108. Journal Club with BMJ Thorax – Bronchiectasis

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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

To submit a journal club article of your own to Thorax, you can contact Chris directly – christopher.turnbull@ouh.nhs.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

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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

  1. 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.
  2. 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), 833-843
  3. Poletti, V., Ravaglia, C., & Tomassetti, S. (2016). Transbronchial  cryobiopsy in diffuse parenchymal lung diseases. Current opinion in pulmonary medicine, 22(3), 289-296.
  4. 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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Radiology Rounds – 9/24/25

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We’re back with another Pulm PEEPs Radiology Rounds!

That’s right! All of the findings are present

History and physical exam are essential. Here are a few can’t miss diagnoses when working up a young adult with bilateral hilar adenopathy.

Pathology is consistent with a non-caseating granuloma. What is the most likely diagnosis?

Imaging and pathology were consistent with sarcoidosis and after negative work-up for alternative causes. The patient will follow-up with outpatient pulmonary for sarcoidosis management. Don’t forget about the Sarcoid 1-2-3 sign!

106. Pulm PEEPs Pearls: ICI Pneumonitis

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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

  1. Epidemiology & Pathophysiology
    • Increasingly common as immunotherapy use grows in oncology.
    • Caused by immune activation from PD-1, PD-L1, or CTLA-4 inhibitors.
    • Mechanisms:
      1. Overactive T cells
      2. Autoantibody production
      3. Cytokine-mediated inflammation (e.g., ↑IL-1, ↑IL-6)
  1. Clinical Suspicion & Diagnosis
    • Any 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).
  1. 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.
  1. Steroid Management
    • Typical taper: over 6 weeks for grade ≥3.
      • Week 1: 1–2 mg/kg/day
      • Gradual 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.
  1. 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).
  1. Emerging Therapies
    • JAK inhibitors are under investigation as possible future options.
  1. Multidisciplinary Care
    • ICU management is a team sport — coordinate with oncology, critical care, infectious disease, and pharmacy.

 

Infographic

 

References and Further Reading

  1. Managing Immune Checkpoint Inhibitor Pneumonitis in the ICU. Montemayor, Kristina et al.CHEST Critical Care, Volume 3, Issue 1, 100126
  2. Lavalle 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.
  3. 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

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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 Presentation

  • ICU-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 weakness
  • CNS: 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-AW
  • Critical 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-AW
      • Score < 36: severe ICU-AW
    • Handgrip dynamometry: <11 kg (men), <7 kg (women)
    • Electrophysiology: EMG/NCS to distinguish CIM vs CIP
    • Muscle ultrasound: bedside monitoring
    • MRI/CT/Muscle biopsy: rarely used due to practical limitation

    Risk Factors

    Modifiable:

    • Hyper/hypoglycemia
    • Electrolyte derangement
    • Parenteral nutrition
    • Immobility
    • Medications (steroids, NM blockers, sedatives, aminoglycosides)

    Non-modifiable:

    • Age, female sex, comorbidities
    • Severity of illness, prolonged ventilation
    • Sepsis, multi-organ failure

     Management & Prevention

    • Prevention is key:
      • Early treatment of sepsis and inflammation
      • Glycemic control
      • Early enteral nutrition
      • Minimize sedation (A-F bundle)
      • Early mobilization and physical therapy
    • NMES (neuromuscular electrical stimulation): emerging therapy, needs more evidence

    Outcomes

    • Short-term: increased LOS, ventilation duration, mortality
    • Long-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

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    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

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    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, mycobacterial
      • Cytology, galactomannan, histo/blasto urine antigens
    • Bronch 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 safe
        • 100–150 → ~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

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    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

    To submit a journal club article of your own to Thorax, you can contact Chris directly – christopher.turnbull@ouh.nhs.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

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    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 RCT
    • Conducted in 18 countries from 2017-2020
    • N = 1,061 patients, aged 12-80 with moderate to severe asthma
    • All were on medium/high-dose ICS + controller med
    • Required ≥2 exacerbations in prior year

     

    📌 Outcomes

    • Primary Outcome: Annualized rate of asthma exacerbations (events per patient-year)
    • Secondary Outcomes:
      • Change in pre-bronchodilator FEV₁
      • Symptoms & 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 exacerbations
    • Exclusion: recent biologic use, mild/asymptomatic asthma, no reversibility on spirometry

     

    📌 Patient Population (Table 1 Summary)

    • Middle-aged, predominantly white, female
    • Poorly controlled severe asthma despite high-intensity therapy
    • ~75% on high-dose ICS, ~10% on oral steroids
    • ~40% had normal FeNO
    • ~60% had eosinophils <300
    • Median 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 effective
    • FEV₁ improved by ~+0.25 L (vs. +0.09 L placebo), significant & sustained from week 2 onward
    • Quality of life: statistically improved but did not meet MCID, so unclear clinical impact
    • Severity 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 tolerated
    • 77% reported adverse events (more common in placebo)
    • No anaphylaxis, no GBS, no cancer signal
    • Most common AEs: URTI, headache, nasopharyngitis
    • Injection 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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    100. ATS 2025 Critical Care Assembly: The Future of Mechanical Ventilation

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    We are podcasting today directly from ATS 2025 in San Francisco! Every year, in collaboration with the ATS Critical Care Assembly, we highlight some of the scientific symposium programming from the conference. Today, Furf and Monty sit down with the three chairs of the scientific symposium entitled: Mechanical Ventilation of the Future: New Foundations For Ventilator Strategies.

    Meet Our Guests

    Juliana Ferreira is an Associate Professor at the University of Sao Paulo, Brazil where she is also co-director of the pulmonary and critical care fellowship program. She is an MD, PhD, and a physician scientist with specific interests in mechanical ventilation and medical education. Finally, she serves ATS as the ATS MECOR Latin America Director.

    Bhakti Patel is an Assistant Professor Medicine at the University of Chicago. She is a dedicated researcher and educator. Her research focuses on non-invasive ventilator support.

    Akram Khan is an Associate Professor of Medicine at Oregon Health and Science University. Akram is a pulmonary, critical care, and sleep provider with specific clinical interests in critical illness, pulmonary vascular disease and sleep apnea. Additionally, he is an accomplished translational science researcher.

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