Diffuse Parenchymal Lund Disease, formerly Interstitial Lung Disease 1

Solomon Sallfors

Group of diseases (“waste basket”) that primarily affects lung parenchyma diffusely

May also affect vasculature, airways, and pleura >100 different diseases Excludes COPD, pulm HTN, and infections 30-40% won’t have clear cause Prevalence: Fewer than <1/1000 Recently reclassified as known or unknown causes

WORK-UP

1. Typical presentation: Progressive dyspnea or cough for >3 mos (some kinds may present after 2 mos), without response to medical treatment for more common diseases.

A few can present acutely. See Appendix 1.

2. History taking important: Ask about hobbies, work, social practices, meds. See Appendix 2 for lists of significant DLPDs. Work related lung injury treated separately in MKSAP. Also see Appendix 3 for extensive table of environmental related exposures.

3. This should always get plain film, which should show some kind of abnormality in 80% of cases. All cough or resp symptoms >8 weeks: CXR.

4. Test of Choice: HRCT (Can specify prone and supine versions if considering dependent atelectasis; or expiratory if suspect air trapping)

5. Analyze for 1) Pattern and 2) distribution, which will strongly suggest diagnosis in 60% See Appendix 4 for table of radiographic findings for different DLPDs.

6. To corroborate your clinical suspicion, some laboratory studies can correlate with various interstitial lung diseases.

See appendix 5 for lab tests. Also can check creatine kinase for myositis.7. If disparate findings, then decide between bronchoscopy with biopsy or open surgical lung biopsy. 8. Also get spirometry, lung volumes, and diffusing capacity.

1 Largely adapted from MKSAP 16 and UP-to-Date

Δ Classic HRCT features of UIP: Reticular opacities in basal and

peripheral distribution

Traction bronchiectasis

Honeycombing (clustered airspaces 3 to

10 mm diameter) in subpleural location Ground glass opacities may be present

but are less extensive than reticular

opacities

BAL: bronchoalveolar lavage;

TBB: transbronchial lung biopsy.

* Serology as indicated by clinical findings: rheumatoid factor, anti-cyclic citrulinated peptide, antinuclear antibody, antisynthetase antibodies, creatine kinase, aldolase, Sjögren's antibodies and scleroderma antibodies.

TYPES OF DPLD

UNKNOWN CAUSES

Idiopathic Pulm. Fibrosis: collagen deposition in peripheral and basal pattern, with septal lines and honeycombing. Median survival 3-5 years. Elhalwagi: “worse than cancer”. Palliative consult.

Nonspecific Interstitial Pneumonia: most often caused by an underlying connective tissue disease. Example: systemic sclerosis: basal predominant (like IPF) with ground-glass appearance without honeycombing. Pathology varies: cellular or collagen. Lung biopsy needed for dx. Tx: steroid with taper, poss. chemo. Relapses common.

Cryptogenic organizing Pneumonia: Persistent cough and symptoms that suggest Comm. Acq pneumonia, which persists 6-8 weeks despite 1 or more courses of antibiotic. TX: steroid with taper. Relapses common. Diffuse bilat. alveolar opacities with normal lung volumes, sometimes also focal consolidation or multiple large nodules or masses. (Cryptogenic= idiopathic; organizing= remodels tissue structure leaving fibrosis).

Acute Interstitial Pneumonia: rapid onset from days to weeks, results in diffuse alveolar damage and ARDS. Diagnosis of exclusion. TX: steroid, supports, low vol ventilation. 50% mortality.

KNOWN CAUSES

Unknown Causes

Smoking related: typically active smokers with subacute, progressive cough and dyspnea. PFTs: obstructive, dec DLCO if severe; if mild, then restrictive, normal, or obstructive. Tx cessation, steroid poss if severe but not well est. Different from COPD?: HRCT may show ground glass or micronodular disease, and thin walled cysts

in upper lobes.

Connective tissue: TX: DMARDS for underlying disease.

Systemic sclerosis: leading cause of mortality. Histopathologic similar to nonspecific interstitial pneumonia. Steroids not effective. Cyclophosphamide: some short-term benefit.

Rheumatoid arthritis: pleural disease, nodules, bronchitis, bronchiectasis, and acute lung injury. If RA and interstitial PNA, then as bad as IFP. TX: steroid and DMARDs.

Hypersensitivity: repeated inhalation of finely dispersed antigens. Presents with flu-like symptoms 4-8 hrs, bilateral hazy opacities, and HRCT= ground-glass opacities with centrilobular nodules in upper- and mid-lungs, resolves 24-48 hrs. Mimics IFP. MC caused by thermophilic actinomycetes, fungi, and bird droppings, could also be fungal, bacterial, or protozoal, animal or insect proteins or small molecular chemical compounds. If chronic: HRCT can show fibrosis with reticular lines, traction bronchiectasis, architectural distortion, and

honeycomb. TX: avoid antigen, steroids for further symptoms, chemo if fibrosis, poss lung transplant.

Drug/radiation induced:

Amioderone: high incidence. Can happen 10 days to 10 years, typically first year. Elderly and higher doses at risk. Many radiographic presentations. TX steroid. Relapses common.

Methotrexate: <5% of those treated. diffuse reticular and/or ground-glass attenuation; with more severe cases there can be dense consolidation. 2/3 have peripheral eosinophils. TX: stop drug, steroids.

Nitrofurantoin: Acute form in several days: fever, chills, dyspnea, cough, wheezing, myalgia, and chest pain, and a cutaneous rash; and chronic form motnhs to years after chronic exposure: chronic cough and progressive dyspnea. TX: stop drug.

Radiation: cough and dyspnea 6 weeks after the exposure. HRCT: hazy opacities with ground-glass attenuation. Typically resolve within 6 months. TX: steroids if severe.

See appendix 6 for list of common drugs causing DPLD.

MISC

Sarcoiddois: 90% have pulm manifestations. Tissue infiltration by mononuclear phagocytes, lymphocytes, and noncaseating granulomas. Can be acute or indolent. PFTs can be obstructive or restrictive. Diagnosis of exclusion. Biopsy may be necessary. TX: low dose steroid with taper if significant symptoms.

LAM: Occurs sporadically in women of childbearing age or in association with tuberous sclerosis. Presents with hyperinflation and dyspnea. Diagnosis requires context and imaging. HRCT: diffuse thin call cysts. Thought to be a kind of low grade cancer. TX: lung transplant poss, med therapy uncertain. Elhalwagi: “You’ll never see it.”

bronchiolitis obliterans organizing pneumonia (BOOP): Acute presentation. Bilateral, diffuse, alveolar opacities in the presence of normal lung volume.

Appendix 1

Appendix 2

Appendix 3

Appendix 3 cont.

Appendix 4

Appendix 4 cont.

HRCT patterns in interstitial lung disease: Up-to-date

Normal Airspace opacitiesHypersensitivity pneumonitis Haze or ground glass attenuation

Sarcoidosis Hypersensitivity pneumonitis

Bronchiolitis obliterans Desquamative interstitial pneumonia

Asbestosis Respiratory bronchiolitis-associated interstitial lung disease

Distribution of disease within the lung Drug toxicity

Peripheral lung zone Pulmonary hemorrhage

Idiopathic pulmonary fibrosis Lung consolidation

Asbestosis Chronic or acute eosinophilic pneumonia

Connective tissue disease Cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia)

Cryptogenic organizing pneumonia Aspiration (lipoid pneumonia)

Eosinophilic pneumonia Alveolar carcinoma

Central disease (bronchovascular thickening) Lymphoma

Sarcoidosis Alveolar proteinosis

Lymphangitic carcinoma Reticular opacitiesUpper zone predominance Idiopathic pulmonary fibrosis

Granulomatous disease Asbestosis

Sarcoidosis Connective tissue disease

Pulmonary histiocytosis X (eosinophilic granuloma) Hypersensitivity pneumonitis

Chronic hypersensitivity pneumonitis NodulesChronic infectious diseases (eg, tuberculosis, histoplasmosis) Hypersensitivity pneumonitis

Pneumoconiosis Respiratory bronchiolitis-associated interstitial lung disease

Silicosis Sarcoidosis

Berylliosis Pulmonary langerhans cell histiocytosis

Coal miners' pneumoconiosis Silicosis

Lower zone predominance Coal workers' pneumoconiosis

Idiopathic pulmonary fibrosis Metastatic cancer

Rheumatoid arthritis (associated with usual interstitial pneumonia) Isolated lung cystsAsbestosis Pulmonary langerhans cell histiocytosis

Lymphangioleiomyomatosis

Chronic Pneumocystis carnii (P. jirovecii) pneumonia

Appendix 5

Laboratory findings in the interstitial lung diseases

Abnormality Associated condition

Leukopenia Sarcoidosis; connective tissue disease; lymphoma; drug-induced

Leukocytosis Hypersensitivity pneumonitis; lymphoma; systemic vasculitis

Eosinophilia Eosinophilic pneumonia; sarcoidosis; systemic vasculitis; drug-induced

(sulfa, methotrexate)

Thrombocytopenia Sarcoidosis; connective tissue disease; drug-induced; Gaucher's disease

Hemolytic anemia Connective tissue disease; sarcoidosis; lymphoma; drug-induced

Normocytic anemia Diffuse alveolar hemorrhage syndromes; connective tissue disease;

lymphangitic carcinomatosis

Hypercalcemia Sarcoidosis; lymphangitic carcinomatosis

Urinary sediment abnormalities Connective tissue disease; systemic vascultiis; drug-induced

Hypogammaglobulinemia Lymphocytic interstitial pneumonitis

Hypergammaglobulinemia Connective tissue disease; sarcoidosis; systemic vasculitis; lymphocytic

interstitial pneumonia; lymphoma; silicosis

Anti-glomerular basement membrane

antibody (anti-GBM)

Anti-GBM disease (Goodpasture disease)

Anti-neutrophil cytoplasmic antibody

(ANCA)

Granulomatosis with polyangiitis (Wegener's); Churg-Strauss syndrome;

microscopic polyangiitis

Serum precipitating antibodies Hypersensitivity pneumonitis

Lymphocyte transformation test Chronic beryllium disease; aluminum potroom workers disease; gold-

induced pneumonitis

Elevation of LDH Alveolar proteinosis; idiopathic pulmonary fibrosis

Appendix 6

Examples of drugs and biologics that can cause interstitial lung disease

Drug-induced systemic lupus Antibiotics

erythematosusHydantoins Ethambutol

Hydralazine hydrochloride Minocycline

Isoniazid Nitrofurantoin, acute and chronic

Penicillamine Chemotherapeutic agentsProcainamide hydrochloride Alkylating agents

Illicit drugs Busulfan

Cocaine Chlorambucil

Heroin Cyclophosphamide

Methadone hydrochloride Melphalan

Propoxyphene hydrochloride (Darvon) Procarbazine hydrochloride

Talc Antibiotics

Miscellaneous Bleomycin sulfate

Bacille Calmette-Guerin (BCG) Mitomycin C

Bromocriptine Antimetabolites

Drugs inducing pulmonary infiltrates and

eosinophilia

Azathioprine

L-tryptophan Cytosine arabinoside

Oxygen Methotrexate

Radiation NitrosoureasStatins BCNU (carmustine)

Anti-inflammatory agents CCNU (lomustine)

Gold Methyl-CCNU (semustine)

Interleukin-1 blockers Other

Leflunomide Alpha interferon

Nonsteroidal antiinflammatory agents Docetaxel

Penicillamine Etoposide (VP-16)

Rituximab (anti-CD20 monoclonal antibody) Gefitinib

Sulfasalazine Nilutamide

Tumor-necrosis factor-alpha blockers Paclitaxel

Anti-arrhythmic agents Temsirolimus

Amiodarone Thalidomide

Tocainide