Interstitial Lung Disease

 Mid to Upper Disease

Ddx: SHORTI

Sarcoid, Hypersensitivity Pneumonitis, Occupational, Radiation, TB/Fungal, IPPFE

Exclude: UIP, NSIP

Sarcoid Traction bronchiectesis Mid to upper disease, central distribution

Hypersensivity pneumonitis: heterogenous distribution and air trapping

radiation sharp borders

Lower lobe predominant diseases - below and above the hila, hila tracted inferiorly

Lower lung disease mainly

HUN

Hypersensivity pneumonitis, Usual interstitial pneumonitis, hypersensitivity pneumonitis

Lower lung disease exclude: Occupational, TB/Fungal/ IPPFE

lower lung predominant disease NSIP, UIP

UIP subpleural, honeycombing, minimal ground glass opacity

craniocaudal distribution

Axial distribution - central and peribronchial disease

Include Sarcoid, NSIP, HP, organizing Pneumonia

Exclude: UIP

Peripheral or subpleural disease: Predominant disease in periphery include UIP, NSIP, HP, Organizing pneumonia, can't exclude

Describe the findings: 

Fleischner society: glossary of terms for thoracic imaging

Fleischner Society: glossary of terms for thoracic imaging

Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008 Mar;246(3):697-722. doi: 10.1148/radiol.2462070712. Epub 2008 Jan 14. PMID: 18195376.

https://pubmed.ncbi.nlm.nih.gov/18195376/

Pattern is not the clinical diagnosis

UIP pattern

UIP: 

Idiopathic pulmonary fibrosis

Rheumatoid Arthritis

Systemic Sclerosis

Hypersensitivity pneumonitis

Drug Reaction

NSIP

Idiopathic NSIP

Systemic Sclerosis

Sjogren's Syndrome

Polymyositis-dermatomyositis

Drug Reaction

OP

Cryptogenic Organizing pneumonia

Infection

Drug Toxicity

Connective Tissue Disease

Idiopathic pneumonias are not the diagnosis, radiologic, histologic pattern paired with history

Die in 3-5 years

Pulmonary Fibrosis foundation care center

H&P, PE, Labs, Functional testing, HRCT, Biopsy

H&P: pattern of dyspnea, slow progression, rapid deterioration or fulminant, events associated with decline

non-productive cough

ROS: rash, arthralgias, base of thumb -> OA, joint stiffness > 30 minutes -> RA, muscle weakness, trouble brushing hair / teeth

GERD, acid reflux, indigestion, heartburn, nausea, upset stomach, dry eyes / mouth naynaud's

https://www.youtube.com/watch?v=9eWVjoT9Wuc

Physical Exam: Exertional Hypoxia, dry crackles / rales, clubbing in 7-72%, autoimmune shawl sign, heliotrope eyelids, mechanic's hands, gottron's papules -> dermatomyositis

Labs: ANA, RF, CCP, CRP/ESR, Jo-1

https://www.vibrant-america.com/connective-tissue-disorder/

<88% supplemental oxygen

Pulmonary function testing

High resolution CT scan

Inspiratory, expiratory

3 main findings honeycombing, reticulation, and ground glass

Ground Glass

Honeycombing peripheral

Reticulation

https://radiologykey.com/diffuse-lung-disease-2/

Fibrotic features: reticulation, honeycombing, traction bronchiectasis

Non-fibrotic features: Ground glass nodules, ground glass, consolidation, mosaicism

HRCT interpretation

Dominant Pattern - fibrotic, nonfibrotic

Distribution - Upper vs lower, central/bronchovascular vs peripheral

https://www.atsjournals.org/doi/full/10.1164/rccm.201807-1255ST

HRCT findings predict certainty from 30% to 95% not 0 or 100%

NSIP: Nonspecific interstitial pneumonia alternative bucket

HRCT - GGO, subpleural sparing, lower lobe

GGO verse consolidation in GGO still see the vasculature

NSIP mc finding in CTD

Hypersensitivity Pneumonitis alternative centrilobular, axial reticulation get from mold, birds, down bedding, hot tub, farming, txtmt: antigen avoidance +/- steroids

Biopsy recommendations based off of HRCT

Key for UIP + Probably UIP no biopsy per fleischner

Richeldi European respiratory journal 2018

https://erj.ersjournals.com/content/52/3/1801485.figures-only

Transcbronchial biopsies - 0.1 to 0.3 cm

adequate sample diagnostic yield 36.1% in sarcoid or hp

transbronchial biopsy BAL bronchoalveolar lavage CD8/CD4 ratio, look for lymphocytosis

less invasive, risk of bleeding is less in transbronchial biopsy

cryobiopsy diagnostic yield is 83% 1.2% of exacerbating interstitial lung disease 5.2% of bleeding 13% of air leak, 3% mortality

surgical lung biopsy gold standard, tissue 4cm of tissue adequate sample in 89% adequate sample in 100%

Clinical conditions with UIP pattern

IPF, CTDs, Drug toxicit, chronic hypersensitivity, asbestosis

IPF

males do worse, FVC drop > 10% within first 6-12 months

desaturating to 89%

presence of secondary pulmonary hypertension

strep and staphylococcal organisms

https://www.nejm.org/doi/full/10.1056/NEJMra1705751

Pirfenidone

Capacity 1 & 2 showed promising but inconsistent effect on FVC

Ascend trial

decreased mortality in ascend + capacity trials when all data is summed

pirfenidone less change in FVC 47.9%

Decreased FVC or death, Decreased  45.1%

decreased walk distance or death 27.5% and decreased progression free survival

Nintedanib PDGF, VEGF, FGF

non-IPF: steroids, steroid sparing agents mycophenolate mofetil, azathioprine, rituxan, cyclophosphamide

Prognosis, should we be using anti-fibrotic agents for RA-UIP

TRAIL1: pirfenidone in RA-ILD

Acute exacerbations associated with 50-80%

exclude infection, empiric txtmt for CAP,s teroids high dose verse pulse dose steroids

lung transplant for Interstitial lung disease - obesity, peripheral vascular disease or coronary artery disease, significant renal insufficiency

disease modifying treatment - pirfenidone, nintedanib

Comorbidity - emphysema, lung cancer, OSA, coronary artery disease, Pulmonary hyeprtension, DVT/PE, hiatal hernia, hypothyroidism, Dm2 -> especially on prednisone

depression - medication / CBT / support

anxiety 

screen for OSA, low dose CT screening, inhaler regimen

For IPF idiopathic pulmonary fibrosis don't use Pred/Azathioprine and NAC or NAC as the Panther trial in 2012 showed increased rate of death and hospitalizations in treatment group

PANTHER - prednisone, azathioprine, N-acetylcysteine 

PAN

Inpulsis-1 Nintedanib ofeb, 150mg BID less FVC decline 115mls vs 240mls

not curative, managed disease inhibit tyrosine kinase targets

Ascend trial - 2014 - end point declinein FVC or death, reduction in patients with a  decline of 10% of FVC or death

reduced decline in 6 months, inhibit TGF beta and TNF-alpha

failed AZA/pred/NAC - panther

Warfarin + AC

abrisentan/Macitentan

lung transplant change in FVC or DLCO > 10% in 6 months, development of pulmonary hypertension 

exacerbation - 3 mnths to live, not enough time to get transplant list, too sick for surgery

Group 3

UIP 70% mortality at 5 years increased risk of lung cancer

JAMA NEtwork Interstitial Lung disease

From the JAMA Network, this  is JAMA Clinical Reviews,  

interviews and ideas about innovations in  medicine, science, and clinical practice.

Hello and welcome to this  JAMA Clinical Review podcast.

I am Mary McDermott, Deputy Editor of  JAMA, and I'm here today with Dr. Toby  

Maher to discuss his recently published  review on interstitial lung disease.

Dr. Maher is Professor of Medicine  

and Director of Interstitial Lung Diseases  at the University of Southern California.

Welcome, Dr. Maher, and thank  you so much for being here today.

Thank you very much for the invitation.

Let's start by having you define for  us, what are interstitial lung diseases?

So the term interstitial lung disease or ILD  is really an umbrella term that is used to  

describe several hundred conditions that can  affect the interstitial space within the lung.

And the interstitial space within  the lung is essentially the region  

of the wall of the alveolus that is  bounded on one side by the epithelium  

and on the other side by capillary  endothelium, and which in health  

normally contains a few structural fibroblasts  but otherwise represents a potential space.

And interstitial lung diseases are  conditions which can cause inflammation  

and or fibrosis within that interstitial space.

How common are these diseases overall  and also what are the most common types?

So as individual entities, each one of the  interstitial lung diseases is relatively rare,  

but in combination, they  form a huge problem really.

So in the United States, for instance,  

there are over 650,000 people living with  some form of interstitial lung disease.

And under that umbrella, the most common ones  that we see are idiopathic pulmonary fibrosis,  

hypersensitivity pneumonitis, and also  interstitial lung disease arising in the  

context of systemic autoimmune diseases such  as rheumatoid arthritis and systemic sclerosis.

So who's at risk for interstitial lung disease?

So for the first two that I just mentioned,  idiopathic pulmonary fibrosis and hypersensitivity  

pneumonitis, the risk tends to increase with age.

So classically, people who develop these  forms of ILD will be in their 60s or 70s.

Idiopathic pulmonary fibrosis is commoner in  male patients, we think, because of industrial  

exposures to things that cause injury to the  lung and also because of past smoking patterns.

Hypersensitivity pneumonitis tends to  affect people who have exposures to  

certain organic antigens such as mold and birds.

So it is seen in particular groups  who are at risk of those exposures.

And then the autoimmune diseases themselves,  so rheumatoid arthritis, systemic sclerosis,  

myositis, all of those are associated  with a risk of ILD of between 10 to 50%.

So individuals with autoimmune disease are  automatically at increased risk of ILD.

So you mentioned that idiopathic  pulmonary fibrosis was one of the  

more common forms of interstitial lung disease.

But your review discusses that really any  

interstitial lung disease can  evolve into pulmonary fibrosis.

Could you talk about that?

As you've alluded to in the question,  an idiopathic pulmonary fibrosis  

really is the archetypal fibrotic lung disease.

The disease, even in its earlier stage, seems to  begin with fibrosis that gets inexorably worse.

However, many of the other  interstitial lung diseases  

actually begin with an inflammatory insult.

And so the autoimmune diseases  would be a good example.

The initial insult is an immune-mediated  injury to the lung, which in some cases,  

if treated early enough, can seemingly  respond to immunomodulatory therapy.

But if that opportunity is missed,  these conditions can progress from  

sort of chronic inflammatory  damage through to fibrosis.

And with many of these diseases, there  seems to be a tipping point that once  

enough fibrosis has developed, that  in itself becomes self-perpetuating.

So although, for instance, scleroderma  and idiopathic pulmonary fibrosis are very  

distinct and separate disorders, towards the end  stages of both diseases, they ultimately affect  

the lung in a very similar way and result in a  very similar level of morbidity and mortality.

What are the typical presenting  symptoms of interstitial lung disease?

So the typical symptoms are  often very subtle to begin with,  

which is one of the challenges in  diagnosing interstitial lung disease.

So typically, the interstitial lung  disease will impair oxygen absorption  

from the alveolus into the blood  within the alveolar capillaries.

And so the symptoms relate to that.

And the very earliest symptom  is exertional breathlessness,  

which to begin with can be very subtle.

But as the disease becomes more severe, then the  level of dyspnea and exercise limitation will  

increase to the point that patients with severe  disease will have resting respiratory failure.

But like I say, at the earliest stages, it tends  just to be subtle exertional breathlessness.

Some patients also have a cough.

Often we diagnose patients a little bit earlier  when they have a cough because that symptom tends  

to be more intrusive and is more easily  noticed by patients or their loved ones.

And what physical exam findings are  typical at the time of diagnosis?

So for interstitial lung diseases alone,  

the very classic clinical finding is the  bilateral basal velcro-like crepitations.

And those can often be heard in  patients with very early disease.

So as pulmonologists, we certainly  encourage careful clinical examination  

of any patient presenting with exertional  breathlessness because those bilateral  

basal crepitations can be the earliest and  most important clue to a diagnosis of ILD.

Beyond that, a proportion of  patients will have finger clubbing.

And then we've mentioned the  association with autoimmune disease.

So sometimes we will see features of connective  tissue disease, so skin thickening in scleroderma.

The changes of Raynaud's phenomenon in  patients with myositis, for instance,  

will often see goctrines,  papules, and mechanics hands.

Or in patients with rheumatoid arthritis,  

you might see arthralgia and arthropathy  affecting the small joints of the hand.

Given that the presenting symptoms that  you mentioned are pretty non-specific,  

shortness of breath on exertion,  cough, when should the primary  

care clinician think about interstitial  lung disease as a possible diagnosis?

Yeah, so there clearly is a challenge  for primary care physicians.

And if you imagine, as I've just told  you, the average patient is in their 60s.

So you have a 60-year-old patient  who's a former smoker who comes to  

you complaining of mild exertional breathlessness.

The obvious differential diagnoses  would include cardiovascular disease,  

COPD, and then probably further down  that list, interstitial lung disease.

And so distinguishing ILD from the more common  

causes of exertional breathlessness  in that age group can be difficult.

I think one of the key clues in the history  is the rapidity of onset of the symptoms.

So patients with COPD will tend to have much  slower onset of breathlessness over many years,  

whereas ILD patients will have noticed a  change over a period usually of a few months.

And then the thing that often distinguishes  it from things like cardiovascular disease or  

asthma is the consistency of the symptom.

The patient will very much notice exercise  limitation at a certain level of exertion,  

and they tend to have stable symptoms day to  day that doesn't tend to be so much variability.

And then as I've said, the clinical finding  of the bilateral basal crepitations should  

really be the red flag that alerts  people to the possibility that this  

is an actual ILD that's causing the  symptoms rather than something else.

And when interstitial lung disease  is suspected as a possible diagnosis,  

what should the generalist start with  with regard to diagnostic testing?

Yeah, so I think if there is a suspicion,  

then obviously one is going to go to  simple investigations to start with.

And spirometry and chest X-ray  can be helpful in that regard.

So in the majority of patients with ILD,  chest X-ray will show some abnormalities.

So in IPF, for instance, you would expect to see  bilateral basal reticular change on a chest X-ray.

Similarly with spirometry, you would expect  to see some evidence of airflow restriction.

That said, neither test alone has  high sensitivity or specificity,  

particularly for early disease, and  it is possible to miss early cases.

And really, the definitive diagnostic  test for identifying ILD is the CT scan.

What type of CT scan?

So classically, people have referred to  the CT scan we do as high resolution CT.

That's a slightly out of date term that refers to  

the technique that was used on  old scanners about 20 years ago.

But nowadays, any volumetric thoracic CT will  ultimately give you the level of resolution  

you need for the lungs to be able to see  even an early interstitial lung disease.

So as long as you ask your radiologist  for a thoracic CT because you suspect ILD,  

you can use the terminology high resolution CT.

Either should work to provide you a  high quality volumetric CT of the lungs.

Let's turn to therapy.

What is first line therapy  for interstitial lung disease?

As we've said, the interstitial lung  diseases are a broad range of conditions,  

and so there isn't one single treatment  for all forms of interstitial lung disease.

Had we been having this discussion 10 years ago,  then we wouldn't really have had any treatments  

to talk about, but thankfully we have seen  some development over that period of time.

So for radiopathic pulmonary  fibrosis, we have anti-fibrotic drugs.

So there are two drugs, bethenadone and tetanib,  

which work to slow the rate  at which fibrosis progresses.

And so those tend to be the first line  treatment for radiopathic pulmonary fibrosis.

For more immune-mediated or inflammatory diseases,  and scleroderma-related ILD is the best example of  

these, because that's the disease in which  most clinical trials have been performed.

We know that immunomodulatory  therapy with things like tocilizumab,  

mycophenolate-mothetal, cyclophosphamide,  rituximab can have an impact on disease  

trajectory and can even in the  short term improve lung function.

And then we know that for  those patients who develop  

pulmonary fibrosis in the context  of their interstitial lung disease,  

that the use of the anti-fibrotic drug nintedinib  can again help to slow disease progression.

So those are our medical options.

In terms of non-medical options, we know  that exercise-based therapy is effective  

for patients in terms of improving  symptoms and exercise capacity.

So we'll typically refer patients for  pulmonary rehabilitation, which is a course  

that encapsulates both a teaching component  to educate patients about their disease,  

but also an important exercise-based component  

where patients do physical training to  try and improve their exercise capacity.

And then for patients who end up with  end-stage disease, we can use oxygen.

So we'll typically prescribe oxygen for  patients to use on exertion if they have  

evidence of desaturation below 88% on a walk test.

And we can show that we can correct  that desaturation and reduce their  

breathlessness with ambulatory oxygen.

And then for patients with  resting respiratory failure,  

so oxygen saturations below 88% at rest, we  will tend to prescribe 24-hour-a-day oxygen.

And then our sort of go-to treatment  for patients who have continued to  

worsen, despite all available  therapies, is lung transplant.

Lung transplant can be a  transformational treatment for patients.

We can take them from respiratory  failure back to leading a normal life.

The downside of transplant is firstly,  the availability of organs is very low.

And so it's probably less than 1% of our  patients will ultimately be transplanted.

And furthermore, transplants  associated with a need for being  

on lifelong immunosuppression and is also  associated with a range of complications,  

including the ever present risk  of rejection and also infection.

So it's an imperfect treatment, but it can be very  important for patients with end stage disease.

And then obviously with many of these diseases  progressing through respiratory failure and death,  

there is an important role for managing symptoms,  both breathlessness and cough, and also together  

with palliative care, we work very hard to manage  end of life decision making and ensure management  

of symptoms at end of life for patients as  these diseases reach their terminal phases.

So I have a few questions  for you about the treatments.

First, how effective are the  drugs that you mentioned?

The anti-fibrotic drugs, perfenedone and  nintedinib, were shown in clinical trials  

to approximately halve the rate at which  idiopathic pulmonary fibrosis progresses.

So the average patient loses about  240 milliliters of FVC a year,  

and that's approximately halved with treatment.

When the drug was approved by the  FDA, the FDA made it clear that  

their opinion was that slowing FVC decline  would ultimately lead to improved survival.

And subsequent real world registries  have suggested that treatment with  

anti-fibrotic drugs is associated  with an improvement in life expectancy  

from about three and a half years in  untreated patients to a life expectancy  

of about five years from diagnosis in  patients treated with anti-fibrotic drugs.

So we have seen this improvement in life  expectancy with treatment, but we've still got  

a very long way to go before we can effectively  prevent fibrotic disease from getting worse.

Treatment in scleroderma ILD, where  we have more options and we can use  

immunomodulatory drugs, is  probably more effective.

Certainly in trials of 12 months duration, we've  been successful in preventing disease decline.

And with some of these immunomodulatory drugs,  

we've even seen modest  improvements in lung function.

We don't have so much long-term data to be able  to say what impact that has had on survival.

Although when you look at survival  in the autoimmune diseases and  

particularly scleroderma, overall,  there has been an improvement in  

life expectancy for patients with these  conditions over the last decade or so.

So I think the drugs do make a difference,  

but we're a long way from preventing,  let alone curing ILD in these conditions.

And can you comment on whether the  oxygen and the exercise therapy are  

mainly to improve symptoms or do they  have any disease modifying effects?

That's a very good question, and I  don't have a complete answer for you.

So the evidence we have really points  

to them improving symptoms and  quality of life for patients.

We suspect that that may well be  associated with life expectancy benefits,  

with pulmonary rehab, but we don't  have the evidence to support that.

And similarly, with oxygen, we believe, at  least theoretically, that the early use of  

oxygen might help prevent the development of  complications such as pulmonary hypertension.

But again, we don't have the evidence to truly  prove that we are doing that with oxygen therapy.

Thanks.

This has been a very informative discussion.

Is there anything else you'd like to add?

I think we've covered a lot in  a very short period of time.

I know I would just emphasize to  listeners that interstitial lung  

disease is undoubtedly more  common than they've realized.

Almost all of the ILDs are life shortening and  have very important implications for our patients.

And I really think being alert to the  possibility of interstitial lung disease  

when you see a breathless patient is important  because early diagnosis allows earlier treatment,  

which in turn, almost certainly  will help improve outcomes and  

life expectancy for patients with these  otherwise very life threatening diseases.

This is Mary McDermott, Deputy Editor of  JAMA, and I've been speaking today with  

Dr. Toby Maher on his JAMA review  about interstitial lung diseases.

For more of our podcasts, please  visit us at jamanetworkaudio.com.

You can subscribe and listen  wherever you get your podcasts.

This episode was produced by  Daniel Morrow at the JAMA Network.

Thanks for listening.

Nintedanib 150 mg twice daily reduced to 100 mg twice daily if adverse effects

Pirfenidone 801mg TID reduced to 534mg TID if adverse effects