Eosinophilic Lung Disease Cases

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Eosinophilic LungDiseaseCases

• William Kelly, MD

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Eosinophil our friend and foe

• Two-lobed, polymorphonuclear leukocyte
• 12 to 15 um diameter
• Created by IL-3, Il-5 and GM-CSF
• Three granule types, largest made up of MBP
  (major basic protein), kills
• Parasites, tumor cells, respiratory epithelium
• Hypodense and normodense varieties

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Eosinophil our friend and foe

• Circulates lt18 hours
• Chemotaxis
• complement, histamine, ECF-A, PAF, leukotrienes,
  lymphokines, tumor factos, IL-5
• 100-400x more in tissues than in blood

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Eosinophil competing theories

• Host defense
• Modulator of inflammation
• Tissue destroyer

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Eosinophils Whats Normal

• Blood EOS () 50-250 per microliter
• Bronchoscopy (BAL) EOS
• Percentage () rather than absolute number
• Normal volunteers lt 1
• ARDS usually none
• Increased ( gt5) five percent of the time
• Mostly PCP, drug-related, idiopathic

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Classification

• Reeder and Goodrich, 1952
• Pulmonary Infiltrates Eosinophilia (PIE)
• Croften et al, 1952
• Simple pulmonary eosinophilia (Lofflers)
• Prolonged pulmonary eosinophilia
• Tropical eosinophilia
• Pulmonary eosinophilia with asthma
• Polyarteritis nodosa (PAN)

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Classification

• Liebow and Carrington, 1969
• Added Chronic eosinophilic pneumonia (CEP)
• McCarthy and Pepys, 1973
• Either ABPA or cryptogenic
• Schatz et al, 1981
• Back to PIE

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Classification

• Airway
• Lung parenchyma known systemic illness
• Lung parenchyma idiopathic

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Airway disorders

• Asthma
• Allergic Bronchopulmonary Aspergillosis
• Bronchocentric granulomatosis

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Lung parenchymaknown systemic illness

• Infections
• Bacterial, mycobacterial, fungal, parasites, AIDS
  (PCP)
• Interstitial lung disease
• IPF/UIP
• Sarcoid
• SLE

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Lung parenchymaknown systemic illness

• Hypereosinophilic syndrome
• Vasculitis (Churg-Strauss)
• Hodgkins disease
• Drug reactions
• Lung cancer

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Lung parenchymaidiopathic

• Simple eosinophilic pneumonia (SEP, Lofflers
  pneumonia)
• Chronic eosinophilic pneumonia (CEP)
• Acute eosinophilic pneumonia (AEP)

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Case 1

• 23 y.o. male nonsmoker with over a year of
  nonproductive cough, wheezing, exertional dyspnea
• Personal and family history of allergies
• WBC 9400 with 6 eosinophils
• Refers himself to U-SCAN at the mall

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Case 1 you should next

• Start oral steroids
• Order thick and thin smears of blood
• Obtain PFTs with bronchodilator
• Start diethyl-carbamazine

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Case 1 you should next

• Start oral steroids
• Order thick and thin smears of blood
• Obtain PFTs with bronchodilator
• Start diethyl-carbamazine

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Asthma

• Peripheral eosinophilia often noted
• intrinsic and extrinsic
• Proportional to airflow obstruction
• Eosinophil MBP results in airway shedding, may
  contribute to creola bodies

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Case 2

• 44 y.o. female with hard-to-treat asthma, just
  weaned off oral steroids (again), presents with
  increased shortness of breath
• Treated with antibiotics over the years for
  pneumonias with radiographic clearing
• Coughs up brown plugs of mucous
• Sputum culture does not show fungus

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Case 2 (contd)

• Peripheral eosinophils and IgE are increased
• Allergist gets wheal and flare when they prick
  the skin with aspergillus antigens
• Radiologist says CXR shows tram-tracking
• Chest CT is obtained

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Case 2 you should next

• Oral steroid burst for 5 days then Advair
• Oral steroids for months
• Itraconazole
• A and C
• B and C

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Case 2 you should next

• Oral steroid burst for 5 days then Advair
• Oral steroids for months
• Itraconazole
• A and C
• B and C

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ABPA

• Asthmatics (6), Cystic fibrosis (10)
• Aspergillus fumigatus
• Others Candida albicans, Heliminthosporium,
  Curvularia lunata
• Proximal obstruction and bronchiectasis

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ABPA

• Difficult asthma
• Blood eosinophilia
• Elevated IgE
• Total and specific
• Aspergillus skin prick
• Aspergillus precipitins
• Radiographic infiltrates

• Aspergillus in sputum
• Brown mucous plugs
• Arthus (Type III) skin reaction
• Radiographic clues
• gloved-finger
• ring shadows
• tram-tracking

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ABPA Staging

• I Acute
• II Remission
• III Exacerbation
• IV Steroid-dependent
• V Fibrotic

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ABPA treatment

• Oral corticosteroids
• Hi-dose for 1-4 weeks
• Change to QOD over next three months
• Slow taper over following three months
• Itraconazole
• Surveillance
• CXR Q4 x 6, Q6 x 2, Q12 months
• IgE Q1 month

Salez F. Chest 1999 116(6) 1665-8
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Case 3

• 54 y.o. male non-smoker presents with an abnormal
  CXR done for a physical exam
• On review he does complain of cough, malaise and
  occasional fevers
• PFTs show mild obstruction which normalize after
  bronchodilator

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Case 3 (contd)

• Blood eosonophils are increased
• Serum RF and C-ANCA are negative
• Biopsy is performed
• No malignancy is found
• Special stains for AFB and fungus are negative
• You review the slides with the pathologist

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Case 3 your diagnosis

• Eosinophilic granuloma
• Smear negative, culture negative TB
• Bronchocentric granulomatosis
• Sarcoidosis

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Case 3 your diagnosis

• Eosinophilic granuloma
• Smear negative, culture negative TB
• Bronchocentric granulomatosis
• Sarcoidosis

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Bronchocentric granulomatosis

• Liebow 1973
• Clinical and radiographic pattern variable
• Surgical biopsy required
• Inflammation, esosinophilia, Charcot-Leyden
  crystals
• NO extrabronchial granulomas
• Diagnosis of exclusion
• TB, fungal infection
• Wegeners or Rheumatoid lung disease
• Aspiration

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Bronchocentric granulomatosis

• 1/3 of patients
• Asthma, eosinophilia, fungal hyphae on bx,
  aspergillus in sputum
• tissue-destructive ABPA
• 2/3 of patients
• Neutrophils without asthma or fungi evident
• Corticosteroids can be effective

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Case 4

• 32 y.o. male with night sweats, weight loss,
  fever, pruritis presents with a cold, pulseless
  foot
• CXR shows interstitial infiltrates and a small
  effusion
• CBC WBC 12000, 56 eosinophils

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Case 4 which is FALSE

• Cardiac involvement is the leading cause of
  mortality
• 50 will have a good response to steroids
• 40 have pulmonary involvement
• Venous thrombosis is more common than arterial

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Case 4 which is FALSE

• Cardiac involvement is the leading cause of
  mortality
• 50 will have a good response to steroids
• 40 have pulmonary involvement
• Venous thrombosis is more common than arterial

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Idiopathic Hypereosinophilic Syndrome (HES)

• eosinophilic leukemia
• Rare, often fatal
• EOS gt1500/microliter for six months
• 71 male predominance
• Usually age 30s (oldest reported 70)
• Blood EOS 30-70
• Bronchoscopy (BAL) EOS up to 73

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Case 5

• 38 y.o. male with 8 year history of asthma,
  chronic rhinitis, presents with fever, malaise,
  weight loss
• Hypertension, mononeuritis multiplex noted
• Labs notable for anemia increased EOS (9400),
  IGE and ESR RF weakly positive microscopic
  hematuria, Scr 0.8 P-ANCA is positive

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Case 5 (contd)

• PFTs show obstruction
• Bronchoscopy reveals 32 eosinophils but cultures
  are negative for bacteria, AFB or fungus
• Thoracentesis reveals an exudate with increased
  eosinophils
• Biopsy is performed

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Necrotizing giant cell vasculitis, small vessel,
with granulomas and eosinophils
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Case 5 which is FALSE

• 50 die in three months without treatment
• With treatment, mean survival has been reported
  as 9 years
• 50 of patients may be ANCA positive (usually
  perinuclear P-ANCA)
• Unlike Wegeners, pulmonary nodules do NOT tend
  to cavitate
• Treatment requires corticosteroids along with
  cytotoxic agents

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Case 5 which is FALSE

• 50 die in three months without treatment
• With treatment, mean survival has been reported
  as 9 years
• 50 of patients may be ANCA positive (usually
  perinuclear P-ANCA)
• Unlike Wegeners, pulmonary nodules do NOT tend
  to cavitate
• Treatment requires corticosteroids along with
  cytotoxic agents

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Churg-Strauss Syndrome

• Churg and Strauss - 1951
• Allergic angiitis and granulomatosis
• Three phases
• Prodromal allergic rhinitis, asthma (years)
• Dramatic peripheral eosinophilia (months, yrs)
• Tissue infiltration like Lofflers or CEP
• Systemic vasculitis

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Churg-Strauss Syndrome

• Upper airway
• Rhinitis, polyps, sinusitis
• Skin (70)
• Nodules, purpura, urticaria
• Neurologic
• Mono.Multiplex (66)
• CNS (27)

• Gastrointestinal
• Abd pain (59)
• Diarrhea (33)
• Bleeding (18)
• Cardiac
• CHF (47)
• Pericarditis (32)
• HTN (29)
• Renal (49)

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Churg-Strauss Syndrome

• Pathologic diagnosis
• Renal histology non-specific, often no
  granulomas
• TBBX probably inadequate
• Open lung biopsy gold standard
• Treatment steroids x 1 yr, relapse rare
• Pulse steroids or cytotoxic agents for failure

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Churg-Strauss Syndromedifferential diagnosis

• Wegeners
• Nodules cavitate
• C-ANCA positive
• Histology different
• PAN
• Medium-sized vessels
• No lung involvement
• No eosinophilia

• CEP
• No granulomas
• Not extra-pulmonary
• Idiopathic hyper-eosinophilia syndrome
• No granulomas
• No vasculitis

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Churg-Strauss Syndrome

• Associated with leukotriene antagonists
• Zafirlukast, montelukast
• Incidence 120,000
• Probably coincidental with steroid tapering of
  primary eosinophilic infiltrative disorder

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Case 6

• 22 y.o. female referred to you for management of
  refractory asthma since returning from the Peace
  Corps in India consisting of nocturnal cough with
  wheezing and malaise
• Moist crackles and wheezes are auscultated, No
  adenopathy or hepatosplenomegaly
• PFTs show a mixed defect
• Serum Eosinophilia is 3400

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Case 6 which is FALSE

• Mosquitoes spread this disease
• Bronchoscopy (BAL) may show 50 EOS
• Blood sampling is not helpful
• Tissue biopsy is required
• Treatment is diethyl-carbamazine

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Case 6 which is FALSE

• Mosquitoes spread this disease
• Bronchoscopy (BAL) may show 50 eos
• Blood sampling is not helpful
• Tissue biopsy is required
• Treatment is diethyl-carbamazine

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Wuchereria bancrofti, filarial worm
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Tropical Pulmonary Eosinophilia

• Ancylostoma sp.
• Ascaris sp.
• Brugia Malayi
• Clonorchis sinesis
• Dicrofilaria immitis
• Echinococcus sp.
• Opisthorchiasis sp.

• Paragonimus westermani
• Schistosoma sp.
• Strongyloides steratocolis
• Toxocara sp.
• Trichinella spiralis
• Wuchereria bancrofti

Can cause infection in United States
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Tropical Pulmonary Eosinophilia

• Ex W. bancrofti
• GI symptoms predominate
• Lymphadenopathy common in children
• Blood EOS gt 3000
• Bronchoscopy (BAL) high EOS, IgE, IgG
• PFTS usually restriction, 30 mixed

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Case 7

• 32 y.o. from southern Texas, 31 weeks pregnant,
  with dry cough and mild SOB
• Dysuria two months ago, nitrofurantoin QD
• Tolerated same with last pregnancy
• PFTs show restriction
• Blood eosinophils are mildly elevated
• Abnormal CXR prompts shielded CT

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Case 7 you recommend

• Induce delivery or C-section
• Stop all medications
• Add oral steroids
• Start empiric anti-parasite medication, using one
  with best FDA pregnancy class
• Open lung biopsy

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Case 7 you recommend

• Induce delivery or C-section
• Stop all medications
• Add oral steroids
• Start empiric anti-parasite medication, using one
  with best FDA pregnancy class
• Open lung biopsy

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Drug reactions

• Common cause of pulmonary infiltrates and blood
  or BAL eosinophilia
• Multiple medications
• Nitrofurantoin, Sulfasalazine, Phenytoin,
  Bleomycin, Tetracycline
• Treatment with dicontinuation of drug and
  possibly corticosteroids

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Drug reactions (Ex. 1)

• Eosinophilic-myalgia syndrome (late 1980s)
• Contaminated L-tryptophan
• 50 of ingestions had myalgias, eosinophilia
• 50 of these had pulmonary involvement cough,
  dyspnea, cxr infiltrates, effusions, muscle
  weakness
• IgE, CK normal, PFTs with restriction
• Histology with vasculitis, eosinophils

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Drug reactions (Ex. 2)

• Toxic oil syndrome (1981-1982)
• 20,000 cases 300 deaths in Spain
• olive oil rapeseed oil with oleoanilide
• Fever, respiratory/GI distress, rash, adenopathy
• CXR interstitial/alveolar infiltrates, Kerley
  Bs
• Steroids helpful acutely, others progressed to
  pulmonary fibrosis of hypertension

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Case 8

• 54 y.o. female with history of atopy, seven
  months of slowly progressive cough, dyspnea,
  fever, malaise and weight loss
• PFTS consistent with asthma
• Blood shows increased IgE and eos
• CXR and CT are obtained

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Diffuse, peripherally-based infiltrates (outer
2/3rds of lung) photographic negative of
pulmonary edema
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Interstitial and alveolar degranulated
eosinophils, eosinophilic microabscesses, Low-grad
e vasculitis, and interstitial fibrosis
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Case 8 you can tell her

• Most cases resolve spontaneously
• It is unusual for women to get this
• It is unusual to get this at her age
• Her asthma was likely diagnosed within the past
  few years

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Case 8 you can tell her

• Most cases resolve spontaneously
• It is unusual for women to get this
• It is unusual to get this at her age
• Her asthma was likely diagnosed within the past
  few years

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Chronic Eosinophilic Pneumonia

• Christoforodis and Molnar 1960 (n2)
• Carrington
• Peak incidence age - 50s
• Insidious onset 7.7 months sxs pre dx
• Cough (90), fever (87), SOB (57), weight loss
  (57), asthma (50 - less than 5 yr duration)
• Peripheral EOS (gt6) 88
• BAL EOS usually gt25 and may be 44

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CEP

• IgE elevated (66)
• ESR, RF, immune complexes, thrombocytosis may be
  found
• Hypoxemia, PFTs with mild restriction
• Peripheral CXR infiltrates (63)
• photonegative of CHF only 25

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CEP

• Unlike simple pulmonary eosinophilia (SPE,
  Lofflers pneumonia) spontaneous resolution is
  rare (lt10)
• Steroids 40 mg/day dramatic resolution
• Symptoms within 1-2 days
• CXR infiltrates within 10 days
• Relapse common in first 6 months

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Case 9

• 39 y.o. male crashes in through the ER with
  Sao2 70s on room air and is intubated
• Per his wife he was in excellent health until the
  onset of the flu with fever to 104 and myalgias
  3 days ago
• CXR shows only a mild interstitial infiltrate in
  fact a CTPA gram is done to exclude PE- but
  infiltrates progress

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Case 9 (contd)

• CBC and blood eosinophils are normal
• Sputum/urine/blood cultures/HIV negative
• Thoracentesis- elevated pH and eosinophils
• Bronchoscopy (BAL) is done to exclude infection-
  42 eosinophilia is noted

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Case 9 you know this differs from CEP because

• Steroids are not effective
• Relapse is uncommon
• Bronchoscopy (BAL) shows EOS
• Peripheral blood EOS can be normal
• B and D

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Case 9 you know this differs from CEP because

• Steroids are not effective
• Relapse is uncommon
• Bronchoscopy (BAL) shows EOS
• Peripheral blood EOS can be normal
• B and D

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Acute Eosinophilic Pneumonia

• First described 1989
• Unknown cause
• ? Inhaled antigen hypersensitivity
• Similar to some cases in CML patients
• Similar to some postoperative events
• Unlike other ARDS (BAL neutrophils)
• Must exclude infection (esp. fungus)

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Acute Eosinophilic Pneumonia

• Acute febrile illness lt 5 days duration
• Hypoxemic respiratory failure
• Diffuse alveolar or mixed CXR infiltrates
• BAL EOS gt 25
• Absence of parasitic, fungal or other infxn
• Prompt/complete response to steroids
• Failure to relapse after steroids

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Miscellaneous thoughts (1)

• Pleural fluid eosinophilia (PFE)
• Pneumothorax most common
• Hemothorax (may take 1-2 weeks)
• Benign asbestos effusion
• Pulmonary embolism
• Parasites/ Fungus/ TB (rare)
• Drug induced
• Lymphoma/ Carcinoma (5-8)

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Miscellaneous thoughts (2)

• Eosinophilic Granuloma (EG)
• Langerhans cell granulomatosis
• 2-5 cases/million, whites, smokers (90)
• Pneumothorax (6-20)
• stellate (star-shaped) fibrosis
• 50 atypical lymphocytes, OKT6, S100
• NO eosinophilia
• Treatment smoking cessation, steroids

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Airway disorders

• Asthma
• Allergic Bronchopulmonary Aspergillosis
• Bronchocentric granulomatosis

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Lung parenchymaknown systemic illness

• Infections
• Bacterial, mycobacterial, fungal, parasites, AIDS
  (PCP)
• Interstitial lung disease
• IPF/UIP
• Sarcoid
• SLE

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Lung parenchymaknown systemic illness

• Hypereosinophilic syndrome
• Vasculitis (Churg-Strauss)
• Hodgkins disease
• Drug reactions
• Lung cancer

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Lung parenchymaidiopathic

• Simple eosinophilic pneumonia (SEP, Lofflers
  pneumonia)
• Chronic eosinophilic pneumonia (CEP)
• Acute eosinophilic pneumonia (AEP)

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Questions ?