med Ed, and dreaming up new medical innovations. Together with cohost Sandra Green, she founded the ITS podcast series in June 2024. Marissa O’Callaghan –LinkedIn

Sandra Green is an Irish-trained respiratory fellow with a strong track record in climate advocacy and multidisciplinary sustainable initiatives, as co-founder of Irish Doctors for the Environment. She has an MSc in Leadership and Innovation in Healthcare at the Royal College of Surgeons Ireland (2023–2025). With Marisssa, she co-founded the Irish Thoracic Society Podcast Productions, launching the platform in 2024 to share knowledge, insights, and innovations in respiratory care. Sandra Green – LinkedIn

Meet Our Guests

Lorcan McGarvey is a professor of respiratory medicine at the University of Belfast, with a focus on the neurobiology of cough. His research has significantly contributed to the understanding of cough hypersensitivity syndrome and the development of new therapeutic strategies. Lorcan is a respected voice in the field, known for his collaborative work and dedication to advancing respiratory health.

Brendan Canning is a distinguished researcher at Johns Hopkins University, specializing in the mechanisms of cough and airway diseases. His pioneering studies on neural pathways and receptor targets have paved the way for novel treatments in refractory chronic cough. Brendan’s expertise and innovative approach make him a key figure in the ongoing efforts to redefine chronic cough management.

In This Episode

The definitions and classifications of chronic cough, including unexplained, refractory, and unexplained refractory cough

The importance of a thorough clinical history and focused diagnostics over exhaustive testing

Common causes of chronic cough

The role of personalized, multidisciplinary management—combining pharmacologic, speech therapy, and psychological support—to improve quality of life for even the most challenging patients.

The concept of cough hypersensitivity syndrome and its role in refractory cases

Evidence-based approach to treatment, including pharmacologic and non-pharmacologic options

Emerging therapies on the horizon, including novel receptor modulators and neuromodulatory agents and ongoing clinical trials in this rapidly evolving field

The impact of chronic cough on mental health, social life, and overall quality of life

The importance of reframing chronic cough as a disease entity in its own right

References and Further Reading

Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371(9621):1364-1374.

Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015;351:h5590.

Matsumoto H, Kanemitsu Y, Ohe M, Tanaka H, Terada K, Nishi K, et al. Real-world usage and response to gefapixant in refractory chronic cough. ERJ Open Res. 2025;11(4):01037-2024. doi:10.1183/23120541.01037-2024.

McGarvey LP, Birring SS. Cough hypersensitivity syndrome: a novel paradigm for understanding cough. Lancet Respir Med. 2014;2(8):647-656.

Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Ribas CD, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136.

Parker SM, Smith JA, Birring SS, Chamberlain-Mitchell S, Gruffydd-Jones K, Haines J, et al. British Thoracic Society clinical statement on chronic cough in adults. Thorax. 2023;78(Suppl 1):S3-S19.

Smith JA, Woodcock A. Chronic cough. N Engl J Med. 2006;354(2):136-144.

Song WJ, Dupont L, Birring SS, Chung KF, Dąbrowska M, Dicpinigaitis P, et al. Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study. ERJ Open Res. 2023;9(6):00618-2023. doi:10.1183/23120541.00618-2023.

Song WJ, McGarvey L, Cho PSP, Mazzone SB, Chung KF, editors. Chronic cough. Sheffield: European Respiratory Society; 2025.

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119. Guideline Series: Pulmonary Embolism

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We are unbelievably excited this week to be reviewing the hot-off-the-presses 2026 Multi-Society (AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN) Pulmonary Embolism Guidelines with lead author Dr. Mark A. Creager. We will talk about key updates in these guidelines compared to prior practice, including the new risk classification model, and provide an overview from diagnosis to follow-up. Given the clinical importance and prevalence of pulmonary embolism, these guidelines are certainly going to shape practice going forward, so this episode is a can’t miss!

Watch the full video of this episode with graphics and helpful teaching visuals on our YouTube channel: https://www.youtube.com/@pulmpeeps

Meet Our Guest

Dr. Mark Creager is a Professor of Medicine at Dartmouth Hitchcock Medical Center where he specializes in Cardiovascular Medicine with an emphasis on venous thromboembolic disease. He served as the lead author of the 2026 Pulmonary Embolism Guidelines.

Article and Reference

Creager MA, Barnes GD, Giri J, Mukherjee D, Jones WS, Burnett AE, Carman T, Casanegra AI, Castellucci LA, Clark SM, Cushman M, de Wit K, Eaves JM, Fang MC, Goldberg JB, Henkin S, Johnston-Cox H, Kadavath S, Kadian-Dodov D, Keeling WB, Klein AJP, Li J, McDaniel MC, Moores LK, Piazza G, Prenger KS, Pugliese SC, Ranade M, Rosovsky RP, Russo F, Secemsky EA, Sista AK, Tefera L, Weinberg I, Westafer LM, Young MN. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2026 Feb 19:S0735-1097(25)10161-7. doi: 10.1016/j.jacc.2025.11.005. Epub ahead of print. PMID: 41712898.

Key Learning Points

Why these guidelines matter:

This is the first joint AHA/ACC clinical practice guideline specifically on acute PE, bringing together a truly multidisciplinary writing committee (cardiology, pulmonology, hematology, emergency medicine, interventional radiology, surgery, and others). Prior guidelines existed from individual societies, but nothing this comprehensive had been updated in roughly five to six years.

New PE clinical categories (A through E):

One of the most impactful changes is replacing the old “massive/submassive” and “low/intermediate/high risk” labels with five categories that form a severity continuum. Category A is subclinical (incidental PE found on imaging in asymptomatic patients). Category B covers symptomatic but low-severity patients. Category C is where much of the clinical complexity lives — symptomatic, hemodynamically stable patients subdivided into C1, C2, and C3 based on RV function and biomarkers. Category D represents incipient cardiopulmonary failure (transient hypotension, normotensive shock with end-organ dysfunction). Category E is frank cardiopulmonary failure, with E2 being the sickest — refractory or recurrent cardiac arrest. Respiratory modifiers (hypoxia requiring supplemental oxygen) layer onto C, D, and E.

Diagnostic approach:

Clinical evaluation comes first — history, exam, and validated decision tools (Wells score, revised Geneva, PERC). If clinical probability is low and D-dimer is normal, imaging can be safely avoided. If either is concerning, imaging is warranted. CTPA remains the preferred imaging modality due to superior sensitivity, specificity, wide availability, and ability to assess clot burden and alternative diagnoses. VQ scanning is still appropriate when CTPA is contraindicated, and VQ SPECT offers better reproducibility and specificity than traditional planar VQ if available. Echocardiography is not a diagnostic test for PE but is important for risk stratification — RV size, TAPSE, and tissue Doppler measures all contribute prognostic information.

Anticoagulation updates:

Anticoagulation remains the cornerstone of treatment. For patients potentially needing advanced therapies (C3, D, E), parenteral anticoagulation is started first. A notable recommendation: low molecular weight heparin is generally preferred over unfractionated heparin, based on evidence showing more effective VTE risk reduction, more predictable pharmacokinetics, no need for routine monitoring, lower rates of heparin-induced thrombocytopenia, and no increase in major bleeding. The committee acknowledged this may create discomfort for clinicians accustomed to unfractionated heparin’s easy reversibility, but the difficulty of achieving and maintaining therapeutic levels with UFH was a significant concern.

Advanced therapies:

Catheter-based thrombolysis, mechanical thrombectomy, systemic thrombolysis, and surgical embolectomy all received mostly class 2B recommendations (“can consider”) for C3 and D categories, reflecting that current evidence shows improvement in short-term surrogate measures (RV/LV ratio, hemodynamics) but lacks definitive hard outcome data on mortality. For category E1 patients, recommendations are stronger (class 2A). Multiple trials are expected soon — HI-PEITHO, PEERLESS-2, PE-TRACT, PERSEVERE, TORPEDO, and PROG — that should substantially inform future updates.

PERT teams:

Pulmonary embolism response teams are encouraged, particularly for C3, D, and E patients. They’ve been shown to reduce length of stay. For institutions without PERT capability, establishing consultation networks with larger centers is recommended.

Post-PE follow-up:

Patients shouldn’t be “left in the wilderness” after discharge. The guidelines recommend communication within the first week to ensure understanding of diagnosis and treatment, an in-person visit at or before three months to assess for persistent symptoms and discuss anticoagulation duration, ongoing surveillance for chronic thromboembolic pulmonary disease, and periodic reassessment for those on extended anticoagulation.

Infographics

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118. Pulm PEEPs Pearls: Methacholine Challenge

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Furf and Monty are back with another Pulm PEEPs Pearls episode. The topic of today’s discussion is an often discussed, but often misunderstood, test; the methacholine challenge. They’ll review when to utilize this test, how it should be performed, and the appropriate interpretation.

Contributors

This episode was prepared with research by Pulm PEEPs Associate Editor George Doumat.

Dustin Latimer, another Pulm PEEPs Associate Editor, assisted with audio and video editing.

Key Learning Points

What the Test Measures

  • Methacholine challenge is a direct bronchial provocation test of airway hyperresponsiveness (AHR), a core physiologic feature of asthma.
  • Anyone will bronchoconstrict at high enough concentrations — the test looks for an abnormal threshold.
  • The key endpoint is the PC20: the methacholine concentration causing a 20% fall in FEV1.
    • Abnormal in adults: PC20 ≤ 8–16 mg/mL

Test Performance

  • Meta-analyses: pooled sensitivity ~60%, specificity ~90%.
  • Real-world cohorts: sensitivity 55–62%, specificity 56–100% (varies by population, protocol, and threshold used).
  • Not a standalone yes/no test — best used as part of a broader diagnostic pathway.

Where It Fits in the Asthma Workup

The test belongs in a stepwise approach:

  1. Step 1: Spirometry + bronchodilator response
  2. Step 2: Add FeNO and/or peak flow variability (if available)
  3. Step 3: If the picture is still unclear → methacholine challenge

It is most useful for symptomatic patients with normal spirometry and no bronchodilator reversibility. Given its cost, mild risk, and discomfort, it should not be a first-line test — most asthma diagnoses do not require it.

Technique and Medication Prep

Technique

  • ERS guidelines favor tidal breathing over deep inspiratory maneuvers.
  • Deep breaths can be bronchoprotective and blunt the response, reducing sensitivity — especially in mild or well-controlled asthma.

Medication Washout (to Avoid False Negatives)

Medication ClassWashout Period
Short-acting beta-agonists (SABA)≥ 6 hours
Long-acting beta-agonists (LABA)~24 hours
Ultra-long-acting beta-agonists~48 hours
Short-acting anticholinergics (e.g., ipratropium)~12 hours
Long-acting muscarinic antagonists (LAMA, e.g., tiotropium)7 days
  • Inhaled corticosteroids, leukotriene blockers, and antihistamines do not significantly affect the test acutely — continue these. Withdrawing ICS also carries its own risk for asthma patients.
  • Practical tip: Spell out exactly what to hold and when — for both the patient and the PFT lab — at the time the test is ordered.

Interpreting Results

Negative Test (PC20 > 16 mg/mL)

  • Very high negative predictive value in symptomatic adults.
  • Makes current asthma quite unlikely (assuming proper test conduct).
  • This is the test’s greatest strength: it is an excellent rule-out test.

Positive Test (PC20 ≤ 8–16 mg/mL)

  • More nuanced — airway hyperresponsiveness is not unique to asthma.
  • Can be positive in: chronic cough, allergic rhinitis, COPD, and even some healthy asymptomatic individuals.
  • A positive result raises probability but must be interpreted alongside the clinical story, variable respiratory symptoms, peak flow variability, FeNO, and ICS response.

Safety and Risks

  • Overall, the test is quite safe; significant adverse effects are rare.
  • Temporary breathing discomfort is expected (bronchoconstriction is being induced).
  • Severe bronchospasm is possible:
    • A trained clinician should be available; SABA inhaler/nebulizer must be immediately on hand; a physician should be reachable in the facility.
  • Contraindications / cautions:
    • Avoid if FEV1 < 70% predicted or < 1–1.5 L (baseline obstruction greatly increases risk).
    • Avoid within 3 months of an acute cardiac event (rare risk of cardiac events with unstable cardiac disease).

Five Pearls — Quick Recap

  1. What it tests: Methacholine challenge is a direct test of AHR with high specificity but variable sensitivity — it belongs inside a diagnostic pathway, not as a standalone asthma test.
  2. When to use it: Most useful for symptomatic patients with normal spirometry and no bronchodilator response, after FeNO and peak flow variability have been considered.
  3. Technique and meds matter: Use tidal breathing protocol; respect washout intervals — especially the 7-day LAMA washout and 24–48 hour LABA window — to avoid false negatives.
  4. Safety: Generally safe, but can induce significant bronchoconstriction. Have a SABA available and avoid the test in patients with FEV1 < 70% predicted.
  5. Interpretation: A negative test (PC20 > 16 mg/mL) strongly argues against current asthma. A positive test raises probability but is not specific — interpret alongside the full clinical picture.

References and Further Reading

  1. Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Håkon Carlsen; Diamant Z, Gauvreau G, Hall GL, Hallstrand TS, Horvath I, de Jongh FHC, Joos G, Kaminsky DA, Laube BL, Leuppi JD, Sterk PJ. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017 May 1;49(5):1601526. doi: 10.1183/13993003.01526-2016. PMID: 28461290.
  2. Lee, J., & Song, J. U. (2021). Diagnostic comparison of methacholine and mannitol bronchial challenge tests for identifying bronchial hyperresponsiveness in asthma: a systematic review and meta-analysis. Journal of Asthma, 58(7), 883–891. https://doi.org/10.1080/02770903.2020.1739704
  3. Davis BE, Blais CM, Cockcroft DW. Methacholine challenge testing: comparative pharmacology. J Asthma Allergy. 2018 May 14;11:89-99. doi: 10.2147/JAA.S160607. PMID: 29785128; PMCID: PMC5957064.

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117. Pulm PEEPs Pearls: Spontaneous Breathing Trials

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This week’s Pulm PEEPs Pearls episode is all about spontaneous breathing trials (SBTs). SBTs are a standard part of the daily practice in the intensive care unit, but the exact methods vary across ICUs and institutions. Listen in to hear about the most common methods of SBTs, the physiology of each method, and what the evidence says.

Contributors

This episode was prepared with research by Pulm PEEPs Associate Editor George Doumat.

Dustin Latimer, another Pulm PEEPs Associate Editor, assisted with audio and video editing.

Key Learning Points

  1. What an SBT is really testing
  • An SBT is a stress test for post-extubation work of breathing, not just a ventilator check.
  • The goal is to balance sensitivity and specificity:
    • Too hard → unnecessary failures and delayed extubation
    • Too easy → false positives and higher risk of reintubation
  1. Common SBT modalities and how they compare
  • T-piece
    • No inspiratory support and no PEEP
    • Highest work of breathing
    • Most “physiologic” but often too strict
  • Pressure support (PS) + PEEP (e.g., 5/5 or 8/5)
    • Offsets ETT resistance and provides modest assistance
    • Easier to pass than T-piece
  • CPAP (0/5)
    • No inspiratory help, but provides PEEP to counter ETT resistance
    • Sits between PS and T-piece in difficulty
  1. Evidence favors pressure-supported SBTs for most patients
  • Large meta-analysis (~6,000 patients, >40 RCTs):
    • Pressure-supported SBTs increase successful extubation (~7% absolute benefit)
    • No increase in reintubation rates
  • Trials (e.g., FAST trial):
    • Patients pass SBTs earlier
    • Leads to earlier extubation and fewer ventilator-associated risks
  • Bottom line: A 30-minute PS 5/5 SBT is evidence-based and appropriate for most stable ICU patients
  1. When a T-piece still makes sense

T-piece SBTs are useful when:

  • Cost of reintubation is high
    • Difficult airway
    • Prior failed extubation
  • Pretest probability of success is low
    • Prolonged or difficult weaning
    • Tracheostomy vs extubation decisions
  • Need to mimic physiology without positive pressure
    • In LV dysfunction or pulmonary edema even small amounts PEEP may significantly improve physiology
  • Some centers use a hybrid approach: PS SBT → short confirmatory T-piece before extubation
  1. CPAP as a middle ground
  • Rationale:
    • Allows full patient effort while compensating for ETT resistance
  • Evidence:
    • Fewer and smaller trials
    • Possible modest improvement in extubation success
    • No clear mortality or LOS benefit
  • Reasonable option based on patient physiology, institutional protocols, and clinician comfort
  1. No single “perfect” SBT mode
  • Across PS, T-piece, CPAP, and newer methods (e.g., high-flow via ETT) there are no consistent differences in mortality or length of stay
  • What matters most:
    • Daily protocolized screening
    • Thoughtful bedside clinical judgment
    • Matching SBT difficulty to patient-specific risk
  1. Institutional variation is normal—and acceptable
  • Examples:
    • PS 10/5 in postoperative surgical ICU patients
    • PS 5/0 as an intermediate difficulty option
  • Key question clinicians should ask: What does passing or failing this specific SBT tell me about this patient’s likelihood of post-extubation success?
  1. Take-home pearls
  1. SBTs are stress tests of post-extubation physiology.
  2. PS 5/5 for 30 minutes is a strong default for most ICU patients.
  3. T-piece trials are valuable when false positives are costly or physiology demands it.
  4. CPAP is reasonable but supported by less robust data.
  5. Consistency, daily screening, and judgment matter more than the exact mode.

References and Further Reading

  • Burns KEA, Khan J, Phoophiboon V, Trivedi V, Gomez-Builes JC, Giammarioli B, Lewis K, Chaudhuri D, Desai K, Friedrich JO. Spontaneous Breathing Trial Techniques for Extubating Adults and Children Who Are Critically Ill: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024 Feb 5;7(2):e2356794. doi: 10.1001/jamanetworkopen.2023.56794. PMID: 38393729; PMCID: PMC10891471.
  • Burns KEA, Sadeghirad B, Ghadimi M, Khan J, Phoophiboon V, Trivedi V, Gomez Builes C, Giammarioli B, Lewis K, Chaudhuri D, Desai K, Friedrich JO. Comparative effectiveness of alternative spontaneous breathing trial techniques: a systematic review and network meta-analysis of randomized trials. Crit Care. 2024 Jun 8;28(1):194. doi: 10.1186/s13054-024-04958-4. PMID: 38849936; PMCID: PMC11162018.
  • Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, García C, Rubio O, Ventura L, López A, de la Torre MC, Keough E, Arauzo V, Hermosa C, Sánchez C, Tizón A, Tenza E, Laborda C, Cabañes S, Lacueva V, Del Mar Fernández M, Arnau A, Fernández R. Effect of Pressure Support vs T-Piece Ventilation Strategies During Spontaneous Breathing Trials on Successful Extubation Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2019 Jun 11;321(22):2175-2182. doi: 10.1001/jama.2019.7234. Erratum in: JAMA. 2019 Aug 20;322(7):696. doi: 10.1001/jama.2019.11119. PMID: 31184740; PMCID: PMC6563557.
  • Burns KEA, Wong J, Rizvi L, Lafreniere-Roula M, Thorpe K, Devlin JW, Cook DJ, Seely A, Dodek PM, Tanios M, Piraino T, Gouskos A, Kiedrowski KC, Kay P, Mitchell S, Merner GW, Mayette M, D’Aragon F, Lamontagne F, Rochwerg B, Turgeon A, Sia YT, Charbonney E, Aslanian P, Criner GJ, Hyzy RC, Beitler JR, Kassis EB, Kutsogiannis DJ, Meade MO, Liebler J, Iyer-Kumar S, Tsang J, Cirone R, Shanholtz C, Hill NS; Canadian Critical Care Trials Group. Frequency of Screening and Spontaneous Breathing Trial Techniques: A Randomized Clinical Trial. JAMA. 2024 Dec 3;332(21):1808-1821. doi: 10.1001/jama.2024.20631. PMID: 39382222; PMCID: PMC11581551.
  • Mahul M, Jung B, Galia F, Molinari N, de Jong A, Coisel Y, Vaschetto R, Matecki S, Chanques G, Brochard L, Jaber S. Spontaneous breathing trial and post-extubation work of breathing in morbidly obese critically ill patients. Crit Care. 2016 Oct 27;20(1):346. doi: 10.1186/s13054-016-1457-4. PMID: 27784322; PMCID: PMC5081985.
  • Yi LJ, Tian X, Chen M, Lei JM, Xiao N, Jiménez-Herrera MF. Comparative Efficacy and Safety of Four Different Spontaneous Breathing Trials for Weaning From Mechanical Ventilation: A Systematic Review and Network Meta-Analysis. Front Med (Lausanne). 2021 Nov 22;8:731196. doi: 10.3389/fmed.2021.731196. PMID: 34881255; PMCID: PMC8647911.​

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116. Guidelines Series: Pulmonary Hypertension – Risk Stratification and Treatment Goals

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On this week’s episode, we’re continuing our Guidelines Series exploring the 2022 ESC/ERS Guidelines for the diagnosis and treatment of Pulmonary Hypertension. If you missed our first episode in the series, give it a listen to hear about the most recent recommendations regarding Pulmonary Hypertension definitions, screening, and diagnostics. Today, we’re talking about the next steps after diagnosis. Specifically, we’ll be discussing risk stratification, establishing treatment goals, and metrics for re-evaluation. We’ll additionally introduce the mainstays of pharmacologic therapy for Pulmonary Hypertension.

Meet Our Co-Hosts

Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a pulmonary and critical care medicine fellow. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs, and bedside medical education.

Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered.

Key Learning Points

1) Episode Roadmap

  • How to set treatment goals, assess symptom burden, and risk-stratify patients with suspected/confirmed pulmonary arterial hypertension (PAH).
  • What tools to use to re-evaluate patients on treatment
  • Intro to major PAH medication classes and how they map to pathways.

2) Case-based diagnostic reasoning

Patient: 37-year-old woman with exertional dyspnea, mild edema, abnormal echo, telangiectasias + epistaxis → raises suspicion for HHT (hereditary hemorrhagic telangiectasia) and/or early connective tissue disease.

  • Key reasoning move: start broad (Groups 2–5) and narrow using history/exam/testing.
  • In a young patient without obvious left heart or lung disease, think more about Group 1 PAH (idiopathic/heritable/associated).

HHT teaching point: HHT can cause PH in more than one way:

  • More common: high-output PH from AVMs (often hepatic/pulmonary)
  • Rare (1–2% mentioned): true PAH phenotype (vascular remodeling; associated with ALK1 in some patients), behaving like Group 1 PAH.

3) Functional class assessment

WHO Functional Class:

  • Class I: no symptoms with ordinary activity, only with exertion
  • Class II: symptoms with ordinary activity
  • Class III: symptoms with less-than-ordinary activity (can’t do usual chores/shopping without dyspnea)
  • Class IV: symptoms at rest

Practical bedside tip they give:

  • Ask if the patient can walk at their own pace or keep up with a similar-age peer/partner. If not, think Class II (or worse).

4) Risk stratification at diagnosis: why, how, and which tools

Big principle: treatment choices are driven by risk, and the goal is to move patients to low-risk quickly.

ESC/ERS approach at diagnosis (as described):

  • Use a 3-strata model predicting 1-year mortality:
    • Low: <5%
    • Intermediate: 5–20%
    • High: >20%

ESC/ERS risk assessment variables (10 domains discussed):

  • Clinical progression, signs of right heart failure, syncope
  • WHO FC
  • Biomarkers (NT-proBNP)
  • Exercise capacity (6MWD)
  • Hemodynamics
  • Imaging (echo; sometimes cardiac MRI)
  • CPET (peak VO₂; VE/VCO₂ slope)

They note: even if you don’t have everything, the calculator can still be useful with ≥3 variables.

REVEAL 2.0:

  • Builds on similar core variables but adds further patient context (demographics, renal function, BP, DLCO, etc.)

Case result: both tools put her in intermediate risk (ESC/ERS ~1.6; REVEAL 2.0 score 8), underscoring that mild symptoms can still equal meaningful mortality risk.

5) Treatment goals and follow-up philosophy

What they explicitly prioritize:

  • Help patients feel better, live longer, and stay out of the hospital
  • Use risk tools to communicate prognosis and to track improvement
  • Reassess frequently (they mention ~every 3 months early on) until low risk is achieved
  • “Time-to-low-risk” is an important treatment goal

Also emphasized:

  • The diagnosis is psychologically heavy; patients need clear counseling, reassurance about the plan, and connection to support groups.

6) Medication classes for the treatment of PAH

Nitric oxide–cGMP pathway

  • PDE5 inhibitors: sildenafil, tadalafil
  • Soluble guanylate cyclase stimulator: riociguat
  • Important safety point: don’t combine PDE5 inhibitors with riociguat (risk of significant hypotension/hemodynamic effects)

Endothelin receptor antagonists (ERAs)

  • “-sentan” drugs: bosentan (less used due to side effects/interactions), ambrisentan, macitentan
  • Teratogenicity emphasized
  • Hepatotoxicity that requires LFT monitoring
  • Can cause fluid retention and peripheral edema

Prostacyclin pathway

  • Prostacyclin analogs/agonists:
    • Epoprostenol (potent; short half-life; IV administration)
    • Treprostinil (IV/SubQ/oral/inhaled options)
    • Selexipag (oral prostacyclin receptor agonist)

7) Sotatercept (post-guidelines)

They note sotatercept wasn’t in 2022 ESC/ERS but is now “a game changer” in practice:

  • Mechanism: ligand trap affecting TGF-β signaling / remodeling biology
  • Positioned as potentially more disease-modifying than pure vasodilators
  • Still evolving: where to place it earlier vs later in regimens is an active question in the field

8) How risk category maps to initial treatment intensity

General approach they outline:

  • High risk at diagnosis: parenteral prostacyclin (IV/SubQ) strongly favored, often aggressive early
  • Intermediate risk: at least dual oral therapy (typically PDE5i + ERA); escalate if not achieving low risk
  • Low risk: at least one oral agent; many still use dual oral depending on etiology/trajectory

For the case: intermediate-risk → start dual oral therapy (they mention tadalafil + ambrisentan as a typical choice), reassess in ~3 months; add a third agent (e.g., selexipag/prostacyclin pathway) if not low risk.

 References and Further Reading

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger 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-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what’s old is new. F1000Res. 2019 Jun 19;8:F1000 Faculty Rev-888. doi: 10.12688/f1000research.18811.1. PMID: 31249672; PMCID: PMC6584967.

Maron BA. Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J Am Heart Assoc. 2023 Apr 18;12(8):e029024. doi: 10.1161/JAHA.122.029024. Epub 2023 Apr 7. PMID: 37026538; PMCID: PMC10227272.

Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M; STELLAR Trial Investigators. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6. PMID: 36877098.

Ruopp NF, Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA. 2022 Apr 12;327(14):1379-1391. doi: 10.1001/jama.2022.4402. Erratum in: JAMA. 2022 Sep 6;328(9):892. doi: 10.1001/jama.2022.13696. PMID: 35412560.

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115. RFJC – FIBRONEER-IPF

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Luke Hedrick, Dave Furfaro, and recurrent RFJC guest Robert Wharton are joined again today by Nicole Ng to discuss the FIBRONEER-IPF trial investigating Nerandomilast in patients with IPF. This trial was published in NEJM in 2025 and looked at Neradomilast vs placebo for treating patients with IPF, on or off background anti-fibrotic therapy. This agents is now FDA approved for pulmonary fibrosis, and understanding the trial results is essential for any pulmonary physician treating patients with IPF or progressive pulmonary fibrosis.

 

Article and Reference

 Today’s episode discusses the FIBRONEER-IPF trial published in NEJM in 2025.

Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, Oldham JM, Valenzuela C, Clerisme-Beaty E, Gordat M, Wachtlin D, Liu Y, Schlecker C, Stowasser S, Zoz DF, Wijsenbeek MS; FIBRONEER-IPF Trial Investigators. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2025 Jun 12;392(22):2193-2202. doi: 10.1056/NEJMoa2414108. Epub 2025 May 18. PMID: 40387033.

https://www.nejm.org/doi/abs/10.1056/NEJMoa2414108

Meet Our Guests

Luke Hedrick is an Associate Editor at Pulm PEEPs and runs the Rapid Fire Journal Club Series. He is a senior PCCM fellow at Emory, and will be starting as a pulmonary attending at Duke University next year.

Robert Wharton is a recurring guest on Pulm PEEPs as a part of our Rapid Fire Journal Club Series. He completed his internal medicine residency at Mt. Sinai in New York City, and is currently a pulmonary and critical care fellow at Johns Hopkins.

Dr. Nicole Ng is an Assistant Profess of Medicine at Mount Sinai Hospital, and is the Associate Director of the Interstitial Lung Disease Program for the Mount Sinai National Jewish Health Respiratory Institute.

Infographic

Key Learning Points

Why this trial mattered

  • IPF therapies remain limited: nintedanib and pirfenidone slow (but do not stop) decline and often cause GI side effects.
  • Nerandomilast is a newer agent (a preferential PDE4B inhibitor) with antifibrotic + immunomodulatory effects.
  • Phase 2 data (NEJM 2022) looked very promising (suggesting near-“halt” of FVC decline), so this phase 3 trial was a big test of that signal.

Trial design essentials

  • Industry-sponsored, randomized, double-blind, placebo-controlled, large multinational study (332 sites, 36 countries).
  • Population: IPF diagnosed via guideline-aligned criteria with central imaging review and multidisciplinary diagnostic confirmation.
  • Intervention: nerandomilast 18 mg BID, 9 mg BID, or placebo; stratified by background antifibrotic use.
  • Primary endpoint: change in FVC at 52 weeks, analyzed with a mixed model for repeated measures.
  • Key secondary endpoint: time to first acute exacerbation, respiratory hospitalization, or death (composite).

Who was enrolled

  • Typical IPF trial demographics: ~80% male, mean age ~70, many former smokers.
  • Many were already on background therapy (~45% nintedanib, ~30–33% pirfenidone).
  • Notable exclusions included significant liver disease, advanced CKD, recent major cardiovascular events, and psychiatric risk (suicidality/severe depression), reflecting class concerns seen with other PDE4 inhibitors.

Efficacy: what the primary endpoint showed

  • Nerandomilast produced a statistically significant but modest reduction in annual FVC decline vs placebo (roughly 60–70 mL difference).
  • Importantly, it did not halt FVC decline the way the phase 2 data suggested; patients still progressed.

Important nuance: interaction with pirfenidone

  • Patients on pirfenidone had ~50% lower nerandomilast trough levels.
  • Clinically: 9 mg BID looked ineffective with pirfenidone, so 18 mg BID is needed if used together.
  • In those not on background therapy or on nintedanib, 9 mg and 18 mg looked similar—suggesting the apparent “dose-response” might be partly driven by the pirfenidone drug interaction

Secondary and patient-centered outcomes were neutral

  • No demonstrated benefit in the composite outcome (exacerbation/resp hospitalization/death) or its components.
  • Quality of life measures were neutral and declined in all groups, emphasizing that slowing FVC alone may not translate into felt improvement without a disease-reversing therapy.
  • The discussants noted this may reflect limited power/duration for these outcomes and mentioned signals from other datasets/pooling that might suggest mortality benefit—but in this specific trial, the key secondary endpoint was not positive.

Safety and tolerability

  • Diarrhea was the main adverse event:
    • Higher overall with the 18 mg dose, and highest when combined with nintedanib (up to ~62%).
    • Mostly mild/manageable; discontinuation due to diarrhea was relatively uncommon (but higher in those on nintedanib).
  • Reassuringly, there was no signal for increased depression/suicidality/vasculitis despite psychiatric exclusions and theoretical class risk.

How to interpret “modest FVC benefit” clinically

  • The group framed nerandomilast as another tool that adds incremental slowing of progression.
  • They emphasized that comparing absolute FVC differences across trials (ASCEND/INPULSIS vs this trial) is tricky because populations and “natural history” in placebo arms have changed over time (earlier diagnosis, improved supportive care, etc.).
  • They highlighted channeling bias: patients already on antifibrotics may be sicker (longer disease duration, lower PFTs, more oxygen), complicating subgroup comparisons.

Practical takeaways for real-world use

  • All three antifibrotics are “fair game”; choice should be shared decision-making based on goals, tolerability, dosing preferences, and logistics.
  • Reasons they favored nerandomilast in practice:
    • No routine lab monitoring (major convenience advantage vs traditional antifibrotics).
    • Generally better GI tolerability than nintedanib.
    • BID dosing (vs pirfenidone TID).
  • Approach to combination therapy:
    • They generally favor add-on rather than immediate combination to reduce confusion about side effects—while acknowledging it may slow reaching “maximal therapy.”
  • Dosing guidance emphasized:
    • Start 18 mg BID for IPF, especially if combined with pirfenidone (since dose reduction may make it ineffective).
    • 9 mg BID may be considered if dose reduction is needed and the patient is not on pirfenidone (e.g., monotherapy or with nintedanib).

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114. Pulm PEEPs Pearls: Airway Clearance Techniques in Non-CF Bronchiectasis

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This week’s Pulm PEEPs Pearls episode is a focused discussion between Furf and Monty about non-pharmacologic techniques for airway clearance in the non-Cystic Fibrosis bronchiectasis population. This is a focused, high-yield discussion of the key points about airway clearance, including practical tips and a discussion of the evidence.

This episode was prepared in conjunction with George Doumat MD. Goerge is an internal medicine resident at UT Southwestern and joined us for a Pulm PEEPs – BMJ Thorax journal club episode. He is now acting as a Pulm PEEPs Editor for the Pulm PEEPs Pearls series.

Key Learning Points

1) Why airway clearance matters in non-CF bronchiectasis

  • Non-CF bronchiectasis is defined by irreversible bronchial dilation with impaired mucociliary clearance, leading to mucus retention.
  • Retained sputum drives the classic vicious cycle: mucus → infection → neutrophilic inflammation → airway damage → worse clearance.
  • Airway clearance techniques (ACTs) are meant to interrupt this cycle, primarily by improving mucus mobilization and symptom control.

2) What ACTs are trying to achieve clinically

  • Main benefits are:
    • More effective sputum clearance
    • Reduced cough/dyspnea burden
    • Improved activity tolerance and quality of life
  • Effects on spirometry are usually small.
  • Exacerbation reduction is possible, but evidence is mixed—some longer-term data suggest benefit for specific techniques.

3) The main ACT “families” and when to use them

Breathing-based techniques (device-free, flexible)

  • ACBT (Active Cycle of Breathing Technique): breath control → deep breaths with holds → huffing.
    • Pros: portable, adaptable, good first-line option.
    • Key requirement: teaching/coaching to get technique right.
  • Autogenic drainage: controlled breathing at different lung volumes to move mucus from peripheral → central airways.
    • Pros: no device, can work well once learned.
    • Cons: more technically demanding, needs training and practice.

PEP / Oscillatory PEP (stents airways + “vibrates” mucus loose)

  • PEP: back-pressure helps prevent small airway collapse during exhalation; often paired with huff/cough.
  • Oscillatory PEP (Flutter/Acapella/Aerobika): adds oscillation that many patients find easy and satisfying to use.
    • Good fit for: people who benefit from airway stenting, want something portable, and prefer a device.

Mechanical/manual techniques (help when patient can’t self-clear well)

  • HFCWO (“the vest”): external chest wall oscillation; helpful for high sputum volumes, dexterity limits, or difficulty coordinating breathing maneuvers.
  • Postural drainage/percussion/vibration: caregiver/therapist-assisted options; still useful but consider:
    • GERD/reflux risk with certain positions
    • Hemoptysis risk with vigorous techniques

4) How to choose the “right” technique (the practical framework)

There is no one-size-fits-all. Match the tool to the patient:

  • Sputum burden (volume/viscosity)
  • Strength, coordination, cognition, dexterity
  • Comorbidities (GERD, hemoptysis history, severe obstruction/airway collapse)
  • Lifestyle + portability (what they’ll actually do)
  • Cost/access and availability of respiratory therapy/physio support

A key mindset from the script: this is not a lifetime contract—reassess and adjust over time with shared decision-making.

5) Evidence takeaways (what improves, what doesn’t)

  • ACTs reliably improve sputum expectoration and often symptoms/QoL.
  • QoL/cough scores (e.g., SGRQ, LCQ) tend to improve modestly, particularly with oscillatory PEP and some vest studies.
  • Lung function: typically minimal change; occasional short-term FEV₁ benefit is reported in some vest trials.
  • Exacerbations: mixed overall; the script highlights a longer-term RCT of ELTGOL showing fewer exacerbations at 12 months vs placebo exercises.
  • Safety: generally excellent; main cautions are hemoptysis and reflux (depending on technique/positioning).

6) Special population pearls

  • Hemoptysis / fragile airways: start with gentle breathing-based ACTs (ACBT, controlled huffing); avoid overly vigorous oscillatory/manual methods if concerned.
  • Severe obstruction or early airway collapse: PEP/oscillatory PEP can help by keeping small airways open on exhalation.
  • Mobility/coordination barriers: consider HFCWO vest or simple oscillatory PEP devices to enable daily adherence.
  • During exacerbations: keep it simple—1–2 reliable techniques, prioritize daily consistency, and re-check technique.

7) The “real” bottom line

  • Start with simple, self-manageable options (often ACBT ± PEP).
  • The “best” ACT is the one the patient will do consistently.
  • Reassess technique and fit over time; education and demonstration are part of the therapy.

References and Further Reading

 Lee AL et al., “Airway clearance techniques for bronchiectasis,” Cochrane Database Syst Rev. 2015; PMC7175838. PMID: 26591003.

Athanazio RA et al., “Airway Clearance Techniques in Bronchiectasis,” Front Med (Lausanne). 2020; PMC7674976. PMID: 33251032.

Iacono R et al., “Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis,” Eur Rev Med Pharmacol Sci. 2015; PMID: 26078380.

Polverino E et al., “European Respiratory Society statement on airway clearance techniques in bronchiectasis,” Eur Respir J. 2023; PMID: 37142337.

Doumat G, Aksamit TR, Kanj AN. Bronchiectasis: A clinical review of inflammation. Respir Med. 2025 Aug;244:108179. doi: 10.1016/j.rmed.2025.108179. Epub 2025 May 25. PMID: 40425105.

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113. RFJC – PREDMETH

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Today, Dave Furfaro, Luke Hedrick, and Robert Wharton discuss the PREDMETH trial published in The New England Journal of Medicine in 2025. This was a non-inferiority trial comparing prednisone to methotrexate for upfront therapy in treatment-naive sarcoidosis patients. Listen in for a break down of the trial, analysis, and clinically applicable pearls.

Article and Reference

Todays’ episode discusses the PREDMETH trial published in NEJM in 2025.

Kahlmann V, Janssen Bonás M, Moor CC, Grutters JC, Mostard RLM, van Rijswijk HNAJ, van der Maten J, Marges ER, Moonen LAA, Overbeek MJ, Koopman B, Loth DW, Nossent EJ, Wagenaar M, Kramer H, Wielders PLML, Bonta PI, Walen S, Bogaarts BAHA, Kerstens R, Overgaauw M, Veltkamp M, Wijsenbeek MS; PREDMETH Collaborators. First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate. N Engl J Med. 2025 Jul 17;393(3):231-242. doi: 10.1056/NEJMoa2501443. Epub 2025 May 18. PMID: 40387020.

https://www.nejm.org/doi/full/10.1056/NEJMoa2501443

Meet Our Hosts

Luke Hedrick is an Associate Editor at Pulm PEEPs and runs the Rapid Fire Journal Club Series. He is a senior PCCM fellow at Emory, and will be starting as a pulmonary attending at Duke University next year.

Robert Wharton is a recurring guest on Pulm PEEPs as a part of our Rapid Fire Journal Club Series. He completed his internal medicine residency at Mt. Sinai in New York City, and is currently a first year pulmonary and critical care fellow at Johns Hopkins.

Key Learning Points

Clinical context

  • Prednisone remains the traditional first-line treatment for pulmonary sarcoidosis when treatment is indicated, with evidence for short-term improvements in symptoms, radiographic findings, and pulmonary function—but with substantial, familiar steroid toxicities (weight gain, insomnia, HTN/DM, infection risk, etc.).
  • Despite widespread use, glucocorticoids haven’t been robustly tested head-to-head against many alternatives as initial therapy, and evidence for preventing long-term decline (especially in severe disease) is limited.
  • Immunosuppressants (like methotrexate) are often used as steroid-sparing agents, but guideline recommendations are generally conditional/low-quality evidence, and practice varies.

Why PREDMETH matters

  • It addresses a real-world question: Can methotrexate be an initial alternative to prednisone in pulmonary sarcoidosis, rather than being reserved only for steroid-sparing later?
  • It also probes a common clinical belief: MTX has slower onset than prednisone (often assumed, not well-proven).

Trial design (what to know)

  • Open-label, randomized, noninferiority trial across 17 hospitals in the Netherlands.
  • Included patients with pulmonary sarcoidosis who had a clear pulmonary indication to start systemic therapy (moderate/severe symptoms plus objective risk features like reduced FVC/DLCO or documented decline, plus parenchymal abnormalities).
  • Excluded: non–treatment-naïve patients and those whose primary indication was extrapulmonary disease.
  • Treat-to-tolerability with escalation: both drugs started low and were slowly increased; switch/add-on allowed for inadequate efficacy or unacceptable side effects.
  • Primary endpoint: change in FVC (with the usual caveat that FVC is “objective-ish,” but effort-dependent and not always patient-centered).
  • Noninferiority margin: 5% FVC, justified as within biologic/measurement variation and “not clinically relevant.”
  • Outcomes assessed at weeks 4, 16, 24; powered for ~110 patients to detect the NI margin.

Patient population (who this applies to)

  • Mostly middle-aged (~40s) with mild-to-moderate physiologic impairment on average (FVC ~77% predicted; DLCO ~70% predicted).
  • Netherlands-based cohort with limited Black representation (~7%), which matters for generalizability.
  • Would have been helpful to know more about comorbidities (e.g., diabetes), which can strongly influence prednisone risk.

Main findings (what happened)

  • Methotrexate was noninferior to prednisone at week 24 for FVC:
    • Between-group difference in least-squares mean change at week 24: −1.17 percentage points (favoring prednisone) with CI −4.27 to +1.93, staying within the 5% NI margin.
  • Timing mattered:
    • Prednisone showed earlier benefit (notably by week 4) in FVC and across quality-of-life measures.
    • By week 24, those early differences largely washed out—possibly because MTX “catches up,” and/or because crossover increased over time.
    • In their reporting, MTX didn’t meet noninferiority for FVC until week 24, supporting the practical message that prednisone works faster.

Crossover and analysis nuance (important for interpretation)

  • Crossover was fairly high, which complicates noninferiority interpretation:
    • MTX arm: some switched to prednisone for adverse events and others had prednisone added for disease progression/persistent symptoms.
    • Prednisone arm: some had MTX added.
  • In noninferiority trials, heavy crossover can bias intention-to-treat analyses toward finding “no difference” (making noninferiority easier to claim). Per-protocol analyses avoid some of that but introduce other biases. They reported both.

Safety signals (what to remember clinically)

  • Adverse events were very common in both arms (almost everyone), mostly mild.
  • Side-effect patterns fit expectations:
    • Prednisone: more insomnia (and classic steroid issues).
    • MTX: more headache/cough/rash, and notably liver enzyme elevations (about 1 in 4), with a small number discontinuing.
  • Serious adverse events were rare; numbers were too small to confidently separate “signal vs noise,” but overall known risk profiles apply.

Limitations (why you shouldn’t over-read it)

  • Open-label design, and FVC—while objective-ish—is still effort-dependent and can be influenced by expectation/behavior.
  • Small trial, limiting subgroup conclusions (e.g., severity strata, different phenotypes).
  • Generalizability issues (Netherlands demographics; US populations have higher rates of obesity/metabolic syndrome, which may tilt the steroid risk-benefit equation).
  • Crossover reduces precision and interpretability of between-group differences over time.

Practice implications (the “so what”)

  • For many patients with pulmonary sarcoidosis needing systemic therapy, MTX is a reasonable initial alternative to prednisone when thinking long-term tolerability and steroid avoidance.
  • Prednisone likely provides faster symptom/QoL relief in the first weeks—so it may be preferable when rapid improvement is important.
  • The trial strengthens the case for a patient-centered discussion: short-term relief vs side-effect tradeoffs, and the possibility of early combination therapy in more severe cases (suggested, not proven).

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112. Guidelines Series: Pulmonary Hypertension – Definitions, Screening, and Diagnosis

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Today we’re kicking off another segment in our Guidelines Series, and doing a deep dive into the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Over a series of episodes we’ll talk about the most recent updates to definitions around pulmonary hypertension, recognizing and diagnosing Group 1 – 5 pulmonary hypertension, risk stratification, and treatments. In this first episode, we will review the most recent definitions, including changes to the definitions that were new in 2022. We’ll then talk about recognizing and diagnosing pulmonary hypertension with tips and insights along the way.

 

Meet Our Co-Hosts

Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a pulmonary and critical care medicine fellow alongside Tom. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs. And she also loves bedside medical education.

Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered in the care they have going forward.

Infographic

Key Learning Points

  1. Why to have a high index of suspicion for pulmonary hypertension (PH)
  • PH often presents subtly with slowly progressive dyspnea on exertion, fatigue, lightheadedness, exertional chest pain, or syncope.
  • There’s often a delay of 1–2+ years from symptom onset to diagnosis, which is associated with worse mortality.
  • Early recognition and treatment, especially for pulmonary arterial hypertension (PAH, WHO group 1), can significantly change outcomes.

 

  1. When to suspect PH

Think PH when:

  • Dyspnea is out of proportion to:
    • CT parenchymal findings (relatively normal lungs)
    • Spirometry (normal FEV₁/FVC, volumes)
  • There are subtle but progressive symptoms over months:
    • Reduced exercise tolerance
    • No obvious alternative explanation (e.g., no overt HF, CAD, big ILD, etc.)
  • Physical exam may show (often late):
    • Elevated JVP, V waves (TR)
    • Peripheral edema, hepatomegaly, ascites
    • Loud P2, RV heave

In the case: a woman with systemic sclerosis + slowly progressive exertional dyspnea + relatively normal CT parenchyma and spirometry → high suspicion.

 

  1. WHO classification: 5 PH groups (big picture + why it matters)

Used for pathophysiology, prognosis, and treatment choices:

  1. Group 1 – PAH
    • Idiopathic, heritable (e.g., BMPR2), drug-induced (e.g., dasatinib)
    • Connective tissue disease (esp. systemic sclerosis)
    • Portal hypertension (portopulmonary HTN)
    • HIV, HHT, congenital heart disease/shunts
    • Rare: PVOD, PCH
  2. Group 2 – PH due to left heart disease
    • HFrEF, HFpEF, valvular disease
    • Most common cause worldwide.
  3. Group 3 – PH due to lung disease/hypoxia
    • COPD, ILD, combined pulmonary fibrosis–emphysema
    • OSA/obesity hypoventilation, chronic hypoxemia
  4. Group 4 – CTEPH
    • Chronic thromboembolic pulmonary hypertension
  5. Group 5 – Multifactorial/unclear
    • Sarcoidosis, myeloproliferative disorders, CKD, sickle cell, etc.

Patients can span multiple groups (e.g., systemic sclerosis: group 1 and/or group 3; sickle cell: many mechanisms).

 

  1. Initial workup & refining pre-test probability

Once you suspect PH, you’re trying to answer:

  1. Does this patient likely have PH?
  2. If yes, what group(s) are most likely?

Core non-invasive tests:

  • NT-proBNP (preferred over BNP)
    • Surrogate of RV strain and prognosis.
    • Normal value makes significant RV failure less likely.
  • Oxygenation & exercise
    • Resting SpO₂ plus ambulatory sats; consider 6-minute walk test.
    • Exertional desaturation is common and clinically meaningful.
  • CXR & ECG
    • Low yield but may show RV enlargement, right axis deviation, etc.
  • Pulmonary function tests
    • Full set: spirometry, volumes, DLCO.
    • Clue: isolated or disproportionately low DLCO with relatively preserved FVC suggests pulmonary vascular disease.
  • Imaging
    • High-res CT chest – parenchymal disease (ILD, emphysema).
    • V/Q scan – best screening test for CTEPH; better than CT angiography for chronic disease.
  • Sleep testing / overnight oximetry
    • When OSA/nocturnal hypoxemia suspected.

 

  1. Echo: estimating PH probability (not diagnosis)

TTE is the key screening tool but does not diagnose PH.

Main elements:

  1. Peak tricuspid regurgitant (TR) velocity
    • Used to estimate pulmonary artery systolic pressure (PASP).
    • Categories:
      • Low probability: TR velocity < 2.8 m/s, no other PH signs.
      • Intermediate: 2.9–3.4 m/s ± other PH signs.
      • High: > 3.4 m/s.

The presence and severity of TR ≠ TR velocity. You can have severe TR without PH.

  1. “Other signs” of PH/RV dysfunction on echo:
    • RV enlargement or systolic dysfunction (qualitative, TAPSE < ~1.7 cm, S′ ↓)
    • RA enlargement
    • Septal flattening (D-shaped LV; systolic = pressure overload, diastolic + systolic = volume + pressure)
    • Dilated PA
    • Pericardial effusion

Interpretation pattern:

  • Low pre-test probability + TR v < 2.8 + no other signs → PH unlikely.
  • Intermediate TR v (2.9–3.4) + high pre-test probability and/or other PH signs → consider RHC.
  • High TR v (>3.4) or clearly abnormal RV → strongly consider RHC if it would change management.

Also:

  • Echo is great to follow RV size/function and PASP over time once PH is diagnosed and treated.

Case echo:

  • TR velocity 3.1 m/s + mild RA enlargement + moderate RV enlargement + TAPSE 1.6 cm → intermediate probability, consistent with PH and RV involvement.

 

  1. Right heart cath (RHC): gold standard & updated definitions

You cannot definitively diagnose or classify PH without RHC.

Key directly measured values:

  • RA, RV, PA pressures
  • Pulmonary capillary wedge pressure (PCWP/PAWP) ≈ LVEDP
  • Oxygen saturations in chambers/vessels
  • Cardiac output (thermodilution)

Key derived values:

  • Cardiac output (Fick)
  • Pulmonary vascular resistance (PVR)

Updated hemodynamic definitions:

  1. Pulmonary hypertension (PH)
    • mPAP ≥ 20 mm Hg (lowered from ≥ 25).
  2. Pre-capillary PH (think PAH, group 1; also groups 3, 4, some 5):
    • mPAP ≥ 20
    • PAWP ≤ 15
    • PVR > 2 Wood units (new lower threshold)
  3. Isolated post-capillary PH (IpcPH) (group 2)
    • mPAP ≥ 20
    • PAWP > 15
    • PVR ≤ 2
  4. Combined pre- and post-capillary PH (CpcPH)
    • mPAP ≥ 20
    • PAWP > 15
    • PVR > 2

Rationale for the changes:

  • Normal mPAP in healthy people is < ~19; 20 is about 2 SD above normal.
  • Patients with mPAP 20–24 (esp. systemic sclerosis) already have worse outcomes than those < 20.
  • Lowering PVR cutoff from 3 → 2 WU better aligns with these new thresholds and catches earlier precapillary disease.

Practical interpretation:

  • You use mPAP + PAWP + PVR to:
    • Confirm PH.
    • Distinguish pre- vs post-capillary.
    • Identify mixed disease.
  • Echo tells you probability; RHC tells you what type and how severe.

 

  1. Vasoreactivity testing (acute vasodilator testing)
  • Only indicated in:
    • Idiopathic (IPAH)
    • Heritable PAH
    • Drug-induced PAH
      → Not routine for all PH patients.
  • Performed in the cath lab with short-acting vasodilator (e.g., inhaled NO).

Positive test:

  • ↓ mPAP ≥ 10 mm Hg
  • To an absolute mPAP ≤ 40 mm Hg
  • No fall in cardiac output

Why it matters:

  • Identifies a small subset who can be treated with high-dose calcium channel blockers long-term and often have better prognosis.
  • Does not predict response to other PAH therapies (ERA, PDE5i, prostacyclin, etc.).

 

  1. Screening high-risk populations

Some groups warrant systematic screening because of high PAH risk.

  1. a) Systemic sclerosis / systemic sclerosis spectrum
  • Annual screening if:
    • Disease duration ≥ 3 years
    • FVC ≥ 40% predicted
    • DLCO < 60% predicted
  • DETECT algorithm (2-step):
    • Step 1: uses labs and simple tests (FVC/DLCO ratio, NT-proBNP, autoantibodies, right axis deviation on ECG, telangiectasias).
    • If positive → Step 2: adds echo (TR velocity, RA size).
    • If high risk after Step 2 → RHC.
  • Goal: catch early PAH before symptoms are severe.
  1. b) Other high-risk groups

Annual screening (usually with echo ± NT-proBNP, PFTs) for:

  • Known heritable PAH mutations (e.g., BMPR2)
  • Portal hypertension (esp. considering liver transplant or TIPS)
  • HIV

Always layer this on top of clinical symptoms and progression.

 

  1. Big practical takeaways (what to apply on Monday)
  1. Don’t label “pulmonary hypertension” off CT or echo alone.
    • Enlarged PA on CT or elevated PASP on echo ≠ diagnosis.
    • RHC is required.
  2. Think PH early when:
    • Dyspnea is out of proportion to imaging and spirometry.
    • There is a relevant risk factor (systemic sclerosis, portal HTN, HIV, prior PE, congenital heart disease, etc.).
  3. Use the WHO groups to structure your differential and workup:
    • Group 1 vs 2 vs 3 vs 4 vs 5 → drives what tests you order and what treatments you eventually consider.
  4. Echo = probability. RHC = truth.
    • Echo gives you low / intermediate / high PH probability.
    • RHC gives you pre- vs post-capillary, PVR, and hemodynamics needed for therapy.
  5. Know the new numbers:
    • mPAP ≥ 20 = PH
    • PAWP cutoff = 15
    • PVR > 2 WU = precapillary component
  6. Don’t forget NT-proBNP, DLCO, V/Q scan, and high-risk screening (especially in systemic sclerosis and BMPR2 carriers).

 

References

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger 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-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what’s old is new. F1000Res. 2019 Jun 19;8:F1000 Faculty Rev-888. doi: 10.12688/f1000research.18811.1. PMID: 31249672; PMCID: PMC6584967.

Maron BA. Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J Am Heart Assoc. 2023 Apr 18;12(8):e029024. doi: 10.1161/JAHA.122.029024. Epub 2023 Apr 7. PMID: 37026538; PMCID: PMC10227272.

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111. Pulm PEEPs Pearls: Methylene Blue

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Furf and Monty are back today with another Pulm PEEPs Pearls episode, and discussing the use of methylene blue for patients with septic shock. They review the clinical scenarios when this comes up, the mechanism, some key data, and some take aways, all in 15 minutes! Let us know any other topics you’d like covered on the show and make sure to like, give us 5 stars, and subscribe wherever you’re listening to this podcast.

This episode was prepared in conjunction with George Doumat MD. Goerge is an internal medicine resident at UT Southwestern and joined us for a Pulm PEEPs – BMJ Thorax journal club episode. He is now acting as a Pulm PEEPs Editor for the Pulm PEEPs Pearls series.

Key Learning Points

  1. Clinical context: when does methylene blue even come up?
  • This is not a first-line sepsis drug.
  • It’s considered in catecholamine-refractory vasoplegic septic shock, typically when:
    • Norepinephrine is at high dose
    • Vasopressin is on board
    • Often a 3rd or 4th vasopressor is being used (e.g., phenylephrine, angiotensin II)
  • The phenotype is strongly vasodilatory/vasoplegic (warm, distributive shock) rather than primarily cardiogenic.
  1. Mechanism of action (why it might help)
  • Methylene blue:
    • Inhibits inducible nitric oxide synthase and guanylate cyclase.
    • Blunts excess nitric oxide and cyclic GMP–mediated vasodilation, which are key in vasoplegic sepsis.
  • Practical translation:
    • It restores vascular tone and can make the vasculature more responsive to catecholamines.
  • It’s also used in post-CPB vasoplegia (e.g., after cardiac surgery, especially in patients on ACE inhibitors) and has migrated from that world into ICU sepsis practice.
  1. Typical dosing strategy (as described in the episode)
  • Common approach:
    • 1–3 mg/kg IV bolus, then
    • Reassess hemodynamics (MAP, dynamic perfusion markers).
    • If there’s a response, consider a continuous infusion or repeat bolus.
  • Key nuance: unlike other pressors that start as drips, methylene blue is often trialed as a bolus first to see if it’s doing anything.
  1. What does the evidence suggest?

Most data are from small, single-center, heterogeneous studies, so evidence quality is low. Meta-analyses and systematic reviews (through ~2024–25) suggest:

  • Hemodynamics
    • Can increase MAP (roughly 1–10 mmHg across studies).
    • May shorten total vasopressor duration (one meta-analysis ~30 hours less, though this is not definitive).
  • Secondary physiologic effects
    • Some small improvements in PaO₂/FiO₂ (P/F) ratio in certain studies.
  • Clinical outcomes
    • Possible reduction in hospital length of stay (≈ up to 2 days in some pooled analyses).
    • Some signal toward lower short-term mortality, but:
      • Studies are small
      • Heterogeneous
      • Evidence is very low certainty
  • Bottom line:
    • There’s a repeatable signal that methylene blue:
      • Raises MAP
      • Helps reduce catecholamine requirements
    • But hard clinical outcomes (mortality, LOS, ventilator days) remain uncertain.
  1. Safety profile & important adverse effects

Things to watch for:

  • Methemoglobinemia
  • Serotonin syndrome
    • Especially in patients on SSRIs, though in life-threatening refractory shock the hosts still lean toward using it with caution.
  • Pulse oximeter artifact
    • Can distort SpO₂ readings.
  • Urine discoloration
    • Blue/green urine—benign but striking.

Notably:

  • Methylene blue is both a treatment for and a potential cause of methemoglobinemia, depending on context and dosing.
  1. Guidelines & where it fits in practice
  • Surviving Sepsis Campaign 2021:
    • Does not recommend methylene blue for routine use in septic shock.
  • No major critical care society includes it in standard septic shock bundles or protocols.
  • The hosts frame methylene blue as:
    • A rescue therapy, not guideline therapy.
    • Something to consider only in refractory vasoplegic shock, ideally with:
      • Multidisciplinary discussion (intensivist, pharmacist, etc.).
      • Clear documentation that this is off-guideline, salvage use.
  1. Practical bedside framing (“2 a.m. in the ICU”)

They emphasize three pillars of practice:

  1. Physiology – mechanism makes sense (NO / cGMP / vasodilation).
  2. Empiric evidence – small studies and meta-analyses show a signal but low-quality data.
  3. Bedside reality – at 2 a.m., with a patient in multi-pressor, refractory vasoplegic shock, you sometimes reach for imperfect tools.

So, the practical take:

  • You should NOT:
    • Use methylene blue early.
    • Treat it as part of standard sepsis care.
  • You may consider it when:
    • Shock is clearly vasoplegic and refractory.
    • Norepi + vasopressin + at least one more vasopressor are maxed.
    • Team agrees this is salvage therapy and understands the limited evidence and side effects.

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