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:
Author Archives: Tim Rowe
ILD Roundup 10/11/22
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:
Grand Rounds – 9/30/22 – Pulmonary Hypertension Updates
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/
Isolated mediastinal and hilar adenopathy – Review
Last week in Pulmonary Report, we talked about a case of isolated mediastinal/hilar adenopathy (IMHL). 4 important differential considerations were discussed:
- Infection (esp. MTB)
- Sarcoidosis
- Malignancy (metastatic solid organ or lymphoma)
- Reactive
We discussed several studies that evaluated the optimal evaluation for suspicious IMHL, as well as factors which were shown retrospectively to be suggestive of reactive adenopathy.
Morning Report – 9/5/22
This week in Pulmonary Report, Dr. Ludwig presented the case of a 68 year old man with chronic exertional dyspnea and abnormal PFTs. Her evaluation (which is still ongoing!) tackled a a high-yield and challenging topic – what happens when your patient has restrictive PFTs but doesn’t have parenchymal disease to explain it?
The broad categories of restrictive lung disease can be remembered with the mnemonic PAINT:
In our patient’s case, an HRCT was performed and did not reveal clear parenchymal/pleural causes of restriction, leading us down the “extra-parenchymal” pathway:
Slide: extra-parenchymal causes of restrictive lung dz
Several maneuvers are available to aid in the differential diagnosis of a restrictive PFT
Supine and upright VC may suggest neuromuscular causes of restrictive lung disease.
- Normal lung function – decrease of 3-8% from upright to supine
- Significant diaphragm dysfunction – >15%
Chest wall and diaphragm mechanics
MVV (or maximal voluntary ventilation) wherein patients are asked to take rapid deep breaths for 12 seconds, is demonstrated in the video below:
MVVpred = FEV1 x ~35-40 (lower values suggestive of neuromuscular weakness)
Maximum inspiratory/expiratory pressure (MIP and MEP) are also decreased in neuromuscular disease:
Pre (upright) and post (supine) flow-volume loop
Pre (upright) and post (supine) vital capacity
MIP and MEP
Diaphragm function may also be evaluated using other modalities:
Diaphragm ultrasound for excursion and fractional thickening
Obtaining a diaphragmatic ultrasound
Thickening fraction: [(thickness at end-inspiration—thickness at end-expiration)/thickness at end-expiration]. <20% is indicative of diaphragmatic weakness
Normal diaphragm excursion: 6cm (female) 7cm (male) during deep breathing
Electromyography of diaphragm to assess for innervation
- Using esophageal or surface electrodes below lower frontal/dorsal ribs
- Negative conduction does not distinguish between neuropathic/myopathic causes and may be followed up with nerve stimulation test
Fluoroscopic sniff test can be used to detect unilateral pathology
- Poor sensitivity in bilateral paralysis; accessory muscle use may cause upward displacement of ribs creating appearance of downward displacement of diaphragm
- Sensitivity in unilateral paralysis is ~90%
Finally, some management considerations for respiratory symptoms in the patient with neuromuscular disease:
Consider blood gas testing for hypercapnia when FVC <40% pred
Thanks Amy!
ILD Roundup – 10/4/22
It’s been awhile since our last ILD round-up, but we are glad to be back in action! This week we talked about a young man with CVID, ITP and persistent groundglass opacities. We discussed a concern for granulomatous and lymphocytic interstitial lung disease (GL-ILD)
I. What is GL-ILD?
Seen in patients with CVID. With the advent of effective therapies (namely IVIG), increased prevalence of non-infectious complications of CVID (non-infectious complications now seen in 70% of patients with CVID).
GL-ILD is seen in 8-20% of cases of CVID, making it the most common ILD in this condition. It may also be seen in CTLA-4 deficiency. Associated with splenomegaly, immune-mediated cytopenias, and ITP. BAL demonstrates increased percentage of CD21lo B cells. Pathology demonstrates a peribronchiolar lymphocytic infiltrate, usually associated with granulomas (94% in one case series) and often with organization.
Image: peribronchial and interstitial lymphocytic infiltration
Image: Epithelioid granuloma
II. What are the characteristic HRCT findings of GL-ILD?
Solid & subsolid nodules, groundglass opacities, reticulations, mediastinal and hilar adenopathy. Less likely to contain reticulation, TBE, honeycombing, masses or consolidation. A radiologic DDX includes infection, organizing pneumonia, LIP, sarcoidosis and lymphoma. As alreadt noted, splenomegaly (bottom image) is common.
III. How is GL-ILD treated?
Consensus guidelines with strong agreement that mainstay of therapy is optimization of IVIG therapy. Whether to proactively treat or enter active surveillance after IVIG optimization is less well established, nor is whether antibiotic prophylaxis (as is often the case in CVID) is warranted. Corticosteroids are frequently used, but without clear evidence basis or consensus. Potential second line agents include azathioprine, rituximab, MMF.
Sources:
- J Allergy Clin Immunol Pract. (2017); 5:938-945. (link)
- Front Immunol. (2021); 12:627423. (link)
- Hum Pathol (2016); 46(9): 1306-1314. (link)
- https://radiopaedia.org/cases/granulomatous-lymphocytic-interstitial-lung-disease?lang=us
Morning Report 8/31/22
This week, second-year fellow Elen Gusman presented a case of non-expanding lung (NEL) which presented as a post-thoracentesis hydropneumothorax. Ouch!
Representative clip of a right-sided hydropneumothorax
What are 3 causes of NEL?
- Endobronchial lesion –> lobar collapse
- Chronic atelectasis
- Trapped lung
What is trapped lung?
- A commonly encountered cause of non-expandable lung (NEL)
- Fibrinous, restrictive layer on visceral pleura
- Caused by remote inflammatory pleural process
- Often p/w chronic pleural effusion (ex vacuo physiology)
When to suspect trapped lung?
- Chronic/recurrent effusion
- Pain with thoracentesis
- CT with visceral pleural thickening & loculations
- Fluid characteristics: low LDH, protein in exudative range, paucicellular & mononuclear
How do we diagnose?
- Gold standard is pleural manometry & elastance
- Pel = change in pleural pressure [CWP] / volume fluid removed [L]
- 14-25 CWP/L associated with trapped lung
Below is a YouTube video walking through three commonly utilized methods of transducing pleural pressure:
Lung ultrasound (LUS) may also predict trapped lung with an absent “sinusoid sign”
How to obtain:
- 2D mode U/S with indicator oriented towards head
- Switch to M mode with indicator through effusion into atelectatic lung
- Assess for respirophasic variation in position of atelectatic lung (sinusoidal pattern)
How to distinguish trapped lung from lung entrapment?
- Entrapment – active disease, exudative effusion, directly restricts expansion
- Trapped – chronic disease, transudative (except protein) effusion, visceral pleural thickening restricts
StatPearls 2022 “Trapped Lung” (link)
Annals ATS 2019;16(4):506-508. (link)
Semin Respir Crit Care Med 2001;22(6):631-6. (link)
ILD Roundup 8/26/22
This week, we discussed a case of a 76 yo F with progressive lower lung predominant reticulations with PFTs showing isolated reduction in DLco and demonstrating exertional hypoxemia. Differential based on her HRCT was chronic hypersensitivity pneumonitis (cHP) versus idiopathic pulmonary fibrosis (IPF). Ultimately, based on the presence of air trapping we felt the HRCT was inconsistent with usual interstitial pneumonia (UIP) pattern.
Why does it matter that we distinguish between IPF and other ILDs that result in a UIP pattern?
A UIP HRCT and histopathologic pattern is the hallmark of idiopathic pulmonary fibrosis (IPF). However, other ILDs (CTD-ILD and cHP) are associated with UIP pattern. Management and prognosis of these conditions are different than for IPF. So consequential are these differences that often a surgical lung biopsy (SLB) is performed to cinch the diagnosis!
Reminder – what defines a UIP HRCT pattern?
- Subpleural and basal predominant, heterogenous, often asymmetric
- Honeycombing +- traction bronchiectasis
- Superimposed with a reticular pattern, relatively mild GGO
- Irregular thickening of interlobular septa
Coronal view of HRCT demonstrating UIP pattern of fibrosis, with subpleural/basilar predominant honeycombing & traction bronchiectasis
By contrast, a UIP pattern with the presence of 3+ lobes of air trapping on HRCT noted to be “inconsistent with UIP” based on 2011 ATS/ERS/JRS/ALAT guidelines and is commonly associated with cHP. HP should be considered when fibrosis and honeycomb cysts predominate in the upper/mid lungs, mosaic attenuation/three density/“head cheese” sign present, or when fibrosis appears diffuse in axial plane
inspiratory (left) and expiratory (right) coronal views of HRCT with UIP pattern due to chronic hypersensitivity pneumonitis. Lobular air trapping (geographic hyperlucent regions) confirmed on expiratory imaging.
By the way – what is the “head cheese” sign?
The headcheese sign is a mixed infiltrative and obstructive process usually associated with bronchiolitis. It is very specific but not pathognomonic for hypersensitivity pneumonitis.
Headcheese IRL…ew
Inspiratory/expiratory cuts showing 3 distinct attenuations
Are air trapping and IPF mutually exclusive?
A 2018 single-center retrospective study looked at patients with UIP and “inconsistent with UIP” HRCT with specific attention to presence and characteristics of air trapping. Among enrollees were patients for whom IPF was the final histopathologic diagnosis although HRCT findings suggested against UIP.
They found:
- Qualitative and quantitative air trapping was common in patients with UIP pattern, whether IPF (41-45%) or non-IPF (30-49%) ILD
- Upper lobe air trapping was rare in IPF and more commonly associated with cHP (11/13 cases)
Takeaways
- IPF (the most commonly encountered ILD) is associated with a UIP HRCT and histopathologic pattern
- UIP HRCT pattern consists of basilar/subpleural fibrosis, traction bronchiectasis and honeycombing with relative paucity of groundglass opacities
- Expiratory air trapping, an HRCT feature commonly associated with cHP, is inconsistent with UIP when present in >3 secondary lobules
- A recent study suggests that upper lobe predominance of air trapping is the feature most suggestive against IPF
- The 2022 ATS/ERS/JRS/ALAT guidelines do not include an update on this subject
Sources:
Eosinophilic pleural effusion review
ILD Roundup 8/19/22
I. A patient with prior clinical diagnosis of pulmonary sarcoidosis presented to care at NMH with progressive pulmonary fibrosis. A transbronchial biopsy with EBUS was performed. The radiographic pattern and biopsy results were thought to be inconsistent with sarcoidosis; a differential of indeterminate UIP v NSIP (idiopathic v IPAF) remained. We discussed sending the patient for Envisia testing.
What do we mean when we say “Envisia”?
- Envisia Genomic Classifier
- Developed using machine learning applied to bulk RNA sequencing data from lung biopsy in combination with histologically-confirmed diagnoses
- Helps differentiate UIP from non-UIP histologic patterns by transcriptomic signature
Envisia was validated in the BRAVE (Bronchial Sample Collection for a Novel Genomic Test) studies
How well can Envisia distinguish UIP from other pathology in conventional TBBx?
- Envisia identified UIP in transbronchial biopsy with a specificity of 88% and sensitivity of 70%
- Among patients who had “possible or inconsistent UIP” on HRCT, Envisia showed 81% positive predictive value for biopsy-proven UIP
Liu et al. BMJ 2022;377:e066354 https://doi.org/10.1136/bmj-2021-066354
Raghu et al. Lancet Respir Med 2019; 7: 487–96 10.1016/S2213-2600(19)30059-1
II. A patient who is undergoing evaluation for transplant had chronic hypersensitivity pneumonitis (cHP) in his differential diagnosis. We discussed the predictive value of BAL lymphocyte count given the fibrotic/chronic nature of his disease
What is the predictive value of BAL lymphocytosis in cHP?
- A 2020 ERJ systematic review and meta-analysis suggested an association between BAL lymphocytosis and fibrotic cHP
- BAL lymphocyte percentage higher in cHP (42.8%, CI 37.7-47.8) compared to IPF (10%, CI 6.9-13.1) and other IIPs
- Analysis demonstrated that a BAL lymph% cutoff >20% optimized sensitivity and specificity for cHP compared to other IIPs
- 2018 ATS/ERS/JRS/ALAT IPF diagnostic guidelines conditionally recommend BAL in patients with suspected IPF and a non-diagnostic HRCT pattern
- A meta-analysis of eight studies in the most recent guidelines found no difference in BAL lymphocyte percentage between IPF and cHP
