Therapeutic Plasma Exchange, Rituximab and IV Ig for Severe Acute Exacerbation of IPF Admitted in ICU

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative, irreversible disease of unknown cause, occurring mainly in patients older than 50. IPF is a rare but fatal lung disease, with an estimated prevalence of 14 to 28/100000 and a median survival time of 3 years. Acute exacerbation of IPF (AE-IPF) is a major event of IPF, as it is responsible for the death of 30-50 % of IPF patients; its annual incidence varies between 5 and 10%. The current literature indicates that IPF is associated with the development of an auto-immunity process targeting epithelial and endothelial lung cells. Autoantibodies have been associated with a poorer prognosis. A study by DONAHOE et al. (Plos One, 2015) indicates that the combination of corticosteroids, plasma exchanges, rituximab and immunoglobulins may improve the prognosis of the most severe forms of AE-IPF. In that study, the observed survival rate in patients receiving this combination of treatment was 70% as compared with 20% in historical controls. This therapeutic combination approach is designed both to eliminate and inhibit the production of circulating antibodies targeting the lungs. Considering the high mortality rate of an AE-IPF episode and the potential benefit of such an original approach, a well-conducted randomized controlled trial is critical.

Inclusion Criteria: 1. Patient ≥ 18 years of age 2. Admitted to ICU in the last 72 h 3. Definite or probable IPF diagnosis defined on 2018 ATS/ERS/JRS/ALAT guidelines or a possible usual interstitial pneumonia pattern on HRCT without etiology. 4. Definite AE-IPF according to the 2018 revised criteria : 1. Previous or concurrent diagnosis of idiopathic pulmonary fibrosis (if the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and or histopathologic changes consistent with usual interstitial pneumonia (UIP) pattern on the current evaluation); 2. Acute worsening or development of dyspnea typically of less than one-month duration; 3. Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with a UIP pattern (if no previous computed tomography is available, the qualifier "new" can be dropped); 4. Deterioration not fully explained by cardiac failure or fluid overload. 5. PaO2/FiO2 ratio \< 200 measured on FiO2 1 Exclusion Criteria: 1. Known hypersensitivity intravenous immunoglobulins or rituximab 2. Severe heart failure 3. Active and uncontrolled bacterial fungal or parasitic infection ruled out by at least one of these two conditions 1. Procalcitonin value at inclusion \< 0.25 ng/mL OR 2. Adapted antimicrobial therapy for at least 48 hours at inclusion 4. Positive multiplex PCR for Influenzae A and B, or VRS 5. Deep Veinous Thrombosis or Pulmonary embolism in the last six months 6. Prior exposures to human-murine chimeric antibodies 7. Ongoing treatment with a cellular immunosuppressant (e.g., cyclophosphamide, methotrexate, mycophenolate, azathioprine, calcineurin inhibitors, etc.) 8. Subject treated with more than 2 boluses of methylprednisolone (total dose \> 500mg of methylprednisolone) or one dose \> 10mg/kg in the last 72 hours 9. Uncorrectable coagulopathies or thrombocytopenia \< 30000/mm3 10. Active cancer (other than basal cell carcinoma of the skin) 11. Other source of immunosuppression (i.e. HIV infection, solid organ transplant, lymphoma or leukemia) 12. Pregnancy 13. Patient listed for lung transplantation 14. Patient on ECMO 15. Patient with a do-not-intubate order at inclusion 16. Concurrent participation in other experimental trials 17. Not Affiliation to the French social security 18. Not Written informed consent from the patient or a legal representative if appropriate 19. Hypersensitivity to corticosteroids, cotrimoxazole / atovaquone 20. Patients with severe renal insufficiency (creatine clearance \