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.

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

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

Meet Our Guest

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

Article and Reference

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

Key Learning Points

Why these guidelines matter:

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

New PE clinical categories (A through E):

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

Diagnostic approach:

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

Anticoagulation updates:

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

Advanced therapies:

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

PERT teams:

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

Post-PE follow-up:

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

Infographics

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 response

Step 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 days

Inhaled corticosteroids, leukotriene blockers, and antihistamines do not significantly affect the test acutely — continue these. Withdrawing ICS also carries its own risk for asthma patients.

Practical tip: Spell out exactly what to hold and when — for both the patient and the PFT lab — at the time the test is ordered.

Interpreting Results

Negative Test (PC20 > 16 mg/mL)

Very high negative predictive value in symptomatic adults.

Makes current asthma quite unlikely (assuming proper test conduct).

This is the test’s greatest strength: it is an excellent rule-out test.

Positive Test (PC20 ≤ 8–16 mg/mL)

More nuanced — airway hyperresponsiveness is not unique to asthma.

Can be positive in: chronic cough, allergic rhinitis, COPD, and even some healthy asymptomatic individuals.

A positive result raises probability but must be interpreted alongside the clinical story, variable respiratory symptoms, peak flow variability, FeNO, and ICS response.

Safety and Risks

Overall, the test is quite safe; significant adverse effects are rare.

Temporary breathing discomfort is expected (bronchoconstriction is being induced).

Severe bronchospasm is possible:

A trained clinician should be available; SABA inhaler/nebulizer must be immediately on hand; a physician should be reachable in the facility.

Contraindications / cautions:

Avoid if FEV1 < 70% predicted or < 1–1.5 L (baseline obstruction greatly increases risk).

Avoid within 3 months of an acute cardiac event (rare risk of cardiac events with unstable cardiac disease).

Five Pearls — Quick Recap

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/10.1080/02770903.2020.1739704

Davis BE, Blais CM, Cockcroft DW. Methacholine challenge testing: comparative pharmacology. J Asthma Allergy. 2018 May 14;11:89-99. doi: 10.2147/JAA.S160607. PMID: 29785128; PMCID: PMC5957064.

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 testing

An SBT is a stress test for post-extubation work of breathing, not just a ventilator check.

The goal is to balance sensitivity and specificity:

Too hard → unnecessary failures and delayed extubation

Too easy → false positives and higher risk of reintubation

Common SBT modalities and how they compare

T-piece

No inspiratory support and no PEEP

Highest work of breathing

Most “physiologic” but often too strict

Pressure support (PS) + PEEP (e.g., 5/5 or 8/5)

Offsets ETT resistance and provides modest assistance

Easier to pass than T-piece

CPAP (0/5)

No inspiratory help, but provides PEEP to counter ETT resistance

Sits between PS and T-piece in difficulty

Evidence favors pressure-supported SBTs for most patients

Large meta-analysis (~6,000 patients, >40 RCTs):

Pressure-supported SBTs increase successful extubation (~7% absolute benefit)

No increase in reintubation rates

Trials (e.g., FAST trial):

Patients pass SBTs earlier

Leads to earlier extubation and fewer ventilator-associated risks

Bottom line: A 30-minute PS 5/5 SBT is evidence-based and appropriate for most stable ICU patients

When a T-piece still makes sense

T-piece SBTs are useful when:

Cost of reintubation is high

Difficult airway

Prior failed extubation

Pretest probability of success is low

Prolonged or difficult weaning

Tracheostomy vs extubation decisions

Need to mimic physiology without positive pressure

In LV dysfunction or pulmonary edema even small amounts PEEP may significantly improve physiology

Some centers use a hybrid approach: PS SBT → short confirmatory T-piece before extubation

CPAP as a middle ground

Rationale:

Allows full patient effort while compensating for ETT resistance

Evidence:

Fewer and smaller trials

Possible modest improvement in extubation success

No clear mortality or LOS benefit

Reasonable option based on patient physiology, institutional protocols, and clinician comfort

No single “perfect” SBT mode

Across PS, T-piece, CPAP, and newer methods (e.g., high-flow via ETT) there are no consistent differences in mortality or length of stay

What matters most:

Daily protocolized screening

Thoughtful bedside clinical judgment

Matching SBT difficulty to patient-specific risk

Institutional variation is normal—and acceptable

Examples:

PS 10/5 in postoperative surgical ICU patients

PS 5/0 as an intermediate difficulty option

Key question clinicians should ask: What does passing or failing this specific SBT tell me about this patient’s likelihood of post-extubation success?

Take-home pearls

SBTs 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.​

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

Meet Our Co-Hosts

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

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

Key Learning Points

1) Episode Roadmap

How to set treatment goals, assess symptom burden, and risk-stratify patients with suspected/confirmed pulmonary arterial hypertension (PAH).

What tools to use to re-evaluate patients on treatment

Intro to major PAH medication classes and how they map to pathways.

2) Case-based diagnostic reasoning

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

Key reasoning move: start broad (Groups 2–5) and narrow using history/exam/testing.

In a young patient without obvious left heart or lung disease, think more about Group 1 PAH (idiopathic/heritable/associated).

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

More common: high-output PH from AVMs (often hepatic/pulmonary)

Rare (1–2% mentioned): true PAH phenotype (vascular remodeling; associated with ALK1 in some patients), behaving like Group 1 PAH.

3) Functional class assessment

WHO Functional Class:

Class I: no symptoms with ordinary activity, only with exertion

Class II: symptoms with ordinary activity

Class III: symptoms with less-than-ordinary activity (can’t do usual chores/shopping without dyspnea)

Class IV: symptoms at rest

Practical bedside tip they give:

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

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

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

ESC/ERS approach at diagnosis (as described):

Use a 3-strata model predicting 1-year mortality:

Low: <5%

Intermediate: 5–20%

High: >20%

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

Clinical progression, signs of right heart failure, syncope

WHO FC

Biomarkers (NT-proBNP)

Exercise capacity (6MWD)

Hemodynamics

Imaging (echo; sometimes cardiac MRI)

CPET (peak VO₂; VE/VCO₂ slope)

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

REVEAL 2.0:

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

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

5) Treatment goals and follow-up philosophy

What they explicitly prioritize:

Help patients feel better, live longer, and stay out of the hospital

Use risk tools to communicate prognosis and to track improvement

Reassess frequently (they mention ~every 3 months early on) until low risk is achieved

“Time-to-low-risk” is an important treatment goal

Also emphasized:

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

6) Medication classes for the treatment of PAH

Nitric oxide–cGMP pathway

PDE5 inhibitors: sildenafil, tadalafil

Soluble guanylate cyclase stimulator: riociguat

Important safety point: don’t combine PDE5 inhibitors with riociguat (risk of significant hypotension/hemodynamic effects)

Endothelin receptor antagonists (ERAs)

“-sentan” drugs: bosentan (less used due to side effects/interactions), ambrisentan, macitentan

Teratogenicity emphasized

Hepatotoxicity that requires LFT monitoring

Can cause fluid retention and peripheral edema

Prostacyclin pathway

Prostacyclin analogs/agonists:

Epoprostenol (potent; short half-life; IV administration)

Treprostinil (IV/SubQ/oral/inhaled options)

Selexipag (oral prostacyclin receptor agonist)

7) Sotatercept (post-guidelines)

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

Mechanism: ligand trap affecting TGF-β signaling / remodeling biology

Positioned as potentially more disease-modifying than pure vasodilators

Still evolving: where to place it earlier vs later in regimens is an active question in the field

8) How risk category maps to initial treatment intensity

General approach they outline:

High risk at diagnosis: parenteral prostacyclin (IV/SubQ) strongly favored, often aggressive early

Intermediate risk: at least dual oral therapy (typically PDE5i + ERA); escalate if not achieving low risk

Low risk: at least one oral agent; many still use dual oral depending on etiology/trajectory

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

 References and Further Reading

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

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

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

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

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