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 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.

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.

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).

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

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

Key Learning Points

1) Why airway clearance matters in non-CF bronchiectasis

Non-CF bronchiectasis is defined by irreversible bronchial dilation with impaired mucociliary clearance, leading to mucus retention.

Retained sputum drives the classic vicious cycle: mucus → infection → neutrophilic inflammation → airway damage → worse clearance.

Airway clearance techniques (ACTs) are meant to interrupt this cycle, primarily by improving mucus mobilization and symptom control.

2) What ACTs are trying to achieve clinically

Main benefits are:

More effective sputum clearance

Reduced cough/dyspnea burden

Improved activity tolerance and quality of life

Effects on spirometry are usually small.

Exacerbation reduction is possible, but evidence is mixed—some longer-term data suggest benefit for specific techniques.

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

Breathing-based techniques (device-free, flexible)

ACBT (Active Cycle of Breathing Technique): breath control → deep breaths with holds → huffing.

Pros: portable, adaptable, good first-line option.

Key requirement: teaching/coaching to get technique right.

Autogenic drainage: controlled breathing at different lung volumes to move mucus from peripheral → central airways.

Pros: no device, can work well once learned.

Cons: more technically demanding, needs training and practice.

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

PEP: back-pressure helps prevent small airway collapse during exhalation; often paired with huff/cough.

Oscillatory PEP (Flutter/Acapella/Aerobika): adds oscillation that many patients find easy and satisfying to use.

Good fit for: people who benefit from airway stenting, want something portable, and prefer a device.

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

HFCWO (“the vest”): external chest wall oscillation; helpful for high sputum volumes, dexterity limits, or difficulty coordinating breathing maneuvers.

Postural drainage/percussion/vibration: caregiver/therapist-assisted options; still useful but consider:

GERD/reflux risk with certain positions

Hemoptysis risk with vigorous techniques

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

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

Sputum burden (volume/viscosity)

Strength, coordination, cognition, dexterity

Comorbidities (GERD, hemoptysis history, severe obstruction/airway collapse)

Lifestyle + portability (what they’ll actually do)

Cost/access and availability of respiratory therapy/physio support

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

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

ACTs reliably improve sputum expectoration and often symptoms/QoL.

QoL/cough scores (e.g., SGRQ, LCQ) tend to improve modestly, particularly with oscillatory PEP and some vest studies.

Lung function: typically minimal change; occasional short-term FEV₁ benefit is reported in some vest trials.

Exacerbations: mixed overall; the script highlights a longer-term RCT of ELTGOL showing fewer exacerbations at 12 months vs placebo exercises.

Safety: generally excellent; main cautions are hemoptysis and reflux (depending on technique/positioning).

6) Special population pearls

Hemoptysis / fragile airways: start with gentle breathing-based ACTs (ACBT, controlled huffing); avoid overly vigorous oscillatory/manual methods if concerned.

Severe obstruction or early airway collapse: PEP/oscillatory PEP can help by keeping small airways open on exhalation.

Mobility/coordination barriers: consider HFCWO vest or simple oscillatory PEP devices to enable daily adherence.

During exacerbations: keep it simple—1–2 reliable techniques, prioritize daily consistency, and re-check technique.

7) The “real” bottom line

Start with simple, self-manageable options (often ACBT ± PEP).

The “best” ACT is the one the patient will do consistently.

Reassess technique and fit over time; education and demonstration are part of the therapy.

References and Further Reading

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

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

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

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

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