Author Archives: Tim Rowe

Morning Report 8/22/22 – Eosinophilic pleural effusion

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Today’s morning report featured a fascinating case of eosinophilic pleural effusion from second year fellow Ted Cybulski

Second year PCCM fellow Ted Cybulski | http://tedc.cc/  | Twitter: @tdwck

 

First thing’s first – how do we define pleural fluid eosinophilia (PFE), and what are classic associations to be familiar with?

Some more quick facts:

  • Incidence estimated between 5-16% of all pleural effusions
  • More common in men (ratios reported between 2:1 and 9:1)
  • Malignant in roughly 35% of cases, of which 50% are lung ca.

Here a closer look at the broad categories on the differential diagnosis of PFE:

In our discussion, Dr. Sporn added that pleural fluid protein <4 and effusion size >1/3 hemithorax are suggestive against tuberculous effusion. A couple of other important points about TB effusion:

  • Can occur with primary or reactivation of infx
  • Pleural fluid ADA >40 u/L argue strongly for TB especially in lymphocytic exudative effusions (90% of cases)
  • Eosinophilic effusions are relatively rarer presentation

Below Ted details the association of eosinophil count in PFE with malignancy – while a lower count (<40%) is MC in malignancy, a higher count is not necessarily reassuring. Other characteristics which carry higher risk for malignant effusion include advanced age and higher pleural fluid LDH (cutoff >900 suggested)

Takeaways

  • Pleural fluid eosinophilia = >10% eos, found in 6-14% of pleural effusions
  • Classic association with trauma, repeated taps, asbestos.
  • MC etio malignant
  • Lower eos (10-40%), higher LDH (>900) and advanced age associated with higher probability of malignancy
  • TB can present with eosinophilic effusion, but classic presentation is lymphocytic exudate with high ADA (>40)

Thanks for leading a great discussion, Ted!

Sources cited

  • Krenke et al. ERJ 2009; 34(5):1111-1117 (https://pubmed.ncbi.nlm.nih.gov/19386682/)
  • JM Porcel. Lung 2009; 187:263-70 (https://pubmed.ncbi.nlm.nih.gov/19672657/)

ILD roundup 8/12/22

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I. A 62 yo female with family history of pulmonary fibrosis with an NSIP pattern

What is the relationship between telomere length and familial pulmonary fibrosis?

-Heterozygous mutations in coding regions of two telomerase genes (TERT :: protein component, TERC :: RNA component) have been associated (found in 15% of kindreds) with familial IPF  

Pulmonary fibrosis is seen in 50% of women and 60% of men 60 years and older with TERT mutations

 

-UIP radiograph pattern (74% HRCT) and UIP pathologic pattern (86% surgical lung biopsy) is most commonly encountered 

-Even in sporadic cases of IPF, a significantly higher proportion of individuals have telomere lengths <10th percentile compared with controls, even absent TERT/TERC mutations (present in 1-3% of sporadic cases) 

 

Plotting mean telomere length against age with 10-90th percentile in normal controls mapped in blue region

 

https://www.atsjournals.org/doi/pdf/10.1164/rccm.200804-550OC 

https://doi.org/10.1371/journal.pone.0010680 

II. 69 yo F with seropositive RA and progressive fibrosing ILD, found to have upper zone predominant fibrosis, honeycombing, TBE.  

What HRCT & histopathologic patterns are most commonly associated with RA-ILD?
 -UIP pattern on HRCT most commonly encountered, between 40-60% of cases.  

-Histopathology usually correlates with HRCT. MC encountered histopathologic patterns are UIP, NSIP, OP 

 

Aggregated data from multiple studies demonstrating the most common histopathologic patterns in CTD-ILDs. Note larger proportion of UIP in RA-ILD

 

-RA-ILD associated with UIP pattern has an increased risk of disease progression and death, and increased risk of flares compared with RA-ILD with NSIP pattern 

Kaplan-Meier curve showing RA-ILD with UIP pattern; cumulative survival intermediate between RA-ILD with NSIP and IPF (another ILD characterized by UIP HRCT and histopath)

 

What is the role of antifibrotic therapy in non-IPF ILD? 

– A recent trial (INBUILD – 2019) looked at nintedanib (antifibrotic FDA approved for IPF) in patients with non-IPF fibrosing interstitial lung disease (n=663) over 12 months of follow-up 

 

Figure demonstrating the primary endpoint, decline in FVC over period of followup (188 mL in placebo versus 80 mL in nintedanib group).

 

-As a secondary endpoint, mortality was less in intervention group (11.5% placebo vs  8.1% nintedanib) although this was not statistically significant 

– Since publication of INBUILD trial, FDA has approved use of nintedanib/Ofev for non-IPF progressive fibrosing ILDs 

Finally, for a current and comprehensive review of the treatment of fibrosing interstitial lung disease including IPF and other progressive pulmonary fibrosis (PPF), make sure to check out a recent review in BMJ by our very own Gabby Liu, Scott Budinger and Jane Dematte!  

An algorithmic approach to diagnosis and management

 

https://doi.org/10.1378/chest.09-0444 

https://www.nejm.org/doi/full/10.1056/NEJMoa1908681 

https://www.bmj.com/content/377/bmj-2021-066354 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-group-progressive-interstitial-lung-diseases 

 

Morning Report 8/10/22 – Pneumothorax with delayed resolution

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In her morning report case last Wednesday, first year fellow Emily Olson focused on a case of secondary spontaneous pneumothorax (SSP) with delayed resolution. Remember, think about IP/thoracic surgery involvement if you’ve got leak for a week (or 5 days)

One strategy for managing persistent pneumothorax is endobronchial valve use. Because most of us are familiar with use of valves in COPD lung volume reduction, we reviewed the inclusion/exclusion criteria for use in this context (LIBERATE trial, AJRCCM 2018)

While noting that these criteria do not apply to application of valves for persistent pneumothorax

Finally, we discussed 2 methods used to guide endobronchial valve deployment for persistent air leak:

  1. Sequential balloon occlusion – assess collateral ventilation, goal to reduce airflow by >50% with occlusion
  2. Intrapleural methylene blue instillation – tends to follow path of least resistance, meaning that may localize only one target at a time

Source: Respiratory Medicine 137 (2018) 213–218

 

Great discussion, Emily!

Diffuse pleural thickening review

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Morning Report 8/3/22 – Cavitary Lung Diseases

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Wednesday’s Morning Report featured first year Emily Olson (@EmilyOlsonMD) leading a discussion of cavitary lung disease. Let’s review some of her learning points together!

First off, how much better of a mnemonic can you get for cavitary lung diseases than “CAVITY”?

 

It’s always helpful to look at previous chest imaging, and this is especially true in cavitary lung diseases! An important early diagnostic branch point is chronicity of process (12 weeks as the cutoff for a chronic process)

 

 

Histoplasmosis is one differential consideration for subacute/chronic cavitary lung disease which we commonly test for non-invasively.

We learned that the performance characteristics of testing depends on stage of disease.

 

 

Thanks for leading a great discussion, Emily!

 

Sources cited

  1. Chest. 2018 Jun;153(6):1443-1465. doi: 10.1016/j.chest.2018.02.026 
  2. J Clinical Microbiology.2017 Jun;55(6):1612-1620. doi: 10.1128/JCM.02430-16

Pulmonary Report 8/1/22 – Diffuse pleural thickening

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Today’s Morning Report featured a case of restrictive lung disease related to diffuse pleural thickening. Below are some of the points I hope you take away from the discussion:

I. Differential diagnosis of diffuse pleural thickening (DPT)

History is essential for differential diagnosis. 2 general categories:

  • Pleuritis-related
    • Recurrent PNA, empyema
    • Asbestos-related
    • TB
    • Connective tissue disease
    • Drugs
    • Post-radiation
    • Post-CABG
    • Post-traumatic
    • Fibrosing pleuritis
  • Pleural thickening mimickers
    • Pleural plaques
    • Mesothelioma
    • Other pleural-based malignancies

II. Timeline of asbestos-related pulmonary disease

Legend – BAPE (Benign Asbestos-related Pleural Effusion), DPT (Diffuse Pleural Thickening) Clockwise from top left: DPT, pleural plaques, mesothelioma, ILD/asbestosis, BAPE

Remember that timeline is fluid, not absolute!

III. 3 distinct benign responses to asbestos exposure

Asbestos plaques involve parietal pleura only – lung sliding remains intact

 

Asbestosis – pulmonary fibrosis does not involve the pleura; septal thickening, reticulations (left) & honeycombing (center) are observed.

 

Diffuse pleural thickening involves inflammation at the visceral pleural border. Several findings associated with this, clockwise from top left; parenchymal bands “crow’s feet” associated with volume loss, a prominent parenchymal band, rounded atelectasis

 

IV. PET-CT may have utility in diagnostic evaluation of pleural thickening

 

 

Sources cited:

  1. Radiopaedia
  2. Journal of Occupational Medicine and Toxicology 2008, 3:20
  3. Eur Respir J 1998; 11: 1021–1027
  4. J Nucl Med 2004; 45:995–998

Morning Report 7/13/22 – Air Trapping

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Today’s Morning Report from second-year fellow Elen Gusman featured a case of dyspnea with HRCT and PFT findings of air trapping without other parenchymal abnormalities. Below are some of the take-away points from her engaging discussion.

Air trapping – areas of lung parenchyma with less than normal increase in attenuation and lack of volume reduction with expiration (Fleischner Society, 2008)

Image – isolated air trapping due to bronchiolitis obliterans Source: Annals ATS 2014; 11(6):874-881

Expiratory findings:

  • Heterogenous hypoattenuation (air trapped) alongside hyperattenuation (normal ventilation)
  • Areas of air trapping do not decrease in volume like adjacent normal lung

ILD Roundup 7/8/22

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ILD Roundup (7/8/22) 

1. Interstitial pneumonia with autoimmune features (IPAF) was favored as a differential consideration in a patient who presented to NMH for a third opinion for her ILD 

ERS/ATS research statement (Eur Respiratory Journal 2015;46:976-987) 

On the spectrum between idiopathic interstitial pneumonias (IIP) and connective-tissue disease associated ILDs (CT-ILD) are patients with IPAF. Oftentimes patients with an “autoimmune flavor” of ILD do not meet criteria for CTD diagnosis. 

Why does the distinction matter?  

  • Identifying underlying etiology impacts treatment and prognosis 
  • Expedites linkage to rheumatology care, potentially facilitating CTD diagnosis 
  • Accurate disease epidemiology depends on it 
  • May aid in elucidation of pathophysiologic mechanism of disease 
  • Defined criteria facilitate clinical trial design for future research 

What are the consensus criteria?  

All of the following must be fulfilled: 

  1. Presence of interstitial pneumonia (HRCT/SLB) 
  2. Exclusion of alternative etiologies 
  3. Does not meet criteria for defined connective tissue disease 
  4. At least one feature from 2/3 domains: 
  • Clinical 
  • Serologic 
  • Morphologic 

Pearl from case discussion: If histopathology pattern does not fit expectation but another criterion in this  domain is met (histopathology predominantly UIP pattern, however, there was presence of lymphoid aggregates), the diagnostic criteria for IPAF may still be satisfied!

2. In the same patient as above, we discussed and ultimately decided against use of azathioprine, because she had some HRCT features suggestive of a UIP pattern 

We know that nintedanib (INPULSIS – 2014) and pirfenidone (ASCEND – 2014) are associated with decreased rate of FVC decline in patients with IPF, hence the rationale for their use. Before the advent of antifibrotics, immunosuppressive agents had been used in patients with IPF. Several retrospective studies and small RCTs suggested mortality benefit with combination of steroid + AZA or cyclophosphamide though they were confounded by inclusion of patients who did not meet diagnostic criteria for IPF. Guidelines thus differed: the British Thoracic Society weakly recommended N-acetylcysteine (NAC), prednisolone, and azathioprine based on results from IFIGENIA (decreased decline in FVC and DLCO); whereas, the ATS/ERS recommended lung transplantation and participation in clinical trials. The IFIGENIA trial was limited by substantial drop-out and lack of “no treatment” arm.

Why do we now avoid the use of immunosuppressive medications – and azathioprine in particular – in suspected IPF? 

PANTHER-IPF (NEJM 2012;366:1968-1977) 

  • A double blind RCT wherein a commonly used cocktail of prednisone/azathioprine/NAC was used in 1:1:1 fashion with placebo and NAC alone 
  • A previous study had shown that triple therapy performed superiorly with regards to VC and DLco preservation compared with prednisone/azathioprine alone, but no placebo-controlled data existed 
  • Stopped at interim analysis when control group was found to have significant increase in death and hospitalization rates compared to placebo 

 

3. In another patient, the presenter mentioned that hypersensitivity pneumonitis had not been considered in a patient because he did not have any “clear exposure history”.  

How often is a diagnosis of HP arrived upon without a clear exposure history? Does identification of an exposure matter in patients with HP? 

CHEST 2013;144(5):1644-1651 

  • In a retrospective review of a longitudinal ILD database, 134 consecutive patients with clinico-radiologic diagnosis of HP found that inciting antigen was not identified in 53% of cases.  
  • Inability to identify target antigen was associated with significantly shorter survival (HR 1.76; 1.01-3.07) in this same cohort.  

 

ILD roundup 7/1/22

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1. Association of ANA pattern with CTD-ILDs 

We often talk about ANA titers & pattern in our ILD evaluations – what do they signify?  

  • Cut-off for positive test suggested at 1:160 
  • Variability based on lab/technician 
  • 25-30% of health controls with low Ab titers 
  • 56% +ANA with ILD of unclear cause, despite lower rate of CTD diagnosis (4-20%) in ILD population
  • Increasing age associated with higher prevalence of ANA positivity

General associations to be aware of: 

  • Homogenous –> dsDNA –> SLE 
  • Speckled –> MCTD, Sjogren, SLE, DM 
  • Centromeric or Nucleolar –> SSc 
  • Cytoplasmic –> anti-synthetase syndrome 

ANA profiles

2. Acute interstitial pneumonia/Hamman-Rich Syndrome

What are the clinical characteristics and prognosis of this rare illness? 

  • Rapidly progressive (1-2 weeks) hypoxemic respiratory failure with high mortality (~50%), with bilateral GGOs and consolidation within dependent lung, no clear trigger (ddx ARDS) and without antecedent ILD (ddx flare ILD, esp IPF)
  • Pathology shows diffuse alveolar damage, alveolar wall thickening and pneumocyte hyperplasia
  • Progresses to pattern similar to fibrotic NSIP Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia

HRCT of AIP

Image source: European Respiratory Journal 2009 33:68-76.

3.Idiopathic NSIP

A retrospective analysis of 83 patients with radiological & pathological criteria for iNSIP conducted in the pre-antifibrotic era (between 1991-2006).

Interesting findings included:

  • 10% of patients with iNSIP developed clinically manifest CTD during follow-up
  • Scleroderma, PM/DM, RA, MCTD, PMR
  • These patients tended to be younger and did not have increased risk for recurrence
  • Deterioration of FVC at 6 months correlated most strongly with disease-specific mortality