ILD Roundup 11/11/22

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It’s been a few weeks since our most recent ILD roundup – we’re glad to be back! This weeks ILD conference was chock full of pearls as usual.

1. First, we discussed the implications of leukocyte telomere length (LTL) testing on decision to use immunomodulatory therapy. Recall that PANTHER-IPF showed evidence of harm in patients with IPF receiving prednisone, azathioprine and n-acetylcysteine (NAC).

 

Could LTL serve as a biomarker to predict patients at risk of harm from use of immunomodulatory therapy in IPF?   

This question was asked in a recent post-hoc analysis1 of the PANTHER-IPF2 and unpublished ACE-IPF study. The authors found that short LTL (<10%ile) was associated with an increased risk of the composite outcome of death, lung transplantation or FVC decline in those exposed to prednisone/azathioprine/NAC (HR 2.84; 1.02-7.87, p=0.04). This association was not found in either cohort when patients with LTL >10%ile were examined.  

The authors propose that this may be related to unmasking of an immune dysfunction phenotype in patients with short LTL through immunosuppression. When the same criteria were applied to an unrelated cohort of patients participating in a longitudinal observational study at UTSW, there was actually a significant improvement in the prednisone/azathioprine/mycophenolate group with LTL >10%ile.   

Kaplan-Meier curve – UTSW cohort

 

2. Our next patient was a woman in her 70s with GERD and chronic joint pain. with CT imaging after mechanical fall concerning for ILD. Has developed progressive DOE over past year, with steroid responsiveness. The overall CT pattern was most consistent with fibrotic NSIP, but perilobular opacities were also noted. A differential consideration of organizing pneumonia3 was discussed. 

 

What is a perilobular opacity?  

A perilobular opacity refers to polygonal opacity around interlobular septa and with sparing of the secondary pulmonary lobule. As Dr. Agrawal brought up to the group, this tends to have more diffuse distribution than a a “reversed halo/atoll sign” which is a focal finding.   

“Reverse halo”, or “Atoll” sign in organizing pneumonia

 

Perilobular opacity in association with bronchial wall thickening and bronchial dilation in organizing pneumonia

 

 

What are the radiographic features most consistent with organizing pneumonia, and what are their primary differential considerations?  

 

3. A final case we discussed was a former tobacco user in his 70s, with RA on MTX, Humira and prednisone, former asbestos exposure, who presented to VA clinic with progressive DOE over past 6-12 mo. A transbronchial biopsy performed in 2021 with negative cytology for malignancy but otherwise non-diagnostic. CT with showed significant asbestos related pleural disease. Reticulation was seen mostly in association with pleural plaques. Despite the diagnosis of seropositive RA, our multi-disciplinary consensus was asbestos-related pulmonary fibrosis. The question of anti-fibrotic treatment was raised.  

 

What is the evidence for antifibrotic therapy in asbestos-related pulmonary fibrosis?  

Remember, the INBUILD4 trial showed evidence of benefit (lower annual rate of FVC decline) for antifibrotics in non-IPF fibrosing ILDs. Did they include asbestos-related fibrosis? Hard to say! Looking at the supplementary information (see Table below), 81/663 patients fell into category of “other ILDs” which did include exposure-related ILDs among others, but didn’t specifically mention asbestosis.  

 

The RELIEF5 study was a phase II placebo controlled RCT that looked at use of antifibrotic agents for non-IPF ILDs (fibrosing NSIP, CHP, and asbestos related pulmonary fibrosis). Patients enrolled had experienced disease progression despite conventional therapy. Of note, only 5 of 127 patients included with asbestos-related pulmonary fibrosis. They followed patients for 48 weeks and reported a significantly lower rate of decline in FVC as a % of predicted value.   

The annual rate of decline in FVC (-36.6 vs –114.4, p=0.21) did not meet statistical significance. Why is this relevant? A quick refresher6 on the endpoints for the IPF anti-fibrotic trials:  

 

Sources:

  

 

Morning report 11/14/22

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Elderly man with history of coronary disease and heart failure presenting with respiratory failure and moderate large bilateral effusions. On lifelong DAPT.

1) Will thoracentesis help?

Dyspnea from altered respiratory mechanics (pushing down on diaphragm and against chest wall) and impaired gas exchange, hypoxemia through pulmonary shunt v/q mismatch, and thoracentesis often doesn’t have immediate effect on gas exchange.

Small study – shows improves respiratory mechanics and oxygenation.

2) What should we do about AC?

Old guidelines from 2010 recommend against, practice patterns are all over the place.  Papers with small numbers all had pretty low bleeding outcomes, especially in the hands of an experienced provider with ultrasound use.

More recently, Patel et al reported 451/8951 thoracentesis done on NOAC/antiplatelets, and there were ZERO bleeding complications. Done by IP.

Interestingly, draining one side led to less fluid on the other wise. Suspected to be Buffalo chest – plero-pleural communication – refers to life-threatening condition in which a simultaneous bilateral pneumothorax occurs due to this communication. Can be seen post-op thoracic surgery too.

Thanks for the case, Dr. Rowe!

Timothy Rowe, MD, Pulmonary and Critical Care

Morning report 10/31/22

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Middle aged man with Crohn’s disease referred for cough, mucus production.

CT scan showed diffuse bronchiectasis and narrowed BI.

Bronchiectasis is associated with Crohn’s disease, see Review of pulmonary involvement of Crohn’s – often with suppurative mucus. Unclear if treatment of Crohn’s improves pulmonary features.

Focusing on tracheobronchial stenosis – malignancy, chronic infections, inflammatory (GPA, relapsing polychondritis, associated with IBD, amyloid)

Underwent dilation with IP -> path showing chronic inflammation, cultures negative for infectious organisms -> significant symptomatic improvement.

Thanks, Dr. Ludwig! Happy Halloween!

Amy Ludwig, MD, Pulmonary & Critical Care Medicine

 

First year dinner with Program Leadership!

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Last night our fearless leaders (Clara, Mac and Anthony) and program coordinator Kat (center of the picture and our world) got to spend the evening with our first year fellows (Jose, Emily, Allison, Ashley and Scott). First year keeps us busy and it’s not always easy to get time together, but it’s so nice to catch up as a group from time to time!

Morning Report 10/24/22

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Dr. Lawrence presented a case today of a patient with a 50+ pack-year smoking history with concern for bowel obstruction and need for surgery – imaging showed very significant bulla.

What might you recommend before the surgical procedure?

  • Optimization of medication (referred to COPD clinic)
  • Smoking cessation
  • PFTs (points were brought up about not using DLCO/VA, though might be helpful to compare to TLC; and N2 washout suboptimal in patient with obstruction)

Bullous emphysema – giant bulla is >1cm in diameter and giant bulla occupies at least 30% of hemothorax

Example from online:

Management varies – bullectomy sometimes but practices varies across institution.

Thanks for sharing, Dr. Lawrence!

ILD Roundup 10/19/22

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At ILD conference this week, a patient with progressive RA-ILD was discussed. A change in the patient’s rheumatoid arthritis medication was to be determined with her rheumatologist, but she was also recommended to start nintendanib

I. What is the evidence for anti-fibrotic therapy outside of IPF?

Prior to 2019, the efficacy of antifibrotic therapy in non-IPF fibrosing lung disease was unknown. INBUILD was a double-blind, placebo controlled RCT to investigate the efficacy of antifibrotic therapy in non-IPF fibrosing lung disease.

Let’s approach this study using the PICO framework!

Population:

All patients had to meet criteria for progression of ILD in the past 24 months despite treatment with an FVC =< 45% and DLCO <80%.

Breakdown of population by diagnosis:

·

 

Intervention:

Nintedanib 150mg BID

Comparison:

Placebo

Outcomes:

  • Primary endpoint=annual rate of decline in FVC
  • The annual rate of decline in FVC was significantly lower in patients who received nintedanib than those who received placebo.
  • Diarrhea was a common adverse event

The patient population was stratified by ILD with or without a UIP pattern of fibrosing ILD. Nintendanib decreased the rate of decline in FVC regardless of the pattern of fibrosis in this patient population.

In another case, our thoracic radiologist Dr. Parekh pointed out an example of dendritic pulmonary ossification.

II. What is dendritic pulmonary ossification (DPO)?

  • Chronic, progressive metaplastic ossification of lung parenchyma
  • Pattern of ossification resembles the dendrite of a neuron

Top: neuron with dendrites
Bottom: coronal view of CT showing dendritic pulmonary ossification

  • Dendritic pulmonary ossification is a rare condition (1.6/1000 autopsies) and is associated with IPF, ARDS, COPD, organizing pneumonia, rare earth pneumoconiosis, asbestosis, heavy metal exposure, and chronic aspiration.
  • Many cases are idiopathic and several weak associations with other non-pulmonary diseases have been reported in the literature.

 

Sources:

  1. Flaherty et al. N Engl J Med 2019;381:1718-27. DOI: 10.1056/NEJMoa1908681
  2. Fernández-Bussy et al. Respiratory Care April 2015, 60 (4) e64-e67; DOI: https://doi.org/10.4187/respcare.03531
  3. Reddy TL, von der Thüsen J, Walsh SF. . Idiopathic Dendriform Pulmonary Ossification. Journal of Thoracic Imaging. 2012; 27 (5): W108-W110. doi: 10.1097/RTI.0b013e3182326c38.

 

Morning report 10/17/22

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Thanks to our fearless leader Dr. Schroedl for presenting an interesting case of pulmonary MALT lymphoma!

Young woman with chest pain and dyspnea – left upper lobe lesion that didn’t respond to empiric treatment for CAP or even an empirical treatment for fungal pneumonia (unknown exact regimen). Bloodwork and noninvasive infectious workup were unrevealing. Initial bronchoscopy and biopsy were unrevealing. Repeat imaging six months later showed persistence of left upper lobe mass.

The patient got a repeat CT-guided biopsy that showed MALT lymphoma! This is a rare disease, and an extranodal low-grade B-cell lymphoma.

Treatment: ritxumab

The patient had good imaging response but persistent dyspnea, which is thought to be asthma that upon further probing, seemed present even prior to these.

Nice review article here: https://erj.ersjournals.com/content/34/6/1408

Thanks, Dr. Schroedl!

Clara Schroedl, MD, MSc, Medicine – Pulmonary/Critical Care

Restrictive PFT review

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Last week, we reviewed a differential diagnosis for restrictive lung disease with an emphasis on non-pulmonary causes. As a refresher, PAINT is a helpful mnemonic for restrictive lung disease:

ILD Roundup 10/11/22

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This week, we discussed the case of a 48 yo with chronic cough who presented to care for evaluation of abnormal CT chest, which showed multifocal peripheral and peribronchovascular pulmonary nodules.

I. How can we use distribution of nodules to narrow differential diagnosis? 

Back to our patient! Using our knowledge and the peribronchovascular/subpleural distribution of nodules, a focused differential diagnosis was discussed (sarcoidosis, silicosis/coal-workers pneumoconiosis, lymphangitic carcinomatosis). Absent occupational exposures were noted, and lack of associated adenopathy/effusions/extrathoracic disease was discussed. Bronchoscopy with EBUS/TBNA and TBBx was performed. A representative sample of the transbronchial biopsy is shown below:

Transbronchial biopsy showing tightly packed non-caseating granulomas with partial hyalinization in a peribronchial distribution compatible with nummular sarcoidosis

 

Based on the CT and biopsy findings, the group arrived upon a diagnosis of nummular sarcoidosis. Given relatively mild symptoms and normal pulmonary function tests, Dr. Russell suggested the use of high dose inhaled steroids.  

II. What is the role of inhaled corticosteroids (ICS) in the management of sarcoidosis?

The rationale for use? Sarcoidosis is a disease process that follows a lymphatic distribution in the lungs – ICS targets the endobronchial lymphatics. In short, the data is limited! A Cochrane review of corticosteroid use in sarcoidosis included 7 studies that assessed ICS (budesonide 800-1600 mcg/d or fluticasone 880-2000 mcg/d) use, specifically in patients with stage 1 & 2 disease. No improvements in CXR or PFTs were observed, although one study showed a modest improvement in DLCO/VA and others reported improvement in symptom scores.  

III. What are the extra-pulmonary screening recommendations in sarcoidosis? 

Sources:

  • Chest 2006; 129(3):805-15. (link) 
  • Cochrane Database Syst Rev. 2005; 2005(2): CD001114. (link) 
  • AJRCCM 2020; 201(8):e26-e51. (link) 

Grand Rounds – 9/30/22 – Pulmonary Hypertension Updates

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Last week in Grand Rounds, 3rd year fellow Romy Lawrence treated us an update on the latest advances in Pulmonary Hypertension.

The graphic below provides a helpful organizer for the three physiologic categories of PH: pre-capillary (Pre-PH), combined pre-and-post capillary (Cpc-PH), and isolated post-capillary (Ipc-PH)

Another common characterization for PH is WHO category. As a reminder of categories:

  • 1: PAH
  • 2: 2/2 left heart disease
  • 3: 2/2 lung disease
  • 4: CTEPH
  • 5: Other/misc

 

I. Updates in PH definitions

First, how did the 2022 ESC/ERS update change from the 2018 WSPH Guidelines?

The PVR cutoff was changed to 2! This was decided as it was roughly the cutpoint above which an increased hazard ratio for mortality was observed in the CART cohort. An important point here – these do not yet translate to therapeutic recommendations, as efficacy of PH therapy between mPAP 21-24 and 2-3 WU remains unknown. 

So if the new cutoffs haven’t resulted in updates in therapeutic recommendations, what do we do with them??

 

The entity of exercise PH, defined as a mPAP/CO slope between rest and exercise >3 Hg/L/min, was also defined.

A really important point here – symposia have been exclusively held in affluent countries, despite the fact that most of the global PH burden is in low and middle income countries. What implications does this have for focus of therapeutics, imaging, advocacy?

 

 

II. Pulmonary hypertension therapeutics:

Here’s a broad overview by WHO group:

Romy reminded us that the mainstay of PAH therapy is to target one of three pathways known to be implicated in the pathogenesis of PAH: (1) excessive endothelin-1 production, (2) deficient prostacyclin, and (3) low nitric oxide production.

After vasoreactivity testing and CCB trial if applicable, the most important determinant of treatment is risk assessment (REVEAL score or ESC/ERS risk stratification). An algorithmic approach from there:

The risk calculator is linked below if you’d like to learn more!

 

 

III. PAH in pregnancy

PAH in the pregnant woman – an uncommon situation with extremely high (30-50%) mortality. The WHO recommends against pregnancy in PAH. We also discussed the following:

  • Patients should be counseled around risk and provided contraceptive advice
  • Referral to a PH center if patient considering becoming pregnant and/or if pregnant and considering termination for maternal safety
  • ERAs (macitentan, bosentan, ambrisentan) are teratogenic

 

IV. Chronic thromboembolic pulmonary hypertension (CTEPH)

3 criteria for CTEPH:

  • mPAP >20
  • PCWP <15
  • Evidence of chronic perfusion defects after 3 mo anticoagulation

What is the relationship between acute PE and onset of CTEPH?

Important to know that certain factors increase the likelihood of CTEPH. These include some unsurprising conditions, such as prior PE (OR 19) especially unprovoked (OR 5.7).

Less intuitive – splenectomy (OR 18), ventriculo-atrial shunt or infected pacemaker (OR 76!!)

Finally, an overview of CTEPH treatment pathways:

Balloon pulmonary angioplasty (BPA) is used in distal or surgically inaccessible disease, and/or in patients for whom comorbidities preclude surgery. This is done in series of 4-6 sessions separated in time by several weeks.

Riociguat is approved for use in medical management of inoperable CTEPH based off of the CHEST trials.

The role of medical therapy as a bridge to surgery or BPA is less certain, given that it may delay appropriate referral and expedited treatment.

 

 

A few take home points from the discussion.

Thanks for an outstanding Grand Rounds, Romy!

Sources

  • Humbert et. al. ESC/ERS Guidelines 2022
  • Maron et. al Lancet 2021
  • Auger et al. Clin Chest Med 31 (2010) 741–758
  • Bonderman D et al. Thromb Haemost 2005;93:512-516
  • Humbert M.  Eur Respir Rev 2010; 19: 115, 59–63
  • Pengo V et al. New Engl J Med 2004;350:2257-2264
  • Ghofrani, HA. D’Armini, AM., et. al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013.
  • Jais, X., D’Armini, AM., et. al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension” BENEFiT. J Am Coll Cardiol . 2008.
  • Ghofrani, HA, Simonneau, G., et. al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension. (MERIT-1): Lancet Respir Med 2017.
  • https://pahriskcalculatorre.com/