Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are sudden and severe worsening episodes that can be life-threatening. Currently, no treatment has been proven to clearly improve outcomes during these events. Inflammation and immune system imbalance are thought to play an important role in causing AE-IPF. Early clinical experience suggests that intravenous immunoglobulin (IVIG) can be beneficial for patients suffering from AE-IPF. This clinical trial aims to determine whether adding IVIG to usual treatment can improve outcomes for patients hospitalized with AE-IPF.

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are sudden, life-threatening deteriorations associated with high mortality. Despite their severe impact on a substantial subset of patients with IPF, no treatment has yet demonstrated clear, reproducible benefit, and standardized therapeutic strategies remain lacking.

This prospective, multicenter, randomized study aims to address this critical unmet need by evaluating the efficacy of IVIG in patients with AE-IPF.

Aberrant inflammation and dysregulated immune responses are believed to play a key role in the pathogenesis of AE-IPF. Patients with IPF often display impaired cellular and humoral immunity, further supporting the investigation of immunomodulatory therapies. Intravenous immunoglobulin (IVIG), which has established anti-inflammatory and immunomodulatory effects, is used in other rapidly progressive interstitial lung diseases and in various immune-mediated conditions. Preliminary retrospective data from investigators' center suggest that IVIG may improve gas exchange and survival in patients hospitalized with acute exacerbations of fibrotic interstitial lung disease, including IPF.

Investigators hypothesize that the addition of IVIG to usual treatment may improve clinically relevant outcomes during AE-IPF. In this study, IVIG will be administered as an adjunct to usual care. Usual care will include pulse corticosteroids, broad-spectrum antibiotics, prophylactic anticoagulation, and oxygen therapy. Although the effectiveness of corticosteroids in AE-IPF remains uncertain and is supported only by low-quality evidence, their use is endorsed by current treatment guidelines and remains widespread in clinical practice. In addition, corticosteroids are being evaluated in ongoing trials (e.g., EXAFIP2, NCT05674994). Considering the complex, multi-pathway biology of AE-IPF and the documented synergistic effects of IVIG and corticosteroids in other immune-mediated conditions (such as Kawasaki disease, idiopathic thrombocytopenic purpura, and toxic epidermal necrolysis/Stevens-Johnson syndrome), corticosteroids will be administered to both study arms to avoid withholding a potentially beneficial therapy.

The primary objective of this clinical trial is to evaluate whether IVIG, when added to usual care, improves outcomes compared to usual care alone in patients hospitalized with AE-IPF. The primary endpoint is a composite of all-cause in-hospital mortality or the need for endotracheal intubation. This composite measure was selected because AE-IPF is a rapidly progressive and life-threatening event, and these outcomes represent the most objective, clinically meaningful indicators of deterioration. The use of this endpoint enables a comprehensive assessment of treatment efficacy by capturing both fatal and near-fatal clinical events.

Investigators anticipate that the findings of this study will generate important evidence regarding the potential role of IVIG in the management of AE-IPF and may contribute to future treatment recommendations for this highly lethal condition.

Inclusion Criteria:

1. Patients ≥ 18 years of age

2. Patients with IPF diagnosis that fulfils ATS/ERS Consensus Criteria.

3. Patients hospitalised with a definite or suspected AE-IPF diagnosis, as defined by the international working group criteria and as ascertained by the responsible Primary Investigator.

   The criteria of IPF-AE are as follows:

   • Previous or concurrent diagnosis of IPF
   • Acute worsening or development of dyspnoea typically < 1 month duration
   • Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with usual interstitial pneumonia pattern
   • Deterioration not fully explained by cardiac failure or fluid overload Patients who fail to meet all 4 criteria due to missing computed tomography should be considered as having "suspected Acute Exacerbation".

   A) 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 pattern on the current evaluation.

   B) If no previous computed tomography is available, the qualifier "new" can be dropped from the third AE-IPF criterion.

4. Patient able to understand and sign a written informed consent form. In case of incapacity of the patient, the written informed consent form will be signed by the patients' legally authorized representative.

Exclusion Criteria:

1. Patients with acute worsening due to uncontrolled heart failure or pulmonary embolism.
2. Patients with known hypersensitivity to corticosteroids, IVIG or any component of the study treatment.
3. Patients with known IgA deficiency (IgA level <7 mg/dL)- to preclude IVIG reactions.
4. Patients without a definite diagnosis of IPF or AE-IPF based on clinical, radiological, laboratory evaluation, and multidisciplinary discussion.
5. Patients with active malignancy or currently receiving cancer treatment, except for basal cell or squamous cell skin cancer or low-risk prostate cancer (T1 or T2a stage with PSA <10 ng/dL). These criteria are aligned with current guidelines.
6. Patients that have received treatment for >14 days within the preceding month with >20mg daily prednisone (or equivalent) or any treatment during the last month with immunosuppressants (e.g., cyclophosphamide, mycophenolate etc.) according to already published therapeutic protocols or > 1 mg/kg/d from more than 7 days in the last 15 days.
7. Patients participating to another interventional clinical trial.
8. Patients with documented pregnancy or lactation.
9. Patients under tutorship or curatorship.
10. Patients deprived of liberty or under court protection.
11. Patients who refuse to participate or decline to provide written informed consent.