Rituximab Induced Interstitial Lung Disease.
Authors: Wagner Stephanie A. , Makani Samir S. , Laber Damian A. 
Published: October 2019

Abstract
Interstitial lung disease (ILD) secondary to monoclonal antibodies and tyrosine-kinase inhibitors have been reported. However, little is known about rituximab induced ILD. We report two cases of R-ILD.
CASE 1: A 63 year-old man with DLBCL presented for cycle 6 of R-CHOP complaining of 10 days of dyspnea and fever. Prior to initiation of therapy, he had a normal lung exam along with computerized tomography (CT) of the chest. After three cycles of R-CHOP, repeat CT scans of the chest revealed a favorable response to treatment and continued disease-free lung fields. He had tachypnea, tachycardia, and a normal lung examination. Pulse oximetry on room air was 76%. A helical CT of the chest demonstrated diffuse bilateral pneumonitis with no evidence of pulmonary embolus. Bronchoscopy with bronchoalveolar lavage and biopsy revealed no infection. Biopsy showed evidence of alveolar damage and interstitial fibrosis. He responded to corticosteroids and was discharged home with supplemental oxygen. Two months later, he did not require supplemental oxygen. A CT scan of the chest showed almost complete resolution of his interstitial disease. Pulmonary function tests revealed a mild restrictive pattern with a severe diffusion defect.
CASE 2: A 61 year-old man with DLBCL presented with 3 days of dyspnea, fever and cough. He was on cycle five, day 14 of R-CHOP. Prior to starting therapy, lung examination was normal and a CT of the chest showed no lung abnormalities. He had tachypnea, tachycardia, and inspiratory crackles on lung examination. Arterial blood gas revealed a pO2 of 45 mmHg. He was admitted to the hospital and started on broad spectrum antibiotics and corticosteroids. A helical CT of the chest revealed a diffuse interstitial lung pattern bilaterally consistent with interstitial pneumonitis and no pulmonary embolus. A bronchoscopy with bronchoalveolar lavage showed no infection. A lung biopsy could not be performed because of severe hypoxia. The patient required mechanical ventilation. After one week of intensive treatment the patient expired.
DISCUSSION: Respiratory complications of rituximab include increased cough, rhinitis, brochospasm, dyspnea, and sinusitis. However, R-ILD is very rare. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include a direct injury to the lung tissues, unlikely, as well as the induction of cytotoxic substances. Rituximab acts by binding CD20+ B cells. Toxicity and efficacy are related to events after binding which include B cell signaling, complement activation, direct apoptosis, and antibody dependent cellular cytotoxicity. Complement activation and cytokine secretion, in particular, seems to be the causative factors in side effects associated with infusion reactions. Because of the increasing use of rituximab for a variety of disorders, it is important to recognize and appropriately treat possible fatal toxicities. Our patients presented with dyspnea and fever. In the absence of an infectious etiology further evaluation with a high-resolution CT scan of the chest or bronchoscopy with BAL and biopsy should be pursued. If evaluation suggests an ILD without clear evidence of infection, corticosteroids should be initiated and further treatment with rituximab discontinued.
CONCLUSION: With the increasing use of rituximab and other monoclonal antibodies, clinicians must be aware of this rare but potentially fatal complication.