Rituximab(RTX) has been proved effectively in treating malignant and autoimmune disease including: lymphoma, leukemia, rheumatoid arthritis, Wegeners granulomatosis [4], and benefit non-Hodgkin’s lymphoma (NHL) and RA patients [5, 6]. Infusion-related symptom complex have been observed during the use of RTX which consists fever, chills and rigors. During clinical trials, 9-15% of the patients showed symptoms of infusion-related reactions, while 30% of patients had respiratory manifestations (cough, bronchospasm, sinusitis and rhinitis). These complications are generally mild and self-limited. Severe side effects such as anaphylactic shock and acute respiratory distress syndrome were rare, fatal in 0.04-0.07%. Interstitial lung disease is one of those potentially fatal complications of RTX therapy, it is reported that the overall incidence of RTX-ILD is less than 0.03% in phase III trials [7]. However, it is reviewed that in post-marketing literature the incidence is much higher, ranging from 3.7 -10% [4].The variance between these two incidences might due to different in target population. Phase III trials shown that RTX-ILD is of more severity in lymphoma than in rheumatological disorders, which may due to the difference of dosage used in treatment [8]. As for hematological disorders, the mean dosage of RTX was 7785 mg comparing to 2000 mg in rheumatological disorders. RTX is widely used for patients with B cell lymphoma and the majority case reports are from non-Hodgkin lymphoma patients. According to the previous research of our department, we found that with the use of RTX, the probability of complete response and overall survival in newly diagnosed PCNSL patients had been improved [1]. And this is the first time that R-ILD has been discovered in PCNSL patients.
The pathogenesis of R-ILD remains unclear. One hypothesis is pathogenic cytokine release. Tumor necrosis factor-α(TNF-α) and interleukins are thought to be the dominating contributing cytokines [9, 10]. Recently there was case reported that Nod-like receptor pyrin domain-containing protein 3(NLRP3)may act as an initiator of inflammation process in lung of R-ILD patient. The discovery of NLRP3 and related further researches could open a new sight into the pathologic mechanism and provide a new target for the treatment of RTX-ILD [11].
Rituximab induced lung disease have higher incidence in male and patient of their fifty to sixty. Mostly occurring 2 weeks after the latest cycle of infusion, the fourth cycle of RTX [12], average dose accumulated to 1500 mg/m2. Common complains of RTX-ILD included: dyspnea and cough. Other symptoms like fatigue, rigours, wheeze, hemoptysis, skin rash have also been reported. About 20.7% of the cases is detected radiologically without symptoms. Physical examinations may be unremarkable or without diffuse fine inspiratory crackles. As for typical radiological abnormalities, chest radio graph displaying diffuse bilateral lung infiltrates. In high-resolution or helical thoracic CT, ground-glass opacification(GGO), alveolitis, pulmonary fibrosis, alveolar hemorrhage, pleural effusions and consolidation can also be seen. PET-CT could indicate the activation of neutrophil within the lungs by showing 18-FDG accumulation in hypermetabolic lung nodules. Lung biopsy is not usually performed in RTX-ILD, in our case, the diagnosis was made on clinical and radiological basis. Her respiratory symptoms relieved greatly after steroid treatment thus we didn’t see the further need for invasive investigation. Anyway, pulmonary inflammation is a common feature in reported cases. A recent systematic review of the available studies showed various histological patterns including: organizing pneumonia, interstitial pneumonitis, desquamative interstitial pneumonia, diffuse alveolar damage, and usual interstitial pneumonia [13].
According to Wagner’s review, hypoxemia and saturation of blood oxygen decreasing is uniformly abnormal in RTX-ILD [14]. There’s also research signify fever was the most common presenting symptom [15].
In our case report, the patient was free of respiratory symptoms and no abnormal objective sign in lung except for cyanosis is a crucial clue, suggesting hypoxemia. Following arterial blood gas testing confirmed type I respiratory failure. Pulmonary function tests reveal restrictive pattern on spirometry and significant reduction in carbon monoxide diffusion capacity. Further test could be done to confirm diagnosis and evaluate the efficacy of treatment, like transbronchial lung biopsy, bronchoalveolarlavage. Blood culture, sputum culture, antineutrophil cytoplasmic antibody, procalcitonin, antibodies and DNA testing for acute virus and empirical treatment with antibiotics should be down to rule out bacterial infection.
Once RTX-ILD was considered, RTX treatment should be stopped immediately and provide intravenous steroid. Supporting treatment include oxygen-inspiration and noninvasive mechanical ventilation can be provided contingent on blood oxygen. RTX-ILD patients who do not respond to glucocorticoids is potential fatal. In a 21-day treatment, 5 mg of dexamethasone or 40 mg of methyl-prednisolone were used in the first three consecutive days, followed by prednisone taken orally with slow taper.14 Treatment for such severe RTX-ILD is still challenging. Some authors have suggested anti-TNFα therapy in severe cases. The first TNF-α antagonist and cytokine profiling treating was published by Yong-Kang Wu, but the he did not obtain an ideal outcome. Moreover, some clinical trials even indicated that TNF-α antagonists themselves may lead to a worse prognosis [16].
The retreatment of rituximab may probably deteriorate pulmonary condition among the patients who had experience R-ILD [17, 18]. However some other reports presented opposite result. Those patients who has been retaken Rituximab contained regimens showed uneventful outcome [19]. Therefore, the decision should be made carefully. As the probability of curing the disease may be improved while the incident rate of potential pulmonary toxicity may be improved as well [14].
