Author Archives: Tim Rowe

Pulmonary Report 5-31-23

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Today’s Pulmonary Report from Dr. Smith-Nuñez featured a case of chronic eosinophilic pneumonia which she treated on pulmonary consults.

First, she provided focused differential of pulmonary eosinophilia:

When thinking about eosinophilic pneumonia, what clues do we use to distinguish acute versus chronic?

 

 

Finally, a standard treatment regimen that was used in the care of our own patient:

Takeaways:

Pulmonary eosinophilia carries a broad differential including:

  • Eosinophilic PNA syndromes
  • Drug reactions
  • Parasitic/Helminthic infections
  • ABPA
  • Vasculitis
  • Malignancy

Chronic eosinophilic pneumonia (CEP) is characterized by:

  • >1 mo of symptoms
  • Peripheral and mid-upper zone opacities
  • BAL eos >25%, often + peripheral eos

Corticosteroids are mainstay of therapy, and relapses are common

 

Thanks, Ashley!

Image

Tw: @dra_SmithNunez

ILD Round-up 3-3-23

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Last week, Anthony presented a patient with a reduction in DLCO and mild restrictive spirometric defect on PFTs CT scan showed questionable interstitial changes. We discussed further evaluation and management of ILAs. 

How do we define Interstitial Lung Abnormalities (ILAs) (1)? 

  1. incidentally identified  
  1. non-dependent interstitial changes (reticulation, groundglass, traction bronchiectasis, honeycombing, non-emphysematous cysts) involving  
  1. at least 5% of a lung zone  
  1. in patients for whom ILD is not clinically suspected 

Mimickers of ILAs include dependent atelectasis, interstitial edema, aspiration (GGOs, TiB opacities) and others 

Image: focal paraspinal fibrosis (arrow) in contact with spinal osteophytes, a mimicker of ILAs

 

How common are ILAs, and what is their significance? 

  • Large population-based (MESA, AGES, FHS, Nagano) and smoking/lung ca. screening (ECLIPSE, NLST, COPDGene, MILD) cohorts found that ILAs are present in 4-10% of individuals screened. 
  • Mean age of scan with ILA varies between 62-78 
  • Progression to ILD observed in 20% at 2 years, and 45-65% at 4-6 years (depending on study, not all cohorts assessed for progression) 
  • Mortality risk associations suggested in several studies, with RR between 1.3-2.7 (95% CI >1, depending on study, not all cohorts assessed for mortality) 
  • Risk factors for ILAs are similar to ILD: increased age, male sex, tobacco smoke exposure 

Table: clinical risk factors for ILD progression (2)

 

 

Can ILAs be further categorized, and what are implications of these categories? 

Non-subpleural: usually non-progressive and not associated with increase in mortality 

 

 

Subpleural non-fibrotic: sub pleural distribution associated with higher rates of mortality

 

 

 

Subpleural fibrotic: lower zone predominant, reticulation, traction bronchiectasis associated with 6x increased risk of progression   

 

How should we manage patients with ILAs? 

An algorithmic approach is described in the image below:  

 

Takeaway points:

  • ILAs are (1) incidentally found (2) non-dependent (3) involving at least 5% of lung zone and (4) in patients for whom ILD is not suspected
  • ILAs are present in 4-10% of patients screened, and typically found in 6th/7th decade of life, and are associated with increased mortality (RR 1.3-2.7)
  • Progression is 20% at 2 years, 45-65% at 5 years 
  • Risk of progression is higher in subpleural location and if reticulations/fibrosis are present

Sources: 

  1. PMID: 32649920 / DOI: 10.1016/S2213-2600(20)30168-5
  2.  PMID: 34374589 /  DOI: 10.1148/radiol.2021204367 

 

 

Morning Report 3-1-23

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Today in Pulmonary Report, the Emily Olson series continues with a case of cystic lung disease. Today, Emily described the management of a young woman with recurrent secondary spontaneous pneumothorax, found to have cystic lung disease.

First-year PCCM fellow Emily Olson (@EmilyOlsonMD)

Before we dive into today’s report, we encourage you to take this opportunity for some retrieval practice from prior NU PCCM blog posts:

For review, here are the blog posts associated with polls above

  1. A case of cystic lung disease in patient with Sjogren’s syndrome from ILD Roundup last July.
  2. Management of secondary spontaneous pneumothorax with delayed resolution (Leak for a week!) from Emily’s Morning Report last August
  3. A case of secondary spontaneous pneumothorax from cystic lung disease from Ale’s Morning Report last September

 

Alright! Now that the knowledge is fresh, let’s dive in! First, we discussed definitional criteria and a differential diagnosis (1) of cystic lung disease:

Another outstanding quick reference on this topic is Nick Mark’s OnePager (2):

Emily outlined the pragmatic 5-step approach described by Raoof et al.

Further refinement of differential involves considering the apicobasilar gradient of illness:

Emily’s case presented a bit of a diagnostic dilemma – LAM was clinically suspected but VEGF testing performed and unrevealing. Patient ultimately proceeded to VATS resection of a peripheral cyst/bulla, but pathology was inconclusive. This brought up an important discussion point – does it really matter if we know that cause?

Revealing cause of cystic lung disease may have important management implications for our patients:

  • Genetic inheritance of cystic lung diseases and multi-system illnesses associated. Genetic counseling/sequencing may be indicated
  • Differential considerations for cystic lung diseases include metastatic malignancies and certain infectious processes with specific management

 

Dr. Russell also brought up the higher risk of malignancy in patients with Birt-Hogg-Dube (BHD) specifically – particularly colorectal cancer.  Recall also from Ale’s morning report – 7x risk of RCC, screening with annual ultrasound in US. BHD, which follows an AD inheritance pattern, may be confirmed by genetic testing revealing a mutation in the FLCN gene, although testing may not be covered by insurance.

Dr. Singer also mentioned the NEJM study (3) that found sirolimus to be associated with stabilization of lung function and improved quality of life in patients with Lymphangioleiomyomatosis (LAM).

Some take-home points:

Thanks for an outstanding discussion, Emily!

Sources:

  1. PMID: 31704148 / DOI: 10.1016/j.chest.2019.10.017
  2. https://onepagericu.com/cystic-lung-disease
  3. PMID: 21410393 / DOI: 10.1056/NEJMoa1100391

 

Morning Report 2-22-23

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Today in report, Emily @EmilyOlsonMD discussed a great case  an individual with incidentally discovered pulmonary sequestration who had presented with progressive weakness, and for whom there was concern for malignancy & paraneoplastic syndrome.

First, we discussed a radiographic differential diagnosis:

Emily next took us ALL the way back to medical school embyrology to discuss the two mechanisms of sequestration (intralobar and extralobar)

 

How does the natural history of intralobar vs extralobar sequestration vary?

Emily’s patient ended up undergoing IR embolization before eventually having a resection of their pulmonary sequestration. Fortunately, the explanted lung tissue did not show malignancy.

Here’s some takeaways from her discussion:

Thanks, Emily!!

ILD Round Up 2-19-23

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In last week’s ILD conference, we discussed a patient with seropositive RA for whom RA-ILD was suspected.  

First, a quick reminder of ILD patterns associated with rheumatoid arthritis (1) from July ILD Round Up: 

Dr. Rishi Agrawal mentioned that this patient’s HRCT pattern was most consistent with UIP; however, given this patient’s history of connective tissue disease, “exuberant honeycombing” may be expected, and the lack of any honeycombing was somewhat atypical.  

What characteristics are commonly associated with a UIP pattern in patients with CT-ILD, and how might they differ from UIP in a patient with IPF? 

A 2018 study (2) looked at patients with UIP with either a diagnosis of IPF or CTD-ILD. Exuberant honeycombing was found in only 6% of IPF patients compared to 22% of patients with CTD-ILD.  

While we’re on the subject…what is exuberant honeycombing? 

Exuberant honeycombing (3) refers to extensive honeycomb-like cyst formation within the lungs comprising >70% of the fibrotic portions of the lungs.

Finally, we discussed the patient’s prior treatment regimen, which included methotrexate (MTX).  

What is the likelihood of methotrexate-associated interstitial lung disease in patients with RA-ILD on methotrexate? 

A case-control study (4) looking at the association between MTX exposure and ILD (n=1083 patients)  found an inverse correlation between MTX exposure and RA-ILD (OR 0.46: 0.24-0.90, p=0.02). Another meta-analysis (5) of 30 studies with 15000 total patients found no association (RR 1.02: 0.73-1.44) for non-infectious adverse respiratory events with MTX use.  

Dr. Carrie Richardson noted that many patients with more severe RA will have already failed therapy with methotrexate for their articular symptoms, which may confound anecdotal reports of ILD associated with MTX use.  

Dr. Jane Dematte also mentioned the distinct entity of MTX associated hypersensitivity. This association is well-recognized, with frequency level 5 from Pneumotox profile corresponding to >200 reported cases in the literature.  

The actual frequency of occurrence depends on definitional criteria (see figure below) but is likely <1%. Below, see the commonly used Carson Criteria for diagnosis of MTX associated pneumonitis (MTX-P). 

Sources: 

1. DOI: 10.1183/09059180.00008014 / PMID: 25726549 

2. DOI: 10.2214/AJR.17.18384 / PMID: 29140119 

3. DOI: 10.1016/j.ejro.2022.100419 / PMID: 35445144 

4. DOI: 10.1183/13993003.00337-2020 / PMID: 32646919 

5. DOI: 10.1093/rheumatology/kez337 / PMID: 31504978 

 

Morning Report 11/28/22

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On Monday, second year fellow Tom Bolig presented the course of a middle aged undomiciled man with heroin use disorder and recurrent severe asthma exacerbations. This patient had no history of peripheral eosinophilia or IgE elevation. He was non-adherent to maintenance inhaler therapy. He was admitted to the MICU after intubation for asthma exacerbation following unintentional heroin overdose.

This prompted a discussion of the entity of potentially fatal asthma (PFA), defined by Northwestern’s own Paul Greenberger (1,2)

Potentially fatal asthma (PFA) is a clinical condition wherein 1+ of the following are present:

  1. History of endotracheal intubation
  2. Acute respiratory acidosis or respiratory failure from asthma
  3. 2+ episodes of pneumothorax or pneumomediastinum from asthma
  4. 2+ episodes of acute severe asthma despite long-term use of oral steroids (pre-biologic era) or other asthma medications

Why is this so important?

  • Condition with high risk for mortality and a young (mean 40 ya) patient population!
  • Identification may be the first step to tailored management
  • Loss to follow-up more commonly observed in patients who died of disease
  • Comorbid psychiatric illnesses and social barriers to health commonly observed

Back to Tom’s patient – a NBBAL was performed with PMN predominance, non-pathologic growth on cx, strongly positive amylase and a galactomannan Ag of 3.87. CT imaging showed patchy bibasilar infiltrates, not consistent with invasive pulmonary aspergillosis (IPA).

What are the most recent recommendations on interpretation of testing in suspected IPA?

All of the following from 2019 ATS Guidelines (3) with strong recommendation/high quality evidence

  1. If hematologic malignancy/solid organ transplant with suspected IPA, obtain serum galactomannan
  2. If serum galactomannan negative in above but high suspicion remains, obtain BAL galactomannan
  3. If serum galactommannan positive but risk factors for false positive (active chemotherapy, suspected/confirmed mucositis), obtain BAL galactomannan
  4. If severe immune compromise as above and suspected IPA, add serum aspergillus PCR to testing above

Tom’s patient fell outside the best studied population (hematologic malignancy and transplant) for galactomannan testing for IPA, and suspicion for disease based off of CT evidence was low. Although this has not been described in the literature, Ben Singer raised the possibility of aspiration of fungal cell wall contents from oropharynx as a putative cause of transiently elevated BAL galactomannan.

Finally, Tom discussed “Mab” therapy for asthma, providing a quick reference chart that takes some of the guesswork out of determining indications:

 

 

Thanks, Tom!

Sources:

  1. Allergy and Asthma Proceedings (1988); 9(2):147-152.
  2. Chest (1992);101:401S-402S.
  3. AJRCCM (2019);200:1326

 

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:

  

 

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!

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.