A Case of Pulmonary Alveolar Proteinosis

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A Case of Pulmonary Alveolar Proteinosis

• Geoffrey L. Uy

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Case Presentation

• __ is 44 y/o WF with history of pulmonary
  alveolar proteinosis. She was diagnosed in 1998
  when she presented with a several month history
  of worsening cough and progressive dyspnea on
  exertion which did not improve after several
  courses of antibiotics.
• She was subsequently diagnosed by bronchoscopy.
  She had been treated with lung lavage on 3
  separate occasions for symptomatic relief.
  However she had not responded clinically to her
  most recent treatment. Currently she was
  severely limited in her activities and required
  continuous oxygen therapy.

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Case Presentation

• PMH PAP
• FH hx hemophilia in nephew
• SH married no tobacco use, social EtOH
• PE
• O2 Sat 96 on 3L NC
• Chest diffuse bilateral rales
• Labs
• ABG 7.44 / 39 / 55 on RA
• WBC 8.8 Hgb 13.4 Plt 294,000
• BMP WNL

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Case Presentation
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Why is she in the hematology clinic?

• What is pulmonary alveolar proteinosis?
• Pathogenesis of disease
• Link to GM-CSF
• Lessons from mouse models
• Implications for management

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Lung Histology 101 Surfactant

• Type I Pneumocytes (Epithelial cells)
• Type II Pneumocytes (Surfactant cells)
• secrete surfactant
• BIG, at corners of alveoli
• Macrophages
• within the alveolar space

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Pulmonary Alveolar Proteinosis
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Clinical Features

• Presentation
• Progressive exertional dyspnea and cough
• Bilateral rales
• Epidemiology
• Prevalence of 0.37 per 100,000
• Median age of onset 39 years
• Idiopathic 90, secondary and congenital forms
• CXR bat-wing appearance
• CT scan crazy paving pattern

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Crazy paving pattern
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Clinical Features

• Treatment
• Whole lung lavage
• Clinical Course
• 1/3 of patients have spontaneous remission
• 1/3 need whole lung lavage to relieve symptoms
• 1/3 have progressive disease including pulmonary
  fibrosis recurrent pulmonary infections

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GM-CSF (Granulocyte/Macrophage Colony
Stimulating Factor)

• In vitro stimulates the differentiation of
  neutrophils and macrophages
• Produced by hematopoietic and nonhematopoietic
  tissues
• GM-CSF receptor
• a confers specificity to GM-CSF
• ßc shared by GM-CSF, IL-3, IL-5
• rhuGM-CSF (Leukine)

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GM-CSF knockout

• Dranoff G et al. Science 1994
• Stanley E et al. PNAS 1994
• Essentially normal steady state hematopoiesis
• Normal numbers of peripheral blood cells, BM
  progenitors, tissue hematopoietic cells

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GM-CSF knockout
WT
GM-CSF -/-
Surfactant IHC
Cytospin
Dranoff G et al. Science 1994264 713-716
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Surfactant mRNA levels
Dranoff G et al. Science 1994264 713-716
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(No Transcript)
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Immunity 19952211-222.
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Lessons from Mice
Type II pneumocytes
Surfactant
Alveolar Macrophage
GM
GM
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Treatment with GM-CSF
Seymour JF et al. NEJM 19963351924-1925
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Human PAP

• Congenital
• identified deficiency in GM-CSFR ßc
• Acquired PAP
• No mutations in GM-CSF found in iPAP
• Levels of GM-CSF are elevated in BAL fluid and
  plasma
• GM-CSF produces benefits in only subset of
  patients

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Other lung dz
iPAP patients
Normal
J Exp Med. 1999 Sep 20190(6)875-80.
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Antibody Neutralizes GM-CSF
J Exp Med. 1999 Sep 20190(6)875-80.
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Back to our patient . . .

• Patient had a high-titer neutralizing antibody to
  GM-CSF 13600 (gt1400 abnormal)
• Treated with plasmapheresis followed by rituximab
  375 mg/m2 X 4
• Returned to clinic 2 months later, off O2
  therapy for first time in 3 years, ABG showed
  PaO2 70s
• Returned to work

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The End