Anti-malondialdehyde-acetaldehyde adducts antibodies in lung tissues may play important role in pathogenesis of RA-associated interstitial lung disease, study indicates

By Dr Deepu

Anti-malondialdehyde-acetaldehyde adducts (MAA) antibodies and MAA expression in lung tissues of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) likely play an important role in RA-ILD pathogenesis, and anti-MAA antibodies may function well as serum biomarkers in the identification of this disease manifestation.

Patients with RA face premature mortality and RA-ILD is a major determinant of worse long-term outcomes, with a median survival as short as 3 years after diagnosis. In the present study, researchers compared serum anti-MAA antibodies and MAA expression in lung tissues of patients from 13 sites fulfilling the 1987 American College of Rheumatology criteria by selecting participants from the Veterans Affairs Rheumatoid Arthritis Registry.

Multivariable logistic regression models were used to assess the association between anti-MAA antibodies (immunoglobulins A, M, and G [IgA, IgM, IgG]) and RA-ILD status by combining RA alone with RA+chronic obstructive pulmonary disease (COPD) for a comparator group, as unadjusted comparisons found no significant differences in concentrations of anti-MAA antibodies between these groups. Lung tissues from RA-ILD patients, and other patients with ILD, emphysema, and controls were stained for MAA, macrophages (CD68), citrulline, B cells (CD19/CD27), T cells (CD3), and extracellular matrix proteins (fibronectin, vimentin, type-II collagen). Lung tissue expression and MAA co-localization were quantified and compared.

Among the total 1823 participants with RA, 90 had RA-ILD. Higher serum concentrations of IgM and IgA anti-MAA antibodies were seen in RA-ILD vs RA+COPD or RA alone (P =.005). After adjustment for covariates, the highest quartiles of IgM (odds ratio [OR] 2.23; 95% CI, 1.19-4.15) and IgA (OR 2.09; 95% CI, 1.11-3.90) anti-MAA antibody were significantly associated with RA-ILD. MAA expression in lung tissue was greater in RA-ILD than all other groups (P  <.001). The RA-ILD group also showed the greatest degree of MAA co-localized with CD19+ B cells (r =0.78), citrulline (r =0.79), and extracellular matrix proteins (type-II collagen [r =0.72] and vimentin [r =0.77]).

The study authors concluded the study by noting "These findings suggest that MAA immune responses could play an important role in the pathogenesis of RA-ILD and anti-MAA antibodies may be promising serum biomarkers in the identification of this extra-articular disease manifestation"

The finding were published in arthritis and rheumatology

One-year treatment with cyclophosphamide tied to short-term improvements in patients with symptomatic systemic sclerosis-related interstitial lung disease, study indicates

By Dr Deepu

Researchers found that “in patients with symptomatic systemic sclerosis (SSc)-related interstitial lung disease (ILD), 1-year treatment with the immunosuppressant cyclophosphamide (CYC) is associated with short-term improvements in forced vital capacity (FVC)%-predicted and the modified Rodnan skin score (mRSS), but not in the diffusing capacity of the lungs for carbon monoxide (DLCO)%-predicted.”

Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included in the study. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 months) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yearsrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity.

Researchers found that SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group.

Finally they could conclude that Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis–ILD.

The findings were published in the Journal of Rheumatology.

Antacid therapies may not improve outcomes in patients with IPF

By Dr Deepu

proton pump inhibitors or other antacid therapies” may not “improve outcomes in patients with idiopathic pulmonary fibrosis (IPF), and the treatment may increase infection risk in patients with advanced disease, according to findings from a post-hoc analysis of three large, randomized trials. Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in the analysis. They analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks.
Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, there was no significant difference between groups for disease progression. Rates also did not differ for all-cause mortality, IPF-related mortality, absolute FVC decrease, or mean observed change in FVC. The rate of hospital admission was non-significantly higher in the antacid therapy group . When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; 

ATS Guidelines on childhood ILDs

By Dr Deepu

ATS guidelines on childhood ILDs. Interstitial lung disease (ILD) in infants is caused by entities that are distinct from those that cause ILD in older children and adults. Growing recognition and understanding of the various entities that cause ILD in children has led to the need for improved classification and evaluation. A committee was convened by the American Thoracic Society (ATS) to develop guidelines to inform clinicians, patients, and organizations regarding the classi- fication, evaluation, and management of childhood ILD (chILD).

         There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults.

    A multidisciplinary panel was convened to develop evidence based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient’s or family’s quality of life, and death.  

 After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.

Download the full article here – ILD GUIDELINES 

ILD GUIDELINES

By Dr Deepu

An Official ATS/ERS/JRS/ALAT Guideline: Treatment of IPF (2015)

Executive Summary

Full-length version

Evidence tables

Evidence-to-decision tables

Official ATS/ERS Technical Standards: Field walking tests in chronic respiratory disease (2014)

An Official ATS/ERS Systematic Review: Measurement properties of field walking tests in chronic respiratory disease (2014)

Online supplement

An Official ATS/ACCP Statement: The Choosing Wisely Top 5 List in Adult Pulmonary Medicine (2014)

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias (2013)

An Official ATS Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis In Interstitial Lung Disease (2012)

An Official ATS Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis In Interstitial Lung Disease(2012) - Online Supplement

An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management (2011) Being revised.

NIH/NHLBI Notice re: 3-drug Regimen for IPF (2011)

Statement on Sarcoidosis (1999)

ATS / ERS / WASOG statement on sarcoidosis ERS task force 1999

BTS Interstitial Lung Disease Guideline 2008 BTS

NICE IPF Guideline  NICE 2013

Aide memoire for the first clinic visit in suspected ILD BTS 2008

 Drug induced ILD: classification with examples BTS 2008

Diagnostic algorithm for interstitial lung disease BTS 2008

BASICS OF HRCT PART 7 - DIFFERENTIAL DIAGNOSIS OF ILD

This is the last post in the series of basics of HRCT. links to the previous posts are given at the end of this post.

DIFFERENTIAL DIAGNOSIS OF INTERSTITIAL LUNG DISEASE

Reticular pattern 

1.     Lymphangitic carcinomatosis: irregular septal thickening, usually focal or unilateral 50% adenopathy', known carcinoma.

2.     Cardiogenic pulmonary edema: incidental finding in HRCT, smooth septal thickening with basal predominance (Kerley B lines), ground-glass opacity with a gravitational and perihilar distribution, thickening of the peribronchovascular interstitium (peribronchial cuffing)

3.     Lymphangitic carcinomatosis.

4.     Lymphangitic carcinomatosis with hilar adenopathy.

5.     Alveolar proteinosis: ground glass attenuation with septal thickening (crazy paving).

6.     Cardiogenic pulmonary edema.

Nodular pattern

1.     Hypersensitivity pneumonitis: ill defined centrilobular nodules.

2.     Miliary TB: random nodules

3.     Sarcoidosis: nodules with perilymphatic distribution, along fissures, adenopathy.

4.     Hypersensitivity pneumonitis: centrilobular nodules, notice sparing of the area next to pleura and fissure.

Nodular pattern(2)

1.     Sarcoidosis: nodules with perilymphatic distribution, along fissures, adenopathy.

2.     TB: Tree-in-bud appearance in a patient with active TB.

3.     Langerhans cell histiocytosis: early nodular stage before the typical cysts appear.

4.     Respiratory bronchiolitis in infection.

High Attenuation pattern 

1.     Chronic eosinophilic pneumonia with peripheral areas of ground glass opacity.

2.     Sarcoid end-stage with massive fibrosis in upper lobes presenting as areas of consolidation. Notice lymphadenopathy.

3.     Chronic eosinophilic pneumonia with peripheral areas of consolidation.

4.     Broncho-alveolar cell carcinoma with both areas of ground glass opacity and consolidation

High Attenuation pattern (2) 

1.     Non specific interstitial pneumonitis (NSIP): ground glass with traction bronchiectasis, no honeycombing.

2.     Cryptogenic organizing pneumonia (COP).

3.     Sarcoidosis end-stage: consolidation as a result of massive fibrosis perihilar and in upper lobes.

4.     COP.

Low Attenuation pattern 

1.     Lymphangiomyomatosis (LAM): uniform cysts in woman of child-bearing age; no history of smoking; adenopathy and pleural effusion; sometimes pneumothorax.

2.     LCH: multiple round and bizarre shaped cysts; smoking history.

3.     Honeycombing

4.     Centrilobular emphysema: low attenuation areas without walls.

Low Attenuation pattern (2) 

1.     Centrilobular emphysema: low attenuation areas without walls. Notice the centrilobular artery in the center.

2.     Langerhans cell histiocytosis (LCH): multiple thick walled cysts; smoking history.

3.     Honeycombing.

4.     Lymphangiomyomatosis (LAM): regular cysts in woman of child-bearing age.

suggested reading

• CHEST X RAY INTERPRETATION

• CHEST X RAY PART 1- NORMAL ANATOMY AND ITS VARIANTS

• BASICS OF CHEST X RAY- PART 2 , EASY WAY TO INTERPRET CXR.

• BASICS OF CHEST X RAY PART 3- SYSTEMATIC APPROACH, SILHOUETTE SIGN AND HIDDEN AREAS IN CHEST XRAY

• BASICS OF CHEST X RAY-PART 4, THE HEART AND PERICARDIUM

• BASICS OF CHEST X RAY-PART 5, THE HILUM AND MEDIASTINUM

• BASICS OF CHEST X RAY PART-6, THE LUNGS, PLEURA AND THE CHEST WALL.

• BASICS OF HRCT INTERPRETATION

• BASICS OF HRCT INTERPRETATION-PART 2- RETICULAR PATTERN

• BASICS OF HRCT INTERPRETATION-PART 3- NODULAR PATTERN

• BASICS OF HRCT PART-4 , HIGH ATTENUATION PATTERN

• BASICS OF HRCT PART 5- LOW ATTENUATION PATTERN

• BASICS OF HRCT PART 6 - DISTRIBUTION PATTERN AND ADDITIONAL FEATURES

• BASICS OF HRCT PART 7 - DIFFERENTIAL DIAGNOSIS OF INTERSTITIAL LUNG DISEASE

• HRCT FINDINGS OF ATYPICAL ADENOMATOUS HYPERPLASIA.

• SARCOIDOSIS- CT FINDINGS

• MOUNIER KUHN SYNDROME

• AIR BRONCHOGRAM SIGN

• THE ‘DARK BRONCHUS’ SIGN

• THE RINGS !!!THE TRAMS!!!, CHEST X RAY FINDINGS IN BRONCHIECTASIS

• THE HRCT FINDINGS OF BRONCHIECTASIS.

• GRAND ROUNDS- CANNON BALL SECONDARIES AND PULMONARY METASTASIS...

• GRAND ROUNDS - OPAQUE HEMITHORAX.

• RADIOLOGY- CHEST X RAY SPOTTERS.

• CLINICAL CASE - GIVE YOUR DIAGNOSIS!!!

• SPOTTER : IDENTIFY THE RADIOLOGICAL SIGN IN CHEST X RAY 

• CHEST X RAY- IMPORTANCE OF DIAPHRAGM. THE DIAPHRAGM IS UNIQUE AND PROVIDES 

SARCOIDOSIS

A multisystem granulomatous disorder of unknown etiology.

Clinical manifestations

a.      Mostly young adults.

b.     Any organ may be involved with the lungs, lymphatics, skin, liver, eyes most commonly affected in decreasing order. Some manifestations to watch for:
- Myocardial involvement (possible conduction disturbances)
- Uveitis
- Cranial nerve VII involvement
- Erythema nodosa

c.      PFTs: Decreased volumes, compliance, DLCO, hypoxemia.

d.     BAL: Predominance of T-lymphocytes and macrophages.

e.      Immunology: Activated T-lymphocytes secrete IL-2 which, as a monocyte chemotactic factor, recruit monocytes and thus contribute to granuloma formation.

f.       CXR:
- Stage 0  Clear
- Stage I   Bilateral hilar adenopathy
- Stage II  Hilar adenopathy and parenchymal infiltrates
- Stage III Parenchymal infiltrates only
- State IV Extensive fibrosis and distortion of lung architecture

g.     Gallium-67 Imaging: increased pulmonary uptake with alveolitis.

h.     Hypercalcemia (10-15%), hypercalciuria (20-30%)

i.        Elevated ACE level (nonspecific); however, ACE may be followed for therapeutic response.

j.        Hyperglobulinemia, impaired delayed hypersensitivity.

Diagnosis: Transbronchial lung biopsy showing non-caseating granulomas with compatible clinical picture.

Therapy: Corticosteroids

a.      Indications for prednisone therapy: active alveolitis with severe symptoms, uveitis, liver disease (marked), cardiac disease, CNS disease, hypercalcemia.

b.     Secondary agent: methotrexate, antimalarial agents controversial.

Transplantation

a.      Recurrent sarcoid granulomata noted in allografts; immunosuppression for transplantation may attenuate granulomatous responses in patients having recurrent disease.

IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis is a disease characterized by diffuse interstitial fibrosis of unknown etiology and frequently occurs between the ages of 50-70.

Clinical Picture

• Patients present with dry cough and shortness of breath and sometimes with fever, arthralgias and Raynaud's phenomenon.
• Clubbing (40-70%) tachypnea and persistent coarse basal crackles are encountered on physical exam. Often they are using accessory muscles of inspiration for tidal breathing.
• CXR: Normal to reticulonodular to honeycombing. HRCT may show ground glass appearance or honeycomb cysts.  In Desquamative interstitial pneumonitis alveolar features can be recognized..
• PFT shows a restrictive and diffusion defects. Patients are hypoxic and desaturate significantly with exercise.
• In 25-45%, serum cryoglobulins, RF and ANA are present.
• BAL: Predominance of neutrophils.

Pathology

Desquamative Interstitial pneumonitis(DIP), Usual Interstitial Pneumonitis(UIP), Lymphocytic Interstitial Pneumonitis( LIP) are various subgroups, probably of the same disease process.

a.      Early IPF: Desquamation predominates where alveolar macrophages fill alveolar spaces (desquamative interstitial pneumonitis or DIP).

b.     Late IPF: Inflammation of alveolar walls continues and fibroblast proliferation with collagen formation occurs (usual interstitial pneumonitis or UIP).

Diagnosis

•  By exclusion, it will be necessary to rule out other known causes for fibrosis like Silicosis or drugs. A long list of conditions can give rise to interstitial fibrosis 
• Transbronchial lung biopsy  can identify interstitial fibrosis. Usually need open lung biopsy to confirm.

Treatment

• Therapy is useful in acute stages when there is significant inflammatory process.
• Once the fibrosis is chronic or if the chest X-ray has been stable for years or if there is honeycombing, therapy is of no benefit.
• Corticosteroids + immunosupressants (cyclophosphamide or azathioprine); anecdotal reports describing colchicine or methotrexate or cyclosporine.
• Oxygen is often prescribed for these patients, probably not influencing pulmonary hypertension.
• In some cases  Plasmapheresis and Lung Transplant are considerations.
• Transplantation: 50% two year survival with single lung.

Prognosis

• In the acute progressive form "Hamman-Rich Syndrome" the prognosis is poor.
• In the chronic form patients can live long with disability.

HYPERSENSITIVITY PNEUMONITIS

HYPERSENSITIVITY PNEUMONITIS

A type III and IV hypersensitivity reaction to microbial spores, animal proteins and chemicals.

a.      Farmer's lung is the prototypic disease caused by a reaction to Micropolyspora faeni.

b.     Fever, chills, dyspnea, leukocytosis may occur 4-6 hours after exposure and eventually resolve; symptoms and signs may recur on re-exposure.

c.      CXR: Acute - normal to reticulonodular pattern; Chronic - progressive fibrosis, honeycombing.

d.     BAL: Predominance of lymphocytes; increased IgG, IgM.

e.      Serum precipitins to offending antigen present.

f.       Pathology: - Interstitial alveolitis with lymphocytes and non-caseating granulomas (nonspecific); foam cells present (nonspecific)

Diagnosis: Compatible clinical picture, BAL with lymphocytes; serum precipitins; (inhalational challenge).

Therapy: Avoidance of continued inhalational exposure to causative antigen; corticosteroids in severe cases.