PulmPEEPs

Today, Dave Furfaro, Luke Hedrick, and Robert Wharton discuss the PREDMETH trial published in The New England Journal of Medicine in 2025. This was a non-inferiority trial comparing prednisone to methotrexate for upfront therapy in treatment-naive sarcoidosis patients. Listen in for a break down of the trial, analysis, and clinically applicable pearls. Article and Reference Todays’ episode discusses the PREDMETH trial published in NEJM in 2025. Kahlmann V, Janssen Bonás M, Moor CC, Grutters JC, Mostard RLM, van Rijswijk HNAJ, van der Maten J, Marges ER, Moonen LAA, Overbeek MJ, Koopman B, Loth DW, Nossent EJ, Wagenaar M, Kramer H, Wielders PLML, Bonta PI, Walen S, Bogaarts BAHA, Kerstens R, Overgaauw M, Veltkamp M, Wijsenbeek MS; PREDMETH Collaborators. First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate. N Engl J Med. 2025 Jul 17;393(3):231-242. doi: 10.1056/NEJMoa2501443. Epub 2025 May 18. PMID: 40387020. https://www.nejm.org/doi/full/10.1056/NEJMoa2501443 Meet Our Hosts Luke Hedrick is an Associate Editor at Pulm PEEPs and runs the Rapid Fire Journal Club Series. He is a senior PCCM fellow at Emory, and will be starting as a pulmonary attending at Duke University next year. Robert Wharton is a recurring guest on Pulm PEEPs as a part of our Rapid Fire Journal Club Series. He completed his internal medicine residency at Mt. Sinai in New York City, and is currently a first year pulmonary and critical care fellow at Johns Hopkins. Key Learning Points Clinical context Prednisone remains the traditional first-line treatment for pulmonary sarcoidosis when treatment is indicated, with evidence for short-term improvements in symptoms, radiographic findings, and pulmonary function—but with substantial, familiar steroid toxicities (weight gain, insomnia, HTN/DM, infection risk, etc.). Despite widespread use, glucocorticoids haven’t been robustly tested head-to-head against many alternatives as initial therapy, and evidence for preventing long-term decline (especially in severe disease) is limited. Immunosuppressants (like methotrexate) are often used as steroid-sparing agents, but guideline recommendations are generally conditional/low-quality evidence, and practice varies. Why PREDMETH matters It addresses a real-world question: Can methotrexate be an initial alternative to prednisone in pulmonary sarcoidosis, rather than being reserved only for steroid-sparing later? It also probes a common clinical belief: MTX has slower onset than prednisone (often assumed, not well-proven). Trial design (what to know) Open-label, randomized, noninferiority trial across 17 hospitals in the Netherlands. Included patients with pulmonary sarcoidosis who had a clear pulmonary indication to start systemic therapy (moderate/severe symptoms plus objective risk features like reduced FVC/DLCO or documented decline, plus parenchymal abnormalities). Excluded: non–treatment-naïve patients and those whose primary indication was extrapulmonary disease. Treat-to-tolerability with escalation: both drugs started low and were slowly increased; switch/add-on allowed for inadequate efficacy or unacceptable side effects. Primary endpoint: change in FVC (with the usual caveat that FVC is “objective-ish,” but effort-dependent and not always patient-centered). Noninferiority margin: 5% FVC, justified as within biologic/measurement variation and “not clinically relevant.” Outcomes assessed at weeks 4, 16, 24; powered for ~110 patients to detect the NI margin. Patient population (who this applies to) Mostly middle-aged (~40s) with mild-to-moderate physiologic impairment on average (FVC ~77% predicted; DLCO ~70% predicted). Netherlands-based cohort with limited Black representation (~7%), which matters for generalizability. Would have been helpful to know more about comorbidities (e.g., diabetes), which can strongly influence prednisone risk. Main findings (what happened) Methotrexate was noninferior to prednisone at week 24 for FVC: Between-group difference in least-squares mean change at week 24: −1.17 percentage points (favoring prednisone) with CI −4.27 to +1.93, staying within the 5% NI margin. Timing mattered: Prednisone showed earlier benefit (notably by week 4) in FVC and across quality-of-life measures. By week 24, those early differences largely washed out—possibly because MTX “catches up,” and/or because crossover increased over time. In their reporting, MTX didn’t meet noninferiority for FVC until week 24, supporting the practical message that prednisone works faster. Crossover and analysis nuance (important for interpretation) Crossover was fairly high, which complicates noninferiority interpretation: MTX arm: some switched to prednisone for adverse events and others had prednisone added for disease progression/persistent symptoms. Prednisone arm: some had MTX added. In noninferiority trials, heavy crossover can bias intention-to-treat analyses toward finding “no difference” (making noninferiority easier to claim). Per-protocol analyses avoid some of that but introduce other biases. They reported both. Safety signals (what to remember clinically) Adverse events were very common in both arms (almost everyone), mostly mild. Side-effect patterns fit expectations: Prednisone: more insomnia (and classic steroid issues). MTX: more headache/cough/rash, and notably liver enzyme elevations (about 1 in 4), with a small number discontinuing. Serious adverse events were rare; numbers were too small to confidently separate “signal vs noise,” but overall known risk profiles apply. Limitations (why you shouldn’t over-read it) Open-label design, and FVC—while objective-ish—is still effort-dependent and can be influenced by expectation/behavior. Small trial, limiting subgroup conclusions (e.g., severity strata, different phenotypes). Generalizability issues (Netherlands demographics; US populations have higher rates of obesity/metabolic syndrome, which may tilt the steroid risk-benefit equation). Crossover reduces precision and interpretability of between-group differences over time. Practice implications (the “so what”) For many patients with pulmonary sarcoidosis needing systemic therapy, MTX is a reasonable initial alternative to prednisone when thinking long-term tolerability and steroid avoidance. Prednisone likely provides faster symptom/QoL relief in the first weeks—so it may be preferable when rapid improvement is important. The trial strengthens the case for a patient-centered discussion: short-term relief vs side-effect tradeoffs, and the possibility of early combination therapy in more severe cases (suggested, not proven).

Today we’re kicking off another segment in our Guidelines Series, and doing a deep dive into the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Over a series of episodes we’ll talk about the most recent updates to definitions around pulmonary hypertension, recognizing and diagnosing Group 1 – 5 pulmonary hypertension, risk stratification, and treatments. In this first episode, we will review the most recent definitions, including changes to the definitions that were new in 2022. We’ll then talk about recognizing and diagnosing pulmonary hypertension with tips and insights along the way. Meet Our Co-Hosts Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a pulmonary and critical care medicine fellow alongside Tom. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs. And she also loves bedside medical education. Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered in the care they have going forward. Infographic Key Learning Points Why to have a high index of suspicion for pulmonary hypertension (PH) PH often presents subtly with slowly progressive dyspnea on exertion, fatigue, lightheadedness, exertional chest pain, or syncope. There’s often a delay of 1–2+ years from symptom onset to diagnosis, which is associated with worse mortality. Early recognition and treatment, especially for pulmonary arterial hypertension (PAH, WHO group 1), can significantly change outcomes. When to suspect PH Think PH when: Dyspnea is out of proportion to: CT parenchymal findings (relatively normal lungs) Spirometry (normal FEV₁/FVC, volumes) There are subtle but progressive symptoms over months: Reduced exercise tolerance No obvious alternative explanation (e.g., no overt HF, CAD, big ILD, etc.) Physical exam may show (often late): Elevated JVP, V waves (TR) Peripheral edema, hepatomegaly, ascites Loud P2, RV heave In the case: a woman with systemic sclerosis + slowly progressive exertional dyspnea + relatively normal CT parenchyma and spirometry → high suspicion. WHO classification: 5 PH groups (big picture + why it matters) Used for pathophysiology, prognosis, and treatment choices: Group 1 – PAH Idiopathic, heritable (e.g., BMPR2), drug-induced (e.g., dasatinib) Connective tissue disease (esp. systemic sclerosis) Portal hypertension (portopulmonary HTN) HIV, HHT, congenital heart disease/shunts Rare: PVOD, PCH Group 2 – PH due to left heart disease HFrEF, HFpEF, valvular disease Most common cause worldwide. Group 3 – PH due to lung disease/hypoxia COPD, ILD, combined pulmonary fibrosis–emphysema OSA/obesity hypoventilation, chronic hypoxemia Group 4 – CTEPH Chronic thromboembolic pulmonary hypertension Group 5 – Multifactorial/unclear Sarcoidosis, myeloproliferative disorders, CKD, sickle cell, etc. Patients can span multiple groups (e.g., systemic sclerosis: group 1 and/or group 3; sickle cell: many mechanisms). Initial workup & refining pre-test probability Once you suspect PH, you’re trying to answer: Does this patient likely have PH? If yes, what group(s) are most likely? Core non-invasive tests: NT-proBNP (preferred over BNP) Surrogate of RV strain and prognosis. Normal value makes significant RV failure less likely. Oxygenation & exercise Resting SpO₂ plus ambulatory sats; consider 6-minute walk test. Exertional desaturation is common and clinically meaningful. CXR & ECG Low yield but may show RV enlargement, right axis deviation, etc. Pulmonary function tests Full set: spirometry, volumes, DLCO. Clue: isolated or disproportionately low DLCO with relatively preserved FVC suggests pulmonary vascular disease. Imaging High-res CT chest – parenchymal disease (ILD, emphysema). V/Q scan – best screening test for CTEPH; better than CT angiography for chronic disease. Sleep testing / overnight oximetry When OSA/nocturnal hypoxemia suspected. Echo: estimating PH probability (not diagnosis) TTE is the key screening tool but does not diagnose PH. Main elements: Peak tricuspid regurgitant (TR) velocity Used to estimate pulmonary artery systolic pressure (PASP). Categories: Low probability: TR velocity < 2.8 m/s, no other PH signs. Intermediate: 2.9–3.4 m/s ± other PH signs. High: > 3.4 m/s. The presence and severity of TR ≠ TR velocity. You can have severe TR without PH. “Other signs” of PH/RV dysfunction on echo: RV enlargement or systolic dysfunction (qualitative, TAPSE < ~1.7 cm, S′ ↓) RA enlargement Septal flattening (D-shaped LV; systolic = pressure overload, diastolic + systolic = volume + pressure) Dilated PA Pericardial effusion Interpretation pattern: Low pre-test probability + TR v < 2.8 + no other signs → PH unlikely. Intermediate TR v (2.9–3.4) + high pre-test probability and/or other PH signs → consider RHC. High TR v (>3.4) or clearly abnormal RV → strongly consider RHC if it would change management. Also: Echo is great to follow RV size/function and PASP over time once PH is diagnosed and treated. Case echo: TR velocity 3.1 m/s + mild RA enlargement + moderate RV enlargement + TAPSE 1.6 cm → intermediate probability, consistent with PH and RV involvement. Right heart cath (RHC): gold standard & updated definitions You cannot definitively diagnose or classify PH without RHC. Key directly measured values: RA, RV, PA pressures Pulmonary capillary wedge pressure (PCWP/PAWP) ≈ LVEDP Oxygen saturations in chambers/vessels Cardiac output (thermodilution) Key derived values: Cardiac output (Fick) Pulmonary vascular resistance (PVR) Updated hemodynamic definitions: Pulmonary hypertension (PH) mPAP ≥ 20 mm Hg (lowered from ≥ 25). Pre-capillary PH (think PAH, group 1; also groups 3, 4, some 5): mPAP ≥ 20 PAWP ≤ 15 PVR > 2 Wood units (new lower threshold) Isolated post-capillary PH (IpcPH) (group 2) mPAP ≥ 20 PAWP > 15 PVR ≤ 2 Combined pre- and post-capillary PH (CpcPH) mPAP ≥ 20 PAWP > 15 PVR > 2 Rationale for the changes: Normal mPAP in healthy people is < ~19; 20 is about 2 SD above normal. Patients with mPAP 20–24 (esp. systemic sclerosis) already have worse outcomes than those < 20. Lowering PVR cutoff from 3 → 2 WU better aligns with these new thresholds and catches earlier precapillary disease. Practical interpretation: You use mPAP + PAWP + PVR to: Confirm PH. Distinguish pre- vs post-capillary. Identify mixed disease. Echo tells you probability; RHC tells you what type and how severe. Vasoreactivity testing (acute vasodilator testing) Only indicated in: Idiopathic (IPAH) Heritable PAH Drug-induced PAH→ Not routine for all PH patients. Performed in the cath lab with short-acting vasodilator (e.g., inhaled NO). Positive test: ↓ mPAP ≥ 10 mm Hg To an absolute mPAP ≤ 40 mm Hg No fall in cardiac output Why it matters: Identifies a small subset who can be treated with high-dose calcium channel blockers long-term and often have better prognosis. Does not predict response to other PAH therapies (ERA, PDE5i, prostacyclin, etc.). Screening high-risk populations Some groups warrant systematic screening because of high PAH risk. a) Systemic sclerosis / systemic sclerosis spectrum Annual screening if: Disease duration ≥ 3 years FVC ≥ 40% predicted DLCO < 60% predicted DETECT algorithm (2-step): Step 1: uses labs and simple tests (FVC/DLCO ratio, NT-proBNP, autoantibodies, right axis deviation on ECG, telangiectasias). If positive → Step 2: adds echo (TR velocity, RA size). If high risk after Step 2 → RHC. Goal: catch early PAH before symptoms are severe. b) Other high-risk groups Annual screening (usually with echo ± NT-proBNP, PFTs) for: Known heritable PAH mutations (e.g., BMPR2) Portal hypertension (esp. considering liver transplant or TIPS) HIV Always layer this on top of clinical symptoms and progression. Big practical takeaways (what to apply on Monday) Don’t label “pulmonary hypertension” off CT or echo alone. Enlarged PA on CT or elevated PASP on echo ≠ diagnosis. RHC is required. Think PH early when: Dyspnea is out of proportion to imaging and spirometry. There is a relevant risk factor (systemic sclerosis, portal HTN, HIV, prior PE, congenital heart disease, etc.). Use the WHO groups to structure your differential and workup: Group 1 vs 2 vs 3 vs 4 vs 5 → drives what tests you order and what treatments you eventually consider. Echo = probability. RHC = truth. Echo gives you low / intermediate / high PH probability. RHC gives you pre- vs post-capillary, PVR, and hemodynamics needed for therapy. Know the new numbers: mPAP ≥ 20 = PH PAWP cutoff = 15 PVR > 2 WU = precapillary component Don’t forget NT-proBNP, DLCO, V/Q scan, and high-risk screening (especially in systemic sclerosis and BMPR2 carriers). References Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548. Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what’s old is new. F1000Res. 2019 Jun 19;8:F1000 Faculty Rev-888. doi: 10.12688/f1000research.18811.1. PMID: 31249672; PMCID: PMC6584967. Maron BA. Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J Am Heart Assoc. 2023 Apr 18;12(8):e029024. doi: 10.1161/JAHA.122.029024. Epub 2023 Apr 7. PMID: 37026538; PMCID: PMC10227272.

Furf and Monty are back today with another Pulm PEEPs Pearls episode, and discussing the use of methylene blue for patients with septic shock. They review the clinical scenarios when this comes up, the mechanism, some key data, and some take aways, all in 15 minutes! Let us know any other topics you’d like covered on the show and make sure to like, give us 5 stars, and subscribe wherever you’re listening to this podcast. This episode was prepared in conjunction with George Doumat MD. Goerge is an internal medicine resident at UT Southwestern and joined us for a Pulm PEEPs – BMJ Thorax journal club episode. He is now acting as a Pulm PEEPs Editor for the Pulm PEEPs Pearls series. Key Learning Points Clinical context: when does methylene blue even come up? This is not a first-line sepsis drug. It’s considered in catecholamine-refractory vasoplegic septic shock, typically when: Norepinephrine is at high dose Vasopressin is on board Often a 3rd or 4th vasopressor is being used (e.g., phenylephrine, angiotensin II) The phenotype is strongly vasodilatory/vasoplegic (warm, distributive shock) rather than primarily cardiogenic. Mechanism of action (why it might help) Methylene blue: Inhibits inducible nitric oxide synthase and guanylate cyclase. Blunts excess nitric oxide and cyclic GMP–mediated vasodilation, which are key in vasoplegic sepsis. Practical translation: It restores vascular tone and can make the vasculature more responsive to catecholamines. It’s also used in post-CPB vasoplegia (e.g., after cardiac surgery, especially in patients on ACE inhibitors) and has migrated from that world into ICU sepsis practice. Typical dosing strategy (as described in the episode) Common approach: 1–3 mg/kg IV bolus, then Reassess hemodynamics (MAP, dynamic perfusion markers). If there’s a response, consider a continuous infusion or repeat bolus. Key nuance: unlike other pressors that start as drips, methylene blue is often trialed as a bolus first to see if it’s doing anything. What does the evidence suggest? Most data are from small, single-center, heterogeneous studies, so evidence quality is low. Meta-analyses and systematic reviews (through ~2024–25) suggest: Hemodynamics Can increase MAP (roughly 1–10 mmHg across studies). May shorten total vasopressor duration (one meta-analysis ~30 hours less, though this is not definitive). Secondary physiologic effects Some small improvements in PaO₂/FiO₂ (P/F) ratio in certain studies. Clinical outcomes Possible reduction in hospital length of stay (≈ up to 2 days in some pooled analyses). Some signal toward lower short-term mortality, but: Studies are small Heterogeneous Evidence is very low certainty Bottom line: There’s a repeatable signal that methylene blue: Raises MAP Helps reduce catecholamine requirements But hard clinical outcomes (mortality, LOS, ventilator days) remain uncertain. Safety profile & important adverse effects Things to watch for: Methemoglobinemia Serotonin syndrome Especially in patients on SSRIs, though in life-threatening refractory shock the hosts still lean toward using it with caution. Pulse oximeter artifact Can distort SpO₂ readings. Urine discoloration Blue/green urine—benign but striking. Notably: Methylene blue is both a treatment for and a potential cause of methemoglobinemia, depending on context and dosing. Guidelines & where it fits in practice Surviving Sepsis Campaign 2021: Does not recommend methylene blue for routine use in septic shock. No major critical care society includes it in standard septic shock bundles or protocols. The hosts frame methylene blue as: A rescue therapy, not guideline therapy. Something to consider only in refractory vasoplegic shock, ideally with: Multidisciplinary discussion (intensivist, pharmacist, etc.). Clear documentation that this is off-guideline, salvage use. Practical bedside framing (“2 a.m. in the ICU”) They emphasize three pillars of practice: Physiology – mechanism makes sense (NO / cGMP / vasodilation). Empiric evidence – small studies and meta-analyses show a signal but low-quality data. Bedside reality – at 2 a.m., with a patient in multi-pressor, refractory vasoplegic shock, you sometimes reach for imperfect tools. So, the practical take: You should NOT: Use methylene blue early. Treat it as part of standard sepsis care. You may consider it when: Shock is clearly vasoplegic and refractory. Norepi + vasopressin + at least one more vasopressor are maxed. Team agrees this is salvage therapy and understands the limited evidence and side effects.

For today’s podcast we have a special episode. We were extremely grateful to be invited to present live at CHEST 2025 this year. Kristina Montemayor, and Pulm PEEPs Associate Editors Luke Hedrick, Tom Di Vitantonio, and Rupali Sood hosted a session entitled “Widened Airways and Narrowed Differentials”. It is a great session around bronchiectasis. Enjoy! Meet Our Guests Dr. Doreen Addrizzo-Harris is  a Professor of Medicine at NYU where she is also Associate Director of Clinical and Academic Affairs for the pulmonary and critical care division. In addition to that, she’s the director of the bronchiectasis and NTM program and also serves as a program director for the pulmonary and critical care fellowship. Case Snapshot 60-year-old with CLL (in remission) → recurrent “pneumonias,” diffuse (not single-lobe), later dx’d with CVID; serial CTs: upper-lobe–predominant bronchiectasis, tree-in-bud, mucus impaction; multiple AFB+ cultures (MAC, later M. abscessus); recurrent bacterial flares (MSSA/MRSA). CT Images Key Learning Points Imaging pearls Tree-in-bud = small airways (bronchiolar) impaction/inflammation, not a diagnosis. Differential guided by distribution + chronicity: Acute/diffuse → bacterial/viral/NTM infection Dependent/basal → aspiration Persistent + nodular + bronchiectasis → NTM common Bronchiectasis CT signs (think: “ring, taper, edge”): Broncho-arterial ratio >1 (signet-ring) Lack of normal tapering Visible bronchi within 1 cm of pleura Location matters: Upper lobes → CF, sarcoid, prior TB/radiation Middle lobe/lingula → NTM classic; consider ABPA if central Lower lobes → aspiration, PCD, CTD, immunodeficiency NTM: diagnosis & when to treat Use all three (2020 guideline frame): clinical symptoms, compatible CT, microbiology (≥2 sputum cultures or 1 bronch +, etc.). Not every positive culture = disease needing drugs. If you defer pharmacologic therapy, follow closely (symptoms, sputum, PFTs, interval CT if change). Bug matters: MAC, M. abscessus, kansasii etc. “Low-virulence” species (e.g., M. gordonae) can still flag underlying airway disease. Regimens (MAC, macrolide-susceptible): azithro + ethambutol + rifampin (intermittent for nodular-bronchiectatic; daily ± IV amikacin for fibro-cavitary/advanced). Macrolide is the backbone; the others protect against resistance. M. abscessus: check for inducible macrolide resistance (prolonged in-vitro testing). Monitoring: sputum q1–3 mo; labs (CBC/CMP), vision (ethambutol), hearing (aminoglycosides). Treat ~12 months beyond culture conversion. Anti-inflammatory macrolide for bronchiectasis is contraindicated if macrolide-susceptible NTM is present—risk of resistance. Bronchiectasis management essentials It’s a syndrome: symptoms/exacerbations plus CT changes. Airway clearance is foundational (exercise + devices ± hypertonic saline/DNase when indicated). Expect CT and symptom gains with adherence. Exacerbations often need ~14 days of pathogen-directed antibiotics (short courses may fail). Take the “easy win” when a conventional pathogen explains the flare. Workup framework (start with a core bundle, then target) Core “every patient” bundle CBC with diff (look for eosinophilia/hematologic clues) Quantitative IgG/IgA/IgM (primary/secondary immunodeficiency) ABPA screen: total IgE + Aspergillus-specific IgE/IgG Sputum cultures: routine bacteria + AFB + fungal (if producing) Baseline PFTs Targeted tests (guided by history, distribution, microbes) CF evaluation: sweat chloride and/or CFTR genotyping (especially with upper-lobe disease, chronic sinusitis/nasal polyps, pancreatitis/malabsorption, infertility/CAVD). PCD: nasal NO, genetics, specialized ciliary studies (adult cases may be mild and missed by genetics alone). Alpha-1 antitrypsin (never-smoker emphysema, liver hx) CTD serologies (RA, Sjögren’s, etc.), if suggestive Aspiration/upper-GI assessment when basal-predominant or reflux symptoms For suspected/known CVID: vaccine response assessment if not on replacement (this patient was already on IVIG). Practical diagnostic habits Re-read the CT yourself—radiology may under-call mild bronchiectasis in ED/PE-protocol scans. Use a diagnostic time-out when the course isn’t fitting: name your working dx, list fits/mismatches, consider common diseases with atypical presentations, multi-morbidity, and can’t-miss alternatives; ask for help early; communicate uncertainty. Teach-to-remember pearls from the case Recurrent, geographically scattered pneumonias → think systemic causes (immunodeficiency, CF/PCD), not just focal anatomic problems. Upper-lobe bronchiectasis + CAVD is a CF red flag—even in the 60s. Adult-onset CF is real and actionable. In CF today, MSSA can be more common than Pseudomonas on culture; don’t let absence of Pseudomonas dissuade you. Airway clearance adherence can change CTs; instruct patients to ramp up before surveillance scans for a fair assessment. If symptoms abate with targeted therapy to a conventional pathogen, you may avoid immediate NTM re-treatment—but keep a tight follow-up loop.

In this episode, we’re concluding our review of the Global Initiative for Asthma (GINA) guidelines on asthma today with a cased based episode on special considerations in asthma care. We’ve covered asthma diagnosis and phenotyping, the approach to therapy inhaler and oral medical therapy, and biologic therapy. On today’s episode we’re talking about complex cases that are at the edges of the guidelines, or may be in future guidelines. To help us with this exciting topic we’re joined by an expert in the field. Enjoy!  Meet Our Guest Dr. Meredith McCormack is a Professor of Medicine at Johns Hopkins, where she leads multiple NIH funded endeavors at understanding lung health and disease. She is the Division Director for Pulmonary and Critical Care Medicine, while also directing the Asthma Precision Medicine Center of Excellence, and the BREATHE Center, which focuses on understanding the effects of the environment on lung health and disease through research and community engagement. She is an internationally recognized expert in asthma management and is a dedicated member of the faculty who is committed to the trainees. Meet Our Co-Hosts Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a second year pulmonary and critical care medicine fellow alongside Tom. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs. And she also loves bedside medical education. Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a second year pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered in the care they have going forward. Key Learning Points Episode themesBuilt on GINA 2024: final capstone focusing on evolving topics + case-based application.Three focal areas: (1) obesity/metabolic health (GLP-1s, metformin), (2) dual biologics vs switching, (3) de-escalating inhalers while on biologics.Emphasis throughout on personalized care, shared decision-making, and multidisciplinary collaboration.Obesity & metabolic health in asthmaObesity affects mechanics, inflammation, and treatment response; tackling metabolic dysfunction can improve asthma control.GLP-1 receptor agonists may provide additive benefit beyond weight loss for some patients (early clinical signals; trials ongoing).Metformin is being studied as a potential adjunct targeting metabolic-inflammatory pathways.Practical approach: screen/counsel on weight, activity, and metabolic disease; partner with primary care/endocrine/sleep clinics; consider GLP-1/other agents when indicated for comorbidities, with potential asthma “bonus.”Biologics: switching vs dual therapyConsider switching/adding when control is not achieved or sustained on a biologic despite adherence.Upstream vs downstream targets:Upstream: anti-TSLP (e.g., tezepelumab) may help when multiple pathways/biomarkers (e.g., high IgE + eos) suggest broader blockade.Downstream: IL-5/IL-4/13/IgE agents selected to match phenotype/endotypes.Comorbidities can drive choice:Nasal polyps or upper airway syndromes: there are biologic options that improve upper airway symptoms in addition to asthmaAtopic dermatitis: agents with dual indications can be life-changing.Logistics matter: injection burden/needle phobia and dosing cadence (e.g., every 2 vs 4–8 weeks) can determine real-world success.De-escalating inhalers on biologicsDon’t step down immediately. Ask patients to maintain their full regimen for ~3 months after starting a biologic to gauge true benefit.Set expectations early and share a step-down plan to prevent unsupervised discontinuation.Typical order (individualize):Remove non-essential add-ons first (e.g., antihistamines, leukotriene modifiers).Reduce ICS dose gradually (high → medium → low).Keep ICS/LABA combination among the last therapies to taperTargets while stepping down: “normal” lung function when feasible, minimal/no day or night symptoms, full activity, no exacerbations.When patients don’t respond to biologicsRe-check the fundamentals:Adherence/technique for inhalers and biologic.Biomarkers behaving as expected (e.g., eosinophils falling on anti-IL-5).Revisit the diagnosis and contributors/mimics (e.g., vocal cord dysfunction, upper-airway disease). Consider moving upstream (e.g., to TSLP) if a downstream agent underperforms.Communication & practical pearlsUse visual aids to verify what patients actually take and how (e.g., Asthma & Allergy Network inhaler pictogram).Needle issues are common; home vs clinic administration and family support can make or break adherence.Biologics are transformative for the right patient—consider them early in steroid-dependent or poorly controlled severe asthma.Think longitudinally: plan for monitoring, comorbidity management, and timely adjustments.