Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 3, 2010, pp. 344-346

Journal of Cancer Research and Therapeutics, Vol. 6, No. 3, July-September, 2010, pp. 344-346

Case Report

Rituximab-induced subacute interstitial pneumonitis: A case report and review of literature

Murali Subramanian¹, R Manjunath², Nalini Kilara¹, KN Mohan Rao³

¹ Department of Medical Oncology, M. S. Ramaiah Medical College, Bangalore - 560 054, India
² Department of General Medicine, M. S. Ramaiah Medical College, Bangalore - 560 054, India
³ Department of Chest diseases, M. S. Ramaiah Medical College, Bangalore - 560 054, India

Correspondence Address:Murali Subramanian, Department of Medical Oncology, M.S. Ramaiah Medical College, MSRIT post, Bangalore - 560 054, India, drmuralisubramanian@gmail.com

Code Number: cr10082

PMID: 21119272

DOI: 10.4103/0973-1482.73356

Abstract

Keywords: Interstitial pneumonitis, non-Hodgkin′s lymphoma, Rituximab

Introduction

Rituximab is a chimeric monoclonal anti CD-20 antibody which is primarily used for CD 20 + NHL and in rheumatoid arthritis patients who fail to respond to anti TNF-alpha therapy. Serious pulmonary adverse reactions are sparsely reported. ^[1],[2]

We report a case of subacute interstitial pneumonitis secondary to rituximab use for extranodal NHL. After an extensive search of literature, we conclude that this is the first case to be reported from India.

Case Report

A 53-year-old male was admitted with complaints of insidious onset exertional dyspnea which rapidly progressed to dyspnea at rest over 15 days and dry cough from past 15 days and fever from 3 days. He did not have chest pain or pedal edema. His active medical problem was extranodal (maxillary sinus) diffuse large B cell lymphoma for which he had been on treatment with R-CHOP regimen. He had completed five cycles, the last cycle had been given a month back. Clinical examination was remarkable for tachypnea, tachycardia, and bilateral crepitations, more prominent at the base. His routine blood counts, liver function test, renal function test, urine routine and D-dimer were normal. His ECG showed sinus tachycardia. An X-ray of his chest showed bilateral lower zone haziness. 2D Echo was normal. The condition of the patient deteriorated over the next 24 h with desaturation and development of respiratory distress. He was managed with non invasive ventilation (NIV) and I.V antibiotics. A working diagnosis of rituximab-induced interstitial lung disease was made. 1 g Inj. Methyl prednisolone was given i.v for three days. Broncho alveolar lavage (BAL) fluid showed marked lymphocytosis. Biopsy was not taken in view of worsening hypoxia. The patient was weaned off NIV over the next five days and was treated with oral prednisolone 50 mg once a day. An HRCT done at this stage showed diffuse ground glass opacity [Figure - 1] suggestive of interstitial lung disease (ILD). BAL fluid bacterial and fungal cultures were sterile. Blood culture sensitivity was sterile. CMV serology was negative. The final diagnosis of "rituximab-induced subacute interstitial pneumonitis" was made.

At the time of discharge, after two weeks of hospitalization, significant clinical and radiological improvements were seen. The HRCT done at six weeks showed marked resolution of ground glass opacity [Figure - 2]. Prednisolone was tapered over the next two weeks. The patient′s NHL was further managed with two cycles of CHOP and radiotherapy. Currently the patient is on regular follow up and is asymptomatic for his NHL and ILD.

Discussion

Rituximab has been widely used in nearly 1 million patients with a good safety profile. During clinical trials, infusion-related reactions occurred in 9%-15% of patients and respiratory manifestations like cough, bronchospasm, sinusitis and rhinitis accounted for 30% of them. Serious late onset pulmonary side effects were not reported during clinical trials. ^[2] Incidence of serious pulmonary adverse reactions was <0.03%. ^[3] It is not possible to predict the development of severe reaction. But increased incidence is seen with elderly patients and bulky disease. ^[4]

After a literature search in Pubmed till march 2010, with search terms - "rituximab" and "lung toxicity", "rituximab" and "adverse reactions", "rituximab" and "interstitial pneumonitis", we conclude that 55 cases of rituximab-induced adverse lung reactions have been reported. Each article and all the references were manually checked to avoid double reporting. The Japanese and Chinese populations are hypothesized to be genetically susceptible for drug-induced ILD and hence may account for the increased incidence of the same in these populations. ^[1] Rituximab is an expensive drug and may not be affordable for many people. On an average, we treat about 20 NHL cases annually with R-CHOP regimen. After an extensive search of literature, we conclude that this is the first case to be reported from India.

Depending on the time of onset, there are three types of rituximab-induced lung injury in the reported 55 cases. Eight cases had an acute reaction in the form of ARDS, 43 cases had a delayed presentation in the form of acute to sub acute hypoxemic organizing pneumonia and 4 cases had late onset macronodular organizing pneumonia. ^{[2],[5],[6],[7],[8],[9],[10]}

The mean time from the first infusion to the onset of respiratory manifestation was three months, with a peak incidence at the fourth cycle and a mean cumulative dosage of 1600 mg/m ² . ^[2] In our case, the patient presented with dyspnea and fever after four weeks of the fifth infusion of rituximab i.e. after a cumulative dose of 1875 mg/m ² . The major clinical challenge in this setting would be to rule out infections, timely withholding of causative drug and starting corticosteroids. Sterile BAL fluid cultures will help to rule out bacterial and fungal infections. Viral infections should be ruled out by serological evaluation. ^[3],[5],[11]

Our case satisfies all the criteria for assessing drug causation of lung disease suggested by Mayaud et al, ^[12] except for a rechallenge test. Our patient presented with severe interstitial pneumonitis requiring ventilatory assistance. As the safety of rituximab rechallenge after interstitial pneumonitis is not known ^[4] and with the available data suggesting that subsequent reaction to the drug will be more severe than the first reaction, ^[2] rituximab re challenge was not considered in this case.

The limitation of re challenge is acceptable and rituximab-induced lung injury in our case can still be regarded as highly compatible in view of the preceding data.

Though cyclophosphamide can also cause lung toxicity, it was ruled out in view of the following: 1. A study by Liu X et al. reported that among 107 patients treated with R-CHOP regimen, 9 patients developed interstitial pneumonitis when compared to none out of the 66 patients treated with CHOP alone. ^[1] 2. In a retrospective analysis, 13 of the 90 patients treated with R-CHOP developed interstitial pneumonitis when compared to none out of the 105 patients treated with CHOP alone. ^[13] 3. Our patient was further treated with CHOP alone for his NHL, without further reaction. This could be taken as an unintentional rechallenge test for cyclophosphamide, ^[12] which turned out to be negative.

The pathogenesis of rituximab-induced lung injury is proposed to be secondary to cytotoxic T lymphocytes activation, cytokine release and complement activation after rituximab infusion. Cytotoxic T lymphocytes cause vascular and alveolar damage. Complement activation in turn activates macrophages and mast cells which in turn produce cytokines, C3a and C5a. ^{[6],[11],[14],[15]} As TNF alpha is the main cytokine involved, anti TNF alpha therapy with infliximab can be tried in severe and unresponsive cases, though of unknown benefit. ^[11] In the background of the chimeric nature of rituximab, toxicity can also result from the generation of a self reactive clone due to cross reactivity between the lung and the tumoral antigens. ^{[6],[14],[15]}

To summarize [Table - 1], though pulmonary toxicity is rare with rituximab usage, it is being increasingly reported in the past few years. Since rituximab is being used in a wide spectrum of diseases, clinicians should be aware of the rare complications. A high degree of suspicion, radiological monitoring between two doses of rituximab, timely withholding of rituximab and starting systemic steroids is highly recommended. ^[15],[16]

References

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