Hypersensitivity Pneumonitis

Diagnostic elements

• Hx of relevant exposures (usually organic dusts or aerosols)
• Improvement after cessation of exposure
• Compatible clinical, radiographic or physiologic findings (ie restrictive findings on spirometry/FVC, decreased TLC, decreased DLCO)

Hypersensitivity Pneumonitis

Diagnostic pitfalls

• Precipitins confirm exposure only, they are not diagnositic
• Preciptin panels test only to those antigens, they may not be relevant to patient exposure
• Sampling/culture of area of interest should drive precipitins investigation

Hypersensitivity Pneumonitis

Additional Diagnostic Tools

Biopsy (Usually transbronchial)

• When Ddx is challenging and other immunologic or interstitial diseases are considered
• Path:  poorly formed non-caseating granulomas near bronchioles reflecting DTH/Tcell 
• Mononuclear infilration, histiocytes in alveoli and interstitium 
• Peribronchial fibrosis

• Mid to upper zone predominance of centrilobular groud glass (inflammation) or nodular opacities
• Airtrapping as disease advances
• Reticular/fibrotic changes on high res CT in advanced disease

• Inhalation fever (ie humidifier fever): with inhalation of organisms that produce endotoxin or (metal fume fever) ie welders who work with galvanized steel and inhale Zn, Al oxides that cause cytokine release and have flu like syndrome lasting 24-48 hrs.  No pulm infiltrates

• Organic Dust Toxic Syndrome or grain fever
• Assoc w exposures to endodoxins in grain dust or high levels fungal spores w mycotoxin
• Acute flu like syndromes but no parenchymal involvement, no infiltrates like in Hypersens Pneumonitis

BAL findings in

Hypersensitivity Pneumonitis 

vs

Sarcoid

• HP:  brisk lymphocytosis w predominance CD8 but also seen in asymptomatic patients with high level exposure to same antigens
• Sarcoid:  sequestration of CD4 in lungs, therefore predominance of CD4
• CD4/CD8 ratios are high in sarcoid and low in HP

            Sx           PE            Radiogr

       4-8 hrs        normal vs     normal,       

      f/c,  SOB,      crackles      Hi-Res        

        cough                          CTmid-

                                          upper zones

Hypersensitivity Pneumonitis 

Clinical Spectrum

Subacute

          Sx           PE         Radiogr

     over months     normal vs     GG mixed w 

     SOB, cough      crackles       fibrosis/retic

     weight loss                         honeycombing

Hypersensitivity Pneumonitis

Key Points

• Inflammatory condition of parenchyma, intersitium and terminal bronchioles
• Cause:  Immunologic sensitization to antigens
•        -respirable organic dusts or
•        -reactive chemicals ie diisocyanates
• CXR abn in 10% only.   Hi Res CT is sensitive
• DDX: Atypical pneumonia, sarcoid, BOOP, IPF, humidifier fever
• Causes : see list p 798

Hypersensitivity Pneumonitis

Causes

Thermoactinomyces

Thermophilic bacteria that contaminate vegetative matter 

• Sugar Cane Workers' lung (Bagassosis)  from bagasse (the remnants of pressed sugar cane)

• Farmer's Lung from wet hay, barns

• Humidifier Lung from stagnant water  (pt's w pulm infiltrates in winter only)

Sauna Taker's Disease

Hypersensitivity Pneumonitis

Causes

 Mycobacterium Avium

Hot Tub Lung: mists and mold on ceiling and around tub

(can also be caused by Cladisporium sp)

Hypersensitivity Pneumonitis

Causes

Trichosporon cutaneum

Summer type HP- described in Japan

from a mold in house dust

Hypersensitivity Pneumonitis

Causes

Penicillium casei/Aspergillus clavatus

Cheese Washer's lung from moldy cheese

Hypersensitivity Pneumonitis

Causes

Thermophilic actinomycetes

Mushroom worker's lung

Hypersensitivity Pneumonitis

 Causes

Coffee bean dust

Coffee worker's lung

Hypersensitivity Pneumonitis

Causes

Organic (urine, serum, pelts) animal proteins

Laboratory Worker's lung especially from rats and gerbils

Hypersensitivity Pneumonitis

Causes

Avian proteins

Pigeon, "bird fancier's" lung from bird droppings

Hypersensitivity Pneumonitis

Causes

Methylene diphenyl diisocyanate

Phthalic anhydride

Chemical workers exposed to

isocyanates, epoxy resins, 

(can also cause occupational asthma?)

Hypersensitivity Pneumonitis

Causes

Mycobacterium, pseudomonas flourescens,

?others

Machine operator's (grinding and lathing that use recirculated metal working fluid) lung from contaminated machining fluid

Hypersensitivity Pneumonitis

Management

• Prevention/reduction of ag burden ie wetting compost before handling, abx to sugar cane, moisture contol in indoor envir etc
• Prognosis is good in acute if exposure removed
• OCS accelerate recovery
• Fibrosis portends worse prognosis

ABPA

ESSENTIAL Diagnostic Criteria

•     Asthma (usually steroid dependant)
•     Central bronchiectasis¨     
• ¨    Elevated serum total IgE (>1000ng/ml)
• ¨      Immediate ST reactivity to Aspergillus
• ¨    Elevated serum specific IgE and IgG to Aspergillus fumigatus

ABPA

NON-ESSENTIAL FEATURES

• ¨      Aspergillus cultured in sputum
• ¨      Brown sputum plugs with hyphae
• ¨      Arthus to Asp f
• ¨      A fumigatus precipitins
• ¨      Peripheral eosinophilia
•      Fleeting pulmonary infiltrates

ABPA in CF

MAJOR Diagnostic Criteria

• ¨      Acute or subacute clinical deterioration not otherwise attributable
• ¨      IgE>2400
• ¨      + ST Aspergillus  or +serum IgE antibodies/RASTS
• ¨      + Precipitins to Aspergillus f
• ¨      New CXR or chest CT abnormalities not clearing w antibiotics or physiotherapy

ABPA

Features/misc

• Specific IgE binding to recomb Asp f1  in 70%
• HLA-DR2 and DR5  (mnemonic if you have ABPA you’ll need a DR 2-5 times!!)

ABPA

Stages

• ¨      Stage 1– Acute
• ¨      Stage II- Remission
• ¨      Stage III-Exacerbation
• ¨      Stage IV Corticosteroid dependant asthem
• ¨      Stage V- Pulmonary fibrosis

• Acute exacerbations during stages I-III treated with oral CS

• Cochran review (12 studies):  Itraconazole improved sputum eos, IgE and exacerbations over placebo

Acute exacerbations during stages I-III treated with oral CS

        Cochran review (12 studies):  Itraconazole improved sputum eos, IgE and exacerbations over placebo

PIE (Pulmonary Infiltrates and Eosinophilia)

Multiple Etiologies I

Churg Strauss vascultitis:

• ·      small vessel arteritis
• ·      severe asthma
• ·      granulomas
• ·      eosinophilia
•      mononeuritis multiplex

PIE (Pulmonary Infiltrates and Eosinophilia)

Multiple Etiologies II

Drug induced

• ¨      Most common drugs:
• ·      NSAIDS
• ·      Minocyline
• ·      Nitrofurantoin
• ·      Ampicillin
• ·      Sulfonamides

PIE (Pulmonary Infiltrates and Eosinophilia)

Multiple Etiologies IV

Tropical filiarial pulmonary eosinophilia

• ¨      Wucherieria bancrofti or Burgia mlayi
• ·      Wheezing, coughing
• ·      Pulmonary interstitial infiltrates lead to fibrosis
• ·      Elevated IgE >1000
• ·      Immune response to hematogenous filarial antigens
• (differentiating from Loffler’s and ABPA:  ? evidence of parasites)

PIE (Pulmonary Infiltrates and Eosinophilia)

Multiple Etiologies V

Others

• ¨      “Toxic oil syndrome” from Rapeseed oil
• ¨      “Eosinophilia Myalgia Syndrome”  L-tryptophan ?aspartame
• ¨      Acute idiopathic eosinophilic pneumonia
• ¨      Chronic idiopathic eosinophilic pneumonia
• ·      Peripheral infiltrates on CXR
• ·      ‘Photographic negative’ appearance suggestive of pulm edema

SARCOIDOSIS

FEATURES

• ¨      Incidence: 10-20/100K
• ¨      Onset age 10-40 y/o
• ¨      More severe and more common in African Americans
• ·      Lifetime risk >3 fold greater than other groups
• ¨      Lung involvement in 95%
• ¨      Bilateral hilar adenopathy, pulmonary reticular opacities and endobronchial disease in 70%
• ¨      Upper respiratory manifestations: submucosal granulomas in larynx, pharynx, sinuses et
• ¨      Skin, joint and/or eye lesions

SARCOIDOSIS

LAB Analysis

• ¨      Elevated serum ACE
• ¨      Elevated EST
• ¨      Elevated CD4 in BAL (sequestered to lung/decreased in peripheral blood)   CD4/CD8 ratio high in BAL (ie ratio>4, 100% PPV in distinguishing from other interst dz), low in periphery
• ¨      Hypercalcemia and
• ¨      Hypercalcuria (excess calcitriol by pulm macrophages
• ¨      Hyperglobulinemia (activated B cells
• ¨      Granulomas on bx (r/o AFB, fungus)

SARCOIDOSIS

PATHOGENESIS

• IL-2 release and expansion of lung T cells expressing markers suggestive of clonal response to a specific unknown antigen
• TH-1
• B cell hyperreactivity

SARCOIDOSIS

Staging

•  Stage I  Bilateral hilar adenopathy
• Stage II Hilar adenopathy and reticular opacities in upper lobes
• Stage III Reticular opacities but decreased hilar nodes
• Stage IV Reticular changes chronic, bronchiectasis, fibrosis
• Alveolitis is uncommon  HRCT:  ground glass actually represent granulomatous inflammation

SARCOIDOSIS

EXTRA PULMONARY MANIFESTATIONS

MULTISYTEM GRANULOMAOUS DISORDER:

• Skin 16%  rash, nodules, e nodosum, panniculitis,
• Ocular 12% iridocyclitis, uveitis, retinal vasculitis, keratoconjuctivitis
• Liver 12%
• Hypersplenism 7% due to granulomas: anima, leukopenia, thrombocytopenia
• Cardiac 2%  heart block
• Others:  arthritis, hyperglobulinemia, hypercalcemia, salivary gland hypertrophy, diabetes insipidus, hypopitutary
• Lofgren’s syndrome: E nodosum, hilar adenopathy, migratory polyarthraligias, fever (mostly women)

SARCOIDOSIS

TREATMENT

• OCS NOT indicated

            Stage 1 asx (high rate of spontaneous        remission)
            Stage II asx
·                            Stage III and normal or mild PFT changes, but only 1/3 of Stage III have spontaneous remission

• Oral Corticosteroids indication specific to:

·                          Worsening PFT, deteriorating lung function’

                Progressive radiologic changes

CHRONIC BERYLLIUM DISEASE

EXPOSURE

• Ultrafine beryllium particles
• Metal machining, ceramics, nuclear weapons
• 100-800K workers exposed in US

CHRONIC BERYLLIUM DISEASE

FINDINGS

•  Dry cough
• SOB
• Night Sweats
• Fatigue
• Weight loss
• Lung infiltrates w CD4 Tcells (must differentiate from sarcoidosis)

CHRONIC BERYLLIUM DISEASE

DIAGNOSIS

• Non caseating granulomas on bx
•  Exposure hx
• Lymphocyte prolif in vitro w beryllium (send to    National Jewish)
• DTH prolif in vitro
•  HLA DPB1 0201 in 97% affected workers vs 30% exposed but no disease

GOODPASTURES DISEASE

• ·      Diffuse pulm hemorrage, hemosiderin laden macrophages, neutrophils
• ·      Crescentic GN w linear IgG and complement on BM
• ·      Anti GBM in serum that fix complement in 90%,
• o      Antibodies against type IV collagen of BM correlelates with disease activity
• ·      P-ANCA in 30%   (p…pulmonary)
• MHC DR 15 and DR4