Study of Therapeutic Plasma Exchange, Rituximab, and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (Strive-IPF) (H-46682)

Objective: To determine the effects of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) in comparison to effects of treatment as usual (TAU), among AE-IPF patients.

Hypothesis: Autoantibody reduction is beneficial for AE-IPF patients.

Inclusion Criteria: 

1. Age between 40-85 years old.
2. Diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.
3. Hospitalized patient with diagnosis of AE-IPF, as ascertained by responsible Primary Investigator (PI), with findings that include worsening or new development of dyspnea or hypoxemia within the last 30 days.
4. Ground-glass abnormality and/or consolidation superimposed on a reticular or honeycomb UIP pattern on locally read chest CT scan.
5. Ability and willingness to give informed consent and adhere to study requirements.

Exclusion Criteria: 

1. Diagnosis of current infection per clinical or microbial assessments.
2. Diagnoses of an additional or alternative etiology for respiratory dysfunction based upon clinical assessment, including congestive heart failure, sepsis, thromboembolism, etc
3. History or serological evidence of hepatitis B, or current hepatitis C infection.
4. Coagulopathy, defined as an INR >1.6, PTT > 2x control, fibrinogen <100 mg/dL, or platelet count <50K unless these abnormalities can be reversed safely.
5. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes, or uncontrolled hypertension (systolic BP >160 mm Hg and diastolic BP >100 mm Hg) that would contraindicate use of corticosteroids. 
6. Hemodynamic instability, defined as an inotrope or vasopressor requirement.  
7. History of reaction to blood products or murine-derivedproducts.
8. Active malignancyor undergoing treatment of malignancy, excluding basal or squamous cell skin cancer and low-risk prostate cancer, the latter defined as stage T1 or T2a, with prostate specific antigen (PSA) less than 10 ng/dl.  The experimental treatments are not known to promote cancer progression, and these criteria are within current guidelines.
9. Unwillingness to accept blood product transfusion. 
10. Diagnosis of major comorbidities, or other considerations, that the responsible physician-investigators believe should disqualify subjects,or areexpected to interfere with study participation.
11. Treatment for >14 days within the preceding month with >20 mg. prednisone (or equivalent) or any treatment during the last month with a cellular immuno-suppressant (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, mycophenolate, azathioprine, etc.).An exception will be made if the patient has a bronchoalveolar lavage (BAL) negative for pathogens. 
12. Presence of a condition or ongoing treatment with a medication that precludes TPE.  
13. Concurrent participation in other experimental trials. 
14. Fertile females who do not agree to contraception or abstinence, or have a positive pregnancy test (urine or blood). IPF is a disease of older adults, and male predominant,so this will not be a frequent consideration. 
15. Presence of positive (abnormal) classical autoimmune tests:ANA, RF, Anti-SSA, and Anti-CCP.  This criterion will eliminate patients with confounding classical autoimmune syndromes.  Many IPFpatients will have already had these tests, which are standard of practice (SOP) at many IPF centers, and these prior results will suffice if the tests were performed within the last year.  Otherwise, these tests need to be performed prior to enrollment andthey canusuallybe procured in 1-2 days.  ANCA will continue to be tested during screening but negative results are no longer a requirement for randomization.  Based on experience,we anticipate ~10% of patients who fulfill all other IPF criteriawill nonetheless be positive for one of these classical autoantibody tests.
16. IgA deficiency(IgA level <7 mg/dL)-to preclude IVIG reactions.
17. Listed with the United Network for Organ Sharing for lung transplant at the time of enrollment.
18. Patients who are intubated at time of STRIVE enrollment.
19. Prior use of rituximab within the year preceding enrollment.
20. Clinical or Morphologic Domain criteria of IPAF.