PulmPEEPs – Podcast

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

120. Pulm PEEPs & Irish Thoracic Society: Understanding Refractory Chronic Cough
7 Apr· PulmPEEPs
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
24 Mar· PulmPEEPs
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.
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118. Pulm PEEPs Pearls: Methacholine Challenge
24 Feb· PulmPEEPs
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:
Step 1: Spirometry + bronchodilator responseStep 2: Add FeNO and/or peak flow variability (if available)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 PeriodShort-acting beta-agonists (SABA)≥ 6 hoursLong-acting beta-agonists (LABA)~24 hoursUltra-long-acting beta-agonists~48 hoursShort-acting anticholinergics (e.g., ipratropium)~12 hoursLong-acting muscarinic antagonists (LAMA, e.g., tiotropium)7 daysInhaled 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
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.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.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.Safety: Generally safe, but can induce significant bronchoconstriction. Have a SABA available and avoid the test in patients with FEV1 < 70% predicted.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
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.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/10.1080/02770903.2020.1739704Davis 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
10 Feb· PulmPEEPs
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
What an SBT is really testingAn 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 extubationToo easy → false positives and higher risk of reintubation Common SBT modalities and how they compareT-pieceNo inspiratory support and no PEEPHighest work of breathingMost “physiologic” but often too strictPressure support (PS) + PEEP (e.g., 5/5 or 8/5)Offsets ETT resistance and provides modest assistanceEasier to pass than T-pieceCPAP (0/5)No inspiratory help, but provides PEEP to counter ETT resistanceSits between PS and T-piece in difficulty Evidence favors pressure-supported SBTs for most patientsLarge meta-analysis (~6,000 patients, >40 RCTs):Pressure-supported SBTs increase successful extubation (~7% absolute benefit)No increase in reintubation ratesTrials (e.g., FAST trial):Patients pass SBTs earlierLeads to earlier extubation and fewer ventilator-associated risksBottom line: A 30-minute PS 5/5 SBT is evidence-based and appropriate for most stable ICU patients When a T-piece still makes sense
T-piece SBTs are useful when:
Cost of reintubation is highDifficult airwayPrior failed extubationPretest probability of success is lowProlonged or difficult weaningTracheostomy vs extubation decisionsNeed to mimic physiology without positive pressureIn LV dysfunction or pulmonary edema even small amounts PEEP may significantly improve physiologySome centers use a hybrid approach: PS SBT → short confirmatory T-piece before extubation CPAP as a middle groundRationale:Allows full patient effort while compensating for ETT resistanceEvidence:Fewer and smaller trialsPossible modest improvement in extubation successNo clear mortality or LOS benefitReasonable option based on patient physiology, institutional protocols, and clinician comfort No single “perfect” SBT modeAcross PS, T-piece, CPAP, and newer methods (e.g., high-flow via ETT) there are no consistent differences in mortality or length of stayWhat matters most:Daily protocolized screeningThoughtful bedside clinical judgmentMatching SBT difficulty to patient-specific risk Institutional variation is normal—and acceptableExamples:PS 10/5 in postoperative surgical ICU patientsPS 5/0 as an intermediate difficulty optionKey question clinicians should ask: What does passing or failing this specific SBT tell me about this patient’s likelihood of post-extubation success? Take-home pearlsSBTs are stress tests of post-extubation physiology.PS 5/5 for 30 minutes is a strong default for most ICU patients.T-piece trials are valuable when false positives are costly or physiology demands it.CPAP is reasonable but supported by less robust data.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
27 Jan· PulmPEEPs
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 treatmentIntro 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 exertionClass II: symptoms with ordinary activityClass 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, syncopeWHO FCBiomarkers (NT-proBNP)Exercise capacity (6MWD)HemodynamicsImaging (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 hospitalUse risk tools to communicate prognosis and to track improvementReassess 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, tadalafilSoluble guanylate cyclase stimulator: riociguatImportant 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, macitentanTeratogenicity emphasizedHepatotoxicity that requires LFT monitoringCan 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 biologyPositioned as potentially more disease-modifying than pure vasodilatorsStill 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 earlyIntermediate risk: at least dual oral therapy (typically PDE5i + ERA); escalate if not achieving low riskLow 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
13 Jan· PulmPEEPs
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
6 Jan· PulmPEEPs
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 clearanceReduced cough/dyspnea burdenImproved activity tolerance and quality of lifeEffects 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 positionsHemoptysis 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, dexterityComorbidities (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
23 Dec 2025· PulmPEEPs
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
9 Dec 2025· PulmPEEPs
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
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.

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 toleranceNo 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, ascitesLoud P2, RV heave
In the case: a woman with systemic sclerosis + slowly progressive exertional dyspnea + relatively normal CT parenchyma and spirometry → high suspicion.

WHO classification: 5 PH groups (big picture + why it matters)
Used for pathophysiology, prognosis, and treatment choices:
Group 1 – PAHIdiopathic, heritable (e.g., BMPR2), drug-induced (e.g., dasatinib)Connective tissue disease (esp. systemic sclerosis)Portal hypertension (portopulmonary HTN)HIV, HHT, congenital heart disease/shuntsRare: PVOD, PCHGroup 2 – PH due to left heart diseaseHFrEF, HFpEF, valvular diseaseMost common cause worldwide.Group 3 – PH due to lung disease/hypoxiaCOPD, ILD, combined pulmonary fibrosis–emphysemaOSA/obesity hypoventilation, chronic hypoxemiaGroup 4 – CTEPHChronic thromboembolic pulmonary hypertensionGroup 5 – Multifactorial/unclearSarcoidosis, 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).

Initial workup & refining pre-test probability
Once you suspect PH, you’re trying to answer:
Does this patient likely have PH?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 & exerciseResting SpO₂ plus ambulatory sats; consider 6-minute walk test.Exertional desaturation is common and clinically meaningful.CXR & ECGLow yield but may show RV enlargement, right axis deviation, etc.Pulmonary function testsFull set: spirometry, volumes, DLCO.Clue: isolated or disproportionately low DLCO with relatively preserved FVC suggests pulmonary vascular disease.ImagingHigh-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 oximetryWhen OSA/nocturnal hypoxemia suspected.

Echo: estimating PH probability (not diagnosis)
TTE is the key screening tool but does not diagnose PH.
Main elements:
Peak tricuspid regurgitant (TR) velocityUsed 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.
“Other signs” of PH/RV dysfunction on echo:RV enlargement or systolic dysfunction (qualitative, TAPSE < ~1.7 cm, S′ ↓)RA enlargementSeptal flattening (D-shaped LV; systolic = pressure overload, diastolic + systolic = volume + pressure)Dilated PAPericardial 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.

Right heart cath (RHC): gold standard & updated definitions
You cannot definitively diagnose or classify PH without RHC.
Key directly measured values:
RA, RV, PA pressuresPulmonary capillary wedge pressure (PCWP/PAWP) ≈ LVEDPOxygen saturations in chambers/vesselsCardiac output (thermodilution)
Key derived values:
Cardiac output (Fick)Pulmonary vascular resistance (PVR)
Updated hemodynamic definitions:
Pulmonary hypertension (PH)mPAP ≥ 20 mm Hg (lowered from ≥ 25).Pre-capillary PH (think PAH, group 1; also groups 3, 4, some 5):mPAP ≥ 20PAWP ≤ 15PVR > 2 Wood units (new lower threshold)Isolated post-capillary PH (IpcPH) (group 2)mPAP ≥ 20PAWP > 15PVR ≤ 2Combined pre- and post-capillary PH (CpcPH)mPAP ≥ 20PAWP > 15PVR > 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.

Vasoreactivity testing (acute vasodilator testing)Only indicated in:Idiopathic (IPAH)Heritable PAHDrug-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 HgTo an absolute mPAP ≤ 40 mm HgNo 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.).

Screening high-risk populations
Some groups warrant systematic screening because of high PAH risk.
a) Systemic sclerosis / systemic sclerosis spectrumAnnual screening if:Disease duration ≥ 3 yearsFVC ≥ 40% predictedDLCO < 60% predictedDETECT 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.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.

Big practical takeaways (what to apply on Monday)Don’t label “pulmonary hypertension” off CT or echo alone.Enlarged PA on CT or elevated PASP on echo ≠ diagnosis.RHC is required.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.).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.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.Know the new numbers:mPAP ≥ 20 = PHPAWP cutoff = 15PVR > 2 WU = precapillary componentDon’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
25 Nov 2025· PulmPEEPs
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
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 doseVasopressin is on boardOften 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. 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. Typical dosing strategy (as described in the episode)Common approach:1–3 mg/kg IV bolus, thenReassess 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. 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:
HemodynamicsCan 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 effectsSome small improvements in PaO₂/FiO₂ (P/F) ratio in certain studies.Clinical outcomesPossible reduction in hospital length of stay (≈ up to 2 days in some pooled analyses).Some signal toward lower short-term mortality, but:Studies are smallHeterogeneousEvidence is very low certaintyBottom line:There’s a repeatable signal that methylene blue:Raises MAPHelps reduce catecholamine requirementsBut hard clinical outcomes (mortality, LOS, ventilator days) remain uncertain. Safety profile & important adverse effects
Things to watch for:
MethemoglobinemiaSerotonin syndromeEspecially in patients on SSRIs, though in life-threatening refractory shock the hosts still lean toward using it with caution.Pulse oximeter artifactCan distort SpO₂ readings.Urine discolorationBlue/green urine—benign but striking.
Notably:
Methylene blue is both a treatment for and a potential cause of methemoglobinemia, depending on context and dosing. Guidelines & where it fits in practiceSurviving 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. Practical bedside framing (“2 a.m. in the ICU”)
They emphasize three pillars of practice:
Physiology – mechanism makes sense (NO / cGMP / vasodilation).Empiric evidence – small studies and meta-analyses show a signal but low-quality data.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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110. Pulm PEEPs at CHEST 2025 – Widened Airways and Narrowed Differentials
11 Nov 2025· PulmPEEPs
For today’s podcast we have a special episode. We were extremely grateful to be invited to present live at CHEST 2025 this year. Kristina Montemayor, and Pulm PEEPs Associate Editors Luke Hedrick, Tom Di Vitantonio, and Rupali Sood hosted a session entitled “Widened Airways and Narrowed Differentials”. It is a great session around bronchiectasis. Enjoy!

Meet Our Guests
Dr. Doreen Addrizzo-Harris is a Professor of Medicine at NYU where she is also Associate Director of Clinical and Academic Affairs for the pulmonary and critical care division. In addition to that, she’s the director of the bronchiectasis and NTM program and also serves as a program director for the pulmonary and critical care fellowship.
Case Snapshot
60-year-old with CLL (in remission) → recurrent “pneumonias,” diffuse (not single-lobe), later dx’d with CVID; serial CTs: upper-lobe–predominant bronchiectasis, tree-in-bud, mucus impaction; multiple AFB+ cultures (MAC, later M. abscessus); recurrent bacterial flares (MSSA/MRSA).

CT Images

Key Learning Points
Imaging pearls
Tree-in-bud = small airways (bronchiolar) impaction/inflammation, not a diagnosis. Differential guided by distribution + chronicity:Acute/diffuse → bacterial/viral/NTM infectionDependent/basal → aspirationPersistent + nodular + bronchiectasis → NTM commonBronchiectasis CT signs (think: “ring, taper, edge”):Broncho-arterial ratio >1 (signet-ring)Lack of normal taperingVisible bronchi within 1 cm of pleuraLocation matters:Upper lobes → CF, sarcoid, prior TB/radiationMiddle lobe/lingula → NTM classic; consider ABPA if centralLower lobes → aspiration, PCD, CTD, immunodeficiency
NTM: diagnosis & when to treat
Use all three (2020 guideline frame): clinical symptoms, compatible CT, microbiology (≥2 sputum cultures or 1 bronch +, etc.).Not every positive culture = disease needing drugs. If you defer pharmacologic therapy, follow closely (symptoms, sputum, PFTs, interval CT if change).Bug matters: MAC, M. abscessus, kansasii etc. “Low-virulence” species (e.g., M. gordonae) can still flag underlying airway disease.Regimens (MAC, macrolide-susceptible): azithro + ethambutol + rifampin (intermittent for nodular-bronchiectatic; daily ± IV amikacin for fibro-cavitary/advanced).Macrolide is the backbone; the others protect against resistance.M. abscessus: check for inducible macrolide resistance (prolonged in-vitro testing).Monitoring: sputum q1–3 mo; labs (CBC/CMP), vision (ethambutol), hearing (aminoglycosides). Treat ~12 months beyond culture conversion.Anti-inflammatory macrolide for bronchiectasis is contraindicated if macrolide-susceptible NTM is present—risk of resistance.
Bronchiectasis management essentials
It’s a syndrome: symptoms/exacerbations plus CT changes.Airway clearance is foundational (exercise + devices ± hypertonic saline/DNase when indicated). Expect CT and symptom gains with adherence.Exacerbations often need ~14 days of pathogen-directed antibiotics (short courses may fail). Take the “easy win” when a conventional pathogen explains the flare.
Workup framework (start with a core bundle, then target)
Core “every patient” bundle
CBC with diff (look for eosinophilia/hematologic clues)Quantitative IgG/IgA/IgM (primary/secondary immunodeficiency)ABPA screen: total IgE + Aspergillus-specific IgE/IgGSputum cultures: routine bacteria + AFB + fungal (if producing)Baseline PFTs
Targeted tests (guided by history, distribution, microbes)
CF evaluation: sweat chloride and/or CFTR genotyping (especially with upper-lobe disease, chronic sinusitis/nasal polyps, pancreatitis/malabsorption, infertility/CAVD).PCD: nasal NO, genetics, specialized ciliary studies (adult cases may be mild and missed by genetics alone).Alpha-1 antitrypsin (never-smoker emphysema, liver hx)CTD serologies (RA, Sjögren’s, etc.), if suggestiveAspiration/upper-GI assessment when basal-predominant or reflux symptomsFor suspected/known CVID: vaccine response assessment if not on replacement (this patient was already on IVIG).
Practical diagnostic habits
Re-read the CT yourself—radiology may under-call mild bronchiectasis in ED/PE-protocol scans.Use a diagnostic time-out when the course isn’t fitting: name your working dx, list fits/mismatches, consider common diseases with atypical presentations, multi-morbidity, and can’t-miss alternatives; ask for help early; communicate uncertainty.
Teach-to-remember pearls from the case
Recurrent, geographically scattered pneumonias → think systemic causes (immunodeficiency, CF/PCD), not just focal anatomic problems.Upper-lobe bronchiectasis + CAVD is a CF red flag—even in the 60s. Adult-onset CF is real and actionable.In CF today, MSSA can be more common than Pseudomonas on culture; don’t let absence of Pseudomonas dissuade you.Airway clearance adherence can change CTs; instruct patients to ramp up before surveillance scans for a fair assessment.If symptoms abate with targeted therapy to a conventional pathogen, you may avoid immediate NTM re-treatment—but keep a tight follow-up loop.
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109. Guidelines Series: GINA Guidelines – Special Considerations in Asthma Care
28 Oct 2025· PulmPEEPs
In this episode, we’re concluding our review of the Global Initiative for Asthma (GINA) guidelines on asthma today with a cased based episode on special considerations in asthma care. We’ve covered asthma diagnosis and phenotyping, the approach to therapy inhaler and oral medical therapy, and biologic therapy. On today’s episode we’re talking about complex cases that are at the edges of the guidelines, or may be in future guidelines. To help us with this exciting topic we’re joined by an expert in the field. Enjoy!
Meet Our Guest
Dr. Meredith McCormack is a Professor of Medicine at Johns Hopkins, where she leads multiple NIH funded endeavors at understanding lung health and disease. She is the Division Director for Pulmonary and Critical Care Medicine, while also directing the Asthma Precision Medicine Center of Excellence, and the BREATHE Center, which focuses on understanding the effects of the environment on lung health and disease through research and community engagement. She is an internationally recognized expert in asthma management and is a dedicated member of the faculty who is committed to the trainees.
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 second year 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 second year 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.
Key Learning Points
Episode themesBuilt on GINA 2024: final capstone focusing on evolving topics + case-based application.
Three focal areas: (1) obesity/metabolic health (GLP-1s, metformin), (2) dual biologics vs switching, (3) de-escalating inhalers while on biologics.
Emphasis throughout on personalized care, shared decision-making, and multidisciplinary collaboration.Obesity & metabolic health in asthmaObesity affects mechanics, inflammation, and treatment response; tackling metabolic dysfunction can improve asthma control.
GLP-1 receptor agonists may provide additive benefit beyond weight loss for some patients (early clinical signals; trials ongoing).
Metformin is being studied as a potential adjunct targeting metabolic-inflammatory pathways.
Practical approach: screen/counsel on weight, activity, and metabolic disease; partner with primary care/endocrine/sleep clinics; consider GLP-1/other agents when indicated for comorbidities, with potential asthma “bonus.”
Biologics: switching vs dual therapyConsider switching/adding when control is not achieved or sustained on a biologic despite adherence.
Upstream vs downstream targets:

Upstream: anti-TSLP (e.g., tezepelumab) may help when multiple pathways/biomarkers (e.g., high IgE + eos) suggest broader blockade.Downstream: IL-5/IL-4/13/IgE agents selected to match phenotype/endotypes.
Comorbidities can drive choice:

Nasal polyps or upper airway syndromes: there are biologic options that improve upper airway symptoms in addition to asthmaAtopic dermatitis: agents with dual indications can be life-changing.
Logistics matter: injection burden/needle phobia and dosing cadence (e.g., every 2 vs 4–8 weeks) can determine real-world success.De-escalating inhalers on biologicsDon’t step down immediately. Ask patients to maintain their full regimen for ~3 months after starting a biologic to gauge true benefit.Set expectations early and share a step-down plan to prevent unsupervised discontinuation.Typical order (individualize):Remove non-essential add-ons first (e.g., antihistamines, leukotriene modifiers).Reduce ICS dose gradually (high → medium → low).Keep ICS/LABA combination among the last therapies to taper
Targets while stepping down: “normal” lung function when feasible, minimal/no day or night symptoms, full activity, no exacerbations.
When patients don’t respond to biologicsRe-check the fundamentals:Adherence/technique for inhalers and biologic.Biomarkers behaving as expected (e.g., eosinophils falling on anti-IL-5).Revisit the diagnosis and contributors/mimics (e.g., vocal cord dysfunction, upper-airway disease).
Consider moving upstream (e.g., to TSLP) if a downstream agent underperforms.
Communication & practical pearls
Use visual aids to verify what patients actually take and how (e.g., Asthma & Allergy Network inhaler pictogram).Needle issues are common; home vs clinic administration and family support can make or break adherence.Biologics are transformative for the right patient—consider them early in steroid-dependent or poorly controlled severe asthma.Think longitudinally: plan for monitoring, comorbidity management, and timely adjustments.
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108. Journal Club with BMJ Thorax – Bronchiectasis
7 Oct 2025· PulmPEEPs
We’re back with our 4th episode in our collaborative series with BMJ Thorax. This week’s episode covers four articles related to bronchiectasis and covers a range of topics in this domain including novel therapeutics, registry data to understand risk, and health related quality of life.
Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this endeavor. Each month in BMJ Thorax, a journal club is published looking at high yield and impactful publications in pulmonary medicine. We will be putting out quarterly episodes in association with Thorax to discuss a journal club publication and synthesize four valuable papers.
Meet Our Guests
Chris Turnbull is an Associate Editor for Education at Thorax. He is an Honorary Researcher and Respiratory Medicine Consultant at Oxford University Hospitals. In addition to his role as Associate Editor for Education at BMJ Thorax, he is also a prominent researcher in sleep-related breathing disorders.
Dr. George Doumat completed his medical school at the American University of Beirut and now is an internal medicine resident at UT south western in his second year of training. Prior to starting residency he was a research fellow at MGH studying chronic lung disease.
Journal Club Papers
Journal club paper from BMJ ThoraxPhase 3 Trial of the DPP-1 Inhibitor Brensocatib in BronchiectasisCathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF, a phase II randomised, double-blind, placebo-controlled, dose-finding studyFive-Year Outcomes among U.S. Bronchiectasis and NTM Research Registry PatientsAnxiety, depression, physical disease parameters and health-related quality of life in the BronchUK national bronchiectasis cohort
To submit a journal club article of your own to Thorax, you can contact Chris directly – [email protected].uk

To engage with Thorax, please use the social media channels (Twitter – @ThoraxBMJ; Facebook – Thorax.BMJ) and subscribe on your preferred platform, to get the latest episodes directly on your device each month.
Key Learning Points
Four recent papers (2 RCTs, 2 large cohorts) chosen to show both new therapeutics and real-world comorbidities/outcomes, pushing toward precision medicine.
1) ASPEN trial – brensocatib (DPP-1 inhibitor)
Design: Phase 3, ~1,700 pts, 35 countries, 52 weeks; stratified randomization by region.Results: ↓ annualized exacerbation rate (~1.0 vs 1.3/yr; RR≈0.8), longer time to first exacerbation, ~10% absolute ↑ in “exacerbation-free” patients at 1 year, QoL improved, modest FEV1 decline difference (~40 mL/yr).Take: First targeted therapy with consistent benefit; effect on lung function small but directionally supportive.Gaps: Need long-term durability, adolescent data, and comparisons/positioning in pts with asthma/COPD overlap.
2) AIRLEAF (BI 1291583) – reversible cathepsin C inhibitor
Design: Phase 2, 4 arms (3 doses + placebo), model-based dose–response analysis to optimize dose selection.Results: Overall dose–response signal; individual low-dose arms trended to fewer exacerbations but not statistically significant; skin events more common at higher doses.Take: Promising class targeting neutrophil pathway, but needs Phase 3 before clinical use.
3) U.S. Bronchiectasis & NTM Registry – 5-year outcomes
Cohort: >2,600 CT-confirmed; ~59% with baseline NTM identified.Results: 5-yr mortality ~12%; no mortality difference with vs without NTM; predictors = lower baseline FEV1, older age, male sex, prior hospitalization. FEV1 decline ~38 mL/yr. Baseline NTM group had fewer exacerbations (counterintuitive).Interpretation cautions: Likely mix of colonization vs active disease; referral/management effects in specialized centers; registry strengths (size, real-world, longitudinal) vs pitfalls (confounding, data quality, causality).
4) Bronch-UK cohort – anxiety & depression
Cohort: 1,340 adults; HADS screening.Prevalence: Anxiety ~33%, depression ~20%; many undiagnosed (≈26%/16%).Impact: Worse QoL, more severe disease; depression ~1.8× higher hospitalization risk and shorter time to severe exacerbation.Caveat: Association ≠ causation; sicker patients may have more mental health burden.
Practical takeaways for clinic
Consider brensocatib for appropriate non-CF bronchiectasis patients once accessible; frame benefits around fewer exacerbations and QoL, not big lung function gains.Do not introduce cathepsin C inhibitors outside trials yet; discuss as pipeline only.Risk stratify using FEV1, age, sex, and prior hospitalizations; expect ~40 mL/yr average FEV1 decline.Screen mental health routinely (HADS, PHQ-9, GAD-7). Build multidisciplinary pathways; consider brief CBT-style supports embedded in bronchiectasis clinics, with targeted referrals.Registry data ≠ RCTs: Use for counseling and service design, but avoid causal claims.
Research/implementation gaps highlighted
Long-term safety/efficacy and subgroup effects for brensocatib (adolescents, asthma/COPD overlap).Phase 3 confirmation for cathepsin C inhibition and dose selection.Granular NTM phenotyping (colonization vs disease) to reconcile paradoxical exacerbation signals.Scalable mental-health interventions integrated into respiratory clinics; trials to test impact on exacerbations/hospitalizations.
Pro tip from the episode
When appraising trials, check the CONSORT diagram for generalizability and look for stratification methods in multinational RCTs; in phase 2 programs, expect model-based dose–response designs that trade breadth for power.
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107. Fellows’ Case Files: University of Kansas Medical Center KUMC
1 Oct 2025· PulmPEEPs
After a brief hiatus, we are excited to be back today with another Fellows’ Case Files! Today we’re virtually visiting the University of Kansas Medical Center (KUMC) to hear about a fascinating pulmonary presentation. There are some fantastic case images and key learning points. Take a listen and see if you can make the diagnosis along with us. As always, let us know your thoughts and definitely reach out if you have an interesting case you’d like to share.
Meet Our Guests
Dr. Vishwajit Hegde completed his internal medicine residency at University of Kansas Medical Center where he stayed for fellowship and is currently a second year Pulmonary and Critical Care medicine fellow.
Dr. Sahil Pandya is an Associate Professor of Medicine and Program Director of the PCCM Fellowship at KUMC.
Case Presentation
Imaging
Infographic
Key Learning Points
1) Initial frame & diagnostic mindset
Young (26), subacute → chronic dyspnea/cough with diffuse pulmonary nodules; avoid premature closure on TB.Use a Bayesian approach: combine pre-test probability (epidemiology, exposures, tempo) with targeted tests to decide next steps.Always confirm TB when possible (micro/path + resistance testing); empiric RIPE may be reasonable but shouldn’t replace tissue when stakes are high.
2) Imaging pearls—nodular pattern recognition
Ask three things: craniocaudal distribution, symmetry, central vs peripheral.Centrilobular (spares pleura/fissures): airway-centered (e.g., NTM, bronchiolitis, tree-in-bud).Perilymphatic (tracks fissures/pleura & septa): sarcoid, lymphangitic spread.Random/diffuse (involves pleural surfaces): hematogenous spread → think miliary TB, disseminated fungal, septic emboli, metastatic disease.Interval change matters: new cavitation and confluence can upweight infection or aggressive malignancy.
3) Neuro findings—ring-enhancing lesions
Differential: septic emboli/abscess, nocardia, fungal, TB, parasites, metastases, vasculitis, sarcoid.Partner with neuroradiology for pattern nuances; treat seizures but keep searching for the unifying diagnosis.
4) Lab/serology strategy
Broad infectious workup (AFB × multiple, fungal serologies), HIV and basic immune screen.Negative/indeterminate tests don’t end the search—revisit history (e.g., Ohio travel → histo/blasto risk).
5) “Tissue is the issue”—choosing the procedure
For diffuse nodules with mediastinal adenopathy and stable patient: EBUS-TBNA + BAL, consider transbronchial or cryobiopsy.Cryobiopsy pros: larger, less crush artifact, better for molecular testing; cons: ↑ bleeding/pneumothorax vs forceps.VATS still best for certain ILD questions or if less invasive routes are non-diagnostic—but weigh patient preference and stage/likelihood of yield.
6) ROSE (rapid on-site evaluation) in bronchoscopy
Confirms adequacy in real time, steers you away from necrotic zones, helps decide when you’ve got enough for molecular studies, and when to pivot sites—reduces anesthesia time and repeat procedures.
7) Final diagnosis & management
Path: TTF-1+, CK7+, napsin A → pulmonary adenocarcinoma with a fusion driver.Therapy: Targeted TKI (crizotinib) → dramatic radiographic response of miliary lung disease and CNS lesions.Teaching point: even “miliary TB-like” lungs + CNS lesions in a 20-something can be driver-positive lung cancer—don’t let age or pattern blind you.
References and Further Reading
Desai, S., Devaraj, A., Lynch, D., & Sverzellati, N. (2020). Webb, Müller and Naidich’s high-resolution CT of the lung (6th ed.). Lippincott Williams & Wilkins.Rajeswaran, G., Becker, J. L., Michailidis, C., Pozniak, A. L., & Padley, S. P. G. (2006). The radiology of IRIS (immune reconstitution inflammatory syndrome) in patients with mycobacterial tuberculosis and HIV co-infection: appearances in 11 patients. Clinical radiology, 61(10), 833-843Poletti, V., Ravaglia, C., & Tomassetti, S. (2016). Transbronchial cryobiopsy in diffuse parenchymal lung diseases. Current opinion in pulmonary medicine, 22(3), 289-296.Norman, G. R., Monteiro, S. D., Sherbino, J., Ilgen, J. S., Schmidt, H. G., & Mamede, S. (2017). The causes of errors in clinical reasoning: cognitive biases, knowledge deficits, and dual process thinking. Academic Medicine, 92(1), 23-30.
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106. Pulm PEEPs Pearls: ICI Pneumonitis
12 Aug 2025· PulmPEEPs
We are so excited to be launching a new series here at Pulm PEEPs! We’ll be talking about high yield topics in 15 minutes or less. In this series, Furf and Monty will tackle core points and provide an overview, key points, and further reading. We’re starting with a key point review of Immune Checkpoint Inhibitor Pneumonitis. Let us know if there are other topics you want to hear about!
Key Learning Points
Epidemiology & PathophysiologyIncreasingly common as immunotherapy use grows in oncology.Caused by immune activation from PD-1, PD-L1, or CTLA-4 inhibitors.Mechanisms:Overactive T cellsAutoantibody productionCytokine-mediated inflammation (e.g., ↑IL-1, ↑IL-6) Clinical Suspicion & DiagnosisAny new respiratory symptoms in a patient currently or previously on ICI → consider ICI pneumonitis.CT findings are variable: can mimic organizing pneumonia, NSIP, ARDS, or diffuse ground glass opacities. Imaging pattern does not determine severity grade.Diagnosis is of exclusion — infection and malignancy progression must be ruled out first.Workup:Broad infectious evaluation (cultures, viral panel, fungal markers).Early bronchoscopy with BAL if feasible — typically lymphocyte-predominant in ICI pneumonitis.Screen for TB and hepatitis early (in case infliximab is needed). Severity Grading (Symptom- & O₂-based, not imaging-based)Grade 1: Asymptomatic → monitor, may hold ICI.Grade 2: Symptomatic but not hypoxic → prednisone 1 mg/kg/day PO.Grade 3–4: Hypoxemia or ICU-level care → methylprednisolone 1–2 mg/kg/day IV. Usually hold or permanently stop ICI. Steroid ManagementTypical taper: over 6 weeks for grade ≥3.Week 1: 1–2 mg/kg/dayGradual step-down to 0.25 mg/kg/day by week 5, then stop week 6.Chronic/recurrent cases may need slower tapers over months.Add GI prophylaxis and PJP prophylaxis during prolonged steroid use. If Steroids Fail (no improvement after 48–72 hrs)Consider adding:IVIG (2 g/kg over 5 days)Infliximab (TNF-α inhibitor — requires TB/hepatitis screening)Mycophenolate mofetil (1–1.5 g/day BID or TID, start at effective dose quickly)IVIG may have lower mortality in some series but comes with risks (volume overload, thrombosis, infusion reactions). Emerging TherapiesJAK inhibitors are under investigation as possible future options. Multidisciplinary CareICU management is a team sport — coordinate with oncology, critical care, infectious disease, and pharmacy.

Infographic

References and Further Reading
Managing Immune Checkpoint Inhibitor Pneumonitis in the ICU. Montemayor, Kristina et al.CHEST Critical Care, Volume 3, Issue 1, 100126Lavalle S, Masiello E, Valerio MR, Aliprandi A, Scandurra G, Gebbia V, Sambataro D. Immune checkpoint inhibitor therapy‑related pneumonitis: How, when and why to diagnose and manage (Review). Exp Ther Med. 2024 Jul 30;28(4):381. doi: 10.3892/etm.2024.12670. PMID: 39113908; PMCID: PMC11304171.Delaunay M, Prévot G, Collot S, Guilleminault L, Didier A, Mazières J. Management of pulmonary toxicity associated with immune checkpoint inhibitors. Eur Respir Rev. 2019 Nov 6;28(154):190012. doi: 10.1183/16000617.0012-2019. PMID: 31694838; PMCID: PMC9488507.
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105. ICU Acquired Weakness
29 Jul 2025· PulmPEEPs
Today we’re talking about a topic that is relevant for all critical care physicians but under-examined: ICU Acquired Weakness. We are joined by two excellent guests to walk through a case and discuss the diagnosis, pathophysiology, prevention, and treatment of ICU Acquired Weakness. Check out our associated infographics and key learning points below.
Meet Our Guests
Jim Devanney is a Physiatrist who just completed a neurocritical care fellowship at BIDMC. He is transitioning to a clinical associate position at University Health Network – University of Toronto where he will be working as a PM&R consultant within the ICU.
Kalaila Pais is a third year internal medicine resident at BIDMC, interested in pulmonary and critical care and medical education and is returning for her third Pulm PEEPs episode.
Key Learning Points
Definition & Clinical PresentationICU-AW refers to new-onset, generalized muscle weakness that arises during critical illness, not explained by other causes.It typically presents as:Symmetric, proximal > distal weaknessRespiratory muscle involvementPreserved cranial nerve functionNo sensory deficits in myopathy (sensory loss points toward neuropathy)Differential Diagnosis Using Neuroanatomical ApproachAn anatomical approach (central → peripheral) helps localize the etiology weaknessCNS: trauma, stroke, encephalitis, seizuresAnterior horn cells: viral myelitis, motor neuron diseasePeripheral nerves: Guillain-Barré, vasculitis, critical illness polyneuropathy (CIP)Neuromuscular junction: myasthenia gravis, botulism, Lamber EatonMuscle: rhabdomyolysis, inflammatory or drug-induced myopathies, critical illness myopathy (CIM)Subtypes of ICU-AWCritical Illness Myopathy (CIM):Muscle dysfunctionEarly onset (within 48 hrs)Sensation intactproximal > distal weakness
Critical Illness Polyneuropathy (CIP):Nerve involvementDistal > proximal weakness, sensory deficits
Critical Illness Polyneuromyopathy (CIPNM): Combination of both
Diagnosis
Medical Research Council Score (MRC-SS):Score < 48: ICU-AWScore < 36: severe ICU-AWHandgrip dynamometry: <11 kg (men), <7 kg (women)Electrophysiology: EMG/NCS to distinguish CIM vs CIPMuscle ultrasound: bedside monitoringMRI/CT/Muscle biopsy: rarely used due to practical limitation
Risk Factors
Modifiable:
Hyper/hypoglycemiaElectrolyte derangementParenteral nutritionImmobilityMedications (steroids, NM blockers, sedatives, aminoglycosides)
Non-modifiable:
Age, female sex, comorbiditiesSeverity of illness, prolonged ventilationSepsis, multi-organ failure
Management & Prevention
Prevention is key:Early treatment of sepsis and inflammationGlycemic controlEarly enteral nutritionMinimize sedation (A-F bundle)Early mobilization and physical therapyNMES (neuromuscular electrical stimulation): emerging therapy, needs more evidence
Outcomes
Short-term: increased LOS, ventilation duration, mortalityLong-term: decreased function, discharge to rehab, prolonged recovery
Final Takeaways
Prevention is crucial — start interventions early.Systematic approach to ICU weakness helps rule out dangerous mimics.ICU-AW is common but often under-recognized — awareness and early rehab can significantly impact recovery.
Infographics
References and Further Reading

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Devlin JW, Skrobik Y, Gélinas C, et al. Critical Care Medicine. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299.
The ABCDEF Bundle: Science and Philosophy of How ICU Liberation Serves Patients and Families. Ely EW. Critical Care Medicine. 2017;45(2):321-330. doi:10.1097/CCM.0000000000002175.
Caring for Critically Ill Patients With the ABCDEF Bundle: Results of the ICU Liberation Collaborative in Over 15,000 Adults. Pun BT, Balas MC, Barnes-Daly MA, et al. Critical Care Medicine. 2019;47(1):3-14. doi:10.1097/CCM.0000000000003482.
Delirium in Critical Illness: Clinical Manifestations, Outcomes, and Management. Stollings JL, Kotfis K, Chanques G, et al. Intensive Care Medicine. 2021;47(10):1089-1103. doi:10.1007/s00134-021-06503-1.
ICU-acquired Weakness. Vanhorebeek I, Latronico N, Van den Berghe G. Intensive Care Medicine. 2020;46(4):637-653. doi:10.1007/s00134-020-05944-4.
Clinical Review: Intensive Care Unit Acquired Weakness. Hermans G, Van den Berghe G. Critical Care (London, England). 2015;19:274. doi:10.1186/s13054-015-0993-7.
Best Practices for Conducting Interprofessional Team Rounds to Facilitate Performance of the ICU Liberation (ABCDEF) Bundle. Stollings JL, Devlin JW, Lin JC, et al. Critical Care Medicine. 2020;48(4):562-570. doi:10.1097/CCM.0000000000004197.
ABCDE and ABCDEF Care Bundles: A Systematic Review of the Implementation Process in Intensive Care Units. Moraes FDS, Marengo LL, Moura MDG, et al. Medicine. 2022;101(25):e29499. doi:10.1097/MD.0000000000029499.
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104. Pulm PEEPs on Core IM – Pleural Effusions
9 Jul 2025· PulmPEEPs
Hi Pulm PEEPs! Today we have a special episode for you. Monty and Furf were invited on the Core IM Podcast to talk about the work up and management of pleural effusions. This is a great overview and we hope you enjoy listening as much as we did recording. If you want a deeper dive into pleural effusions check out our prior series:
36. Top Consults Series: Approach to Pleural Effusions

37. Top Consults: Approach to Parapneumonic Effusions
49. Top Consults: Malignant Pleural Effusions
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103. Fellows’ Case Files: University of Virginia
1 Jul 2025· PulmPEEPs
Today, we’re virtually visiting the University of Virginia for another Fellows’ Case Files. This is a fantastic case that covers ARDS, the infectious work up of an immunosuppressed patient, and the evaluation of undifferentiated shock. Please let us know what you think of the episode and always feel free to reach out with interesting cases!

Meet Our Guests
John Popovich completed his residency training and chief year at UVA and has stayed on there for his pulmonary and critical care fellowship.
Tim Scialla is an associate professor of medicine at UVA. He completed his residency and fellowship at Johns Hopkins Hospital where he was also an ACS. His clinical and research focuses are advanced airways disease. He is also the program director of the PCCM fellowship.
Matt Freedman completed his residency training at Virginia Commonwealth University and is currently a second year fellow at University of Virginia.

Case Presentation
Patient: 52-year-old male with psoriasis, HIV/AIDS (CD4 count: 71), presenting with progressive shortness of breath, fever, non-productive cough, and weight loss.
Vital signs: Febrile (103°F), tachycardic (HR 110), hypoxemic on 6L O₂ (SpO₂ 90–92%).
Exam: Diffuse crackles, ill-appearing.
Imaging: CXR and CT showed bilateral upper lobe infiltrates, ground-glass opacities, septal thickening, and peripheral cystic changes.

Infographics
POCUS algorithms for investigating shock
Shock physiology:

Key Learning Points
Diagnostic Reasoning in Immunocompromised Hosts
Framework: Anchor the differential based on type of immunosuppression.HIV/AIDS → T-cell dysfunction, affecting susceptibility to PCP, TB, CMV, fungi (e.g. histo/blasto), and common CAP organisms.PCP considerations:PCP can occur despite prophylaxis (e.g. Bactrim), especially if adherence or resistance issues exist.Classic symptoms in AIDS: acute, febrile, hypoxemic respiratory failure.
Use of Serum Markers and Imaging
LDH: Elevated in PCP, but non-specific. High negative predictive value when normal.1,3-β-D-glucan: Elevated in PCP and other fungal infections. Very sensitive for PCP (up to 95%).Imaging: Ground-glass opacities with cystic changes support PCP diagnosis.
Role of Bronchoscopy and Diagnostic Yield
BAL studies to obtain:DFA for PCP (rapid, high specificity, lower sensitivity)PCR for PCP (higher sensitivity, slower turnaround)Cultures: bacterial, fungal, mycobacterialCytology, galactomannan, histo/blasto urine antigensBronch Risk-Benefit:Can change management in 40–60% of cases.Complication rate: ~10–15%, most often hypoxemia.Heuristic for pre-bronch ABG on non-rebreather:PaO₂ >150 → likely safe100–150 → ~25% risk of intubation<100 → high risk of decompensation
Steroids in PCP and Severe CAP
Steroids indicated in PCP with significant hypoxemia (PaO₂ <70 mmHg).With new CAP guidelines (Cape Cod trial), steroids may also be considered in severe bacterial CAP.
Shock Evaluation in ICU
Framework: Simplify into likely causes — distributive most common, but rule out cardiogenic, obstructive, hypovolemic.Physical exam + POCUS essential early.POCUS: cardiac views, IVC, lung US, abdominal free fluid.Low EF doesn’t exclude distributive shock.PA catheter (Swan) utility:Useful when physiology unclear or when tracking response to therapy is critical.Swan data in this patient: low CVP and wedge, high SVR → distributive shock, not cardiogenic despite low EF.
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102. Journal Club with BMJ Thorax – Sleep and Non-Invasive Ventilation
17 Jun 2025· PulmPEEPs
Today is our third episode in our collaborative series with BMJ Thorax. Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this endeavor. Each month in BMJ Thorax, a journal club is published looking at high yield and impactful publications in pulmonary medicine. We will be putting out quarterly episodes in association with Thorax to discuss a journal club publication and synthesize four valuable papers. This week’s episode covers four articles related to obstructive sleep apnea therapies, and the use of non-invasive ventilation and high flow nasal cannula for intubation and COPD exacerbations.
Meet Our Guests
Chris Turnbull is an Associate Editor for Education at Thorax. He is an Honorary Researcher and Respiratory Medicine Consultant at Oxford University Hospitals. In addition to his role as Associate Editor for Education at BMJ Thorax, he is also a prominent researcher in sleep-related breathing disorders.
Natalie McLeod is a resident in respiratory medicine and is currently doing a clinical fellowship in sleep and ventilation at Oxford University Hospitals.
Journal Club Papers
Journal club article from ThoraxEffect of CPAP therapy on blood pressure in patients with obstructive sleep apnoea: a worldwide individual patient data meta-analysisHypoglossal nerve stimulation for obstructive sleep apnea in adults: An updated systematic review and meta-analysisNoninvasive Ventilation for Preoxygenation during Emergency IntubationNasal high flow or noninvasive ventilation? navigating hypercapnic COPD exacerbation treatment: A randomized noninferiority clinical trial
To submit a journal club article of your own to Thorax, you can contact Chris directly – [email protected].uk

To engage with Thorax, please use the social media channels (Twitter – @ThoraxBMJ; Facebook – Thorax.BMJ) and subscribe on your preferred platform, to get the latest episodes directly on your device each month.
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101. RFJC – NAVIGATOR
3 Jun 2025· PulmPEEPs
We’re back with another Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the NAVIGATOR trial published in NEJM in 2021 evaluating tezepelumab for adults with asthma.
Article and Reference
We are talking today about the NAVIGATOR trial evaluating the use of tezepelumab in adults with asthma.
Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, Brightling CE, Griffiths JM, Hellqvist Å, Bowen K, Kaur P, Almqvist G, Ponnarambil S, Colice G. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975. PMID: 33979488.
https://www.nejm.org/doi/full/10.1056/NEJMoa2034975
Key Learning Points
Background & Rationale
Asthma biologics already exist, targeting IgE and type 2 cytokines (IL-4, IL-5, IL-13), but there’s an unmet need for patients with non-allergic or non-eosinophilic phenotypes.Tezepelumab is a monoclonal antibody targeting TSLP (thymic stromal lymphopoietin), an upstream mediator of both T2 and non-T2 inflammation, offering a potentially broader therapeutic effect.

Study Design (Navigator Trial)
Phase 3, double-blind, placebo-controlled RCTConducted in 18 countries from 2017-2020N = 1,061 patients, aged 12-80 with moderate to severe asthmaAll were on medium/high-dose ICS + controller medRequired ≥2 exacerbations in prior year

Outcomes
Primary Outcome: Annualized rate of asthma exacerbations (events per patient-year)Secondary Outcomes:Change in pre-bronchodilator FEV₁Symptoms & quality of life (with predefined MCIDs)Subgroup analyses by eosinophil count, FeNO, and perennial allergen sensitivity

Key Inclusion/Exclusion
Inclusion: 12-80 years, guideline-based therapy, ≥2 exacerbationsExclusion: recent biologic use, mild/asymptomatic asthma, no reversibility on spirometry

Patient Population (Table 1 Summary)
Middle-aged, predominantly white, femalePoorly controlled severe asthma despite high-intensity therapy~75% on high-dose ICS, ~10% on oral steroids~40% had normal FeNO~60% had eosinophils <300Median IgE ~195

Results
Efficacy:
Annualized exacerbation rate:0.93 (tezepelumab) vs. 2.1 (placebo)Rate ratio: 0.44, p<0.001 (very positive)In eosinophils <300 group: rate ratio 0.59, still effectiveFEV₁ improved by ~+0.25 L (vs. +0.09 L placebo), significant & sustained from week 2 onwardQuality of life: statistically improved but did not meet MCID, so unclear clinical impactSeverity of exacerbations reduced: fewer hospitalizations & ED visits in the treatment arm~40% of treated patients still had some exacerbations → not a cure, but improves severity
Safety:
Very well tolerated77% reported adverse events (more common in placebo)No anaphylaxis, no GBS, no cancer signalMost common AEs: URTI, headache, nasopharyngitisInjection site reactions: 3.6%Serious AEs were lower in drug arm than placebo

Overall Takeaway
Tezepelumab significantly reduces asthma exacerbations (including in patients with low eosinophils), improves lung function, and is safe and well tolerated.Provides a broad-acting biologic option even for patients who may not be eligible for existing T2-high biologics.Now widely used as part of the asthma biologic armamentarium for poorly controlled asthma despite maximal inhaled therapy.
Infographic:
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Episodes

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

119. Guideline Series: Pulmonary Embolism

118. Pulm PEEPs Pearls: Methacholine Challenge

117. Pulm PEEPs Pearls: Spontaneous Breathing Trials

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

115. RFJC – FIBRONEER-IPF

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

113. RFJC – PREDMETH

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

111. Pulm PEEPs Pearls: Methylene Blue

110. Pulm PEEPs at CHEST 2025 – Widened Airways and Narrowed Differentials

109. Guidelines Series: GINA Guidelines – Special Considerations in Asthma Care

108. Journal Club with BMJ Thorax – Bronchiectasis

107. Fellows’ Case Files: University of Kansas Medical Center KUMC

106. Pulm PEEPs Pearls: ICI Pneumonitis

105. ICU Acquired Weakness

104. Pulm PEEPs on Core IM – Pleural Effusions

103. Fellows’ Case Files: University of Virginia

102. Journal Club with BMJ Thorax – Sleep and Non-Invasive Ventilation

101. RFJC – NAVIGATOR