Rapid recognition and prompt steroid therapy, if needed, are mandatory for resolution. Background The chimeric anti-CD20 FR194738 free base monoclonal antibody, rituximab (IgG1/ human/murine), has been historically used to treat oncohaematological conditions such as non-Hodgkin’s lymphoma, lymphocytic leukaemia, large B-cell non-Hodgkin’s lymphoma and autoimmune diseases (thrombotic thrombocytopenic purpura, rheumatoid arthritis, etc).1 2 It binds to CD20 expressed by B cells and causes cell lysis via activation of the complement cascade and natural killer cells.3 Thus, rituximab infusion results in significant depletion of peripheral blood B lymphocytes that last 6C9?months after treatment. (ie, ground-glass lesions on CT, negative bronchoscopy with bronchoalveolar lavage and deficit in diffusion lung CO transfer), 14 and 40?days after rituximab infusion, respectively. Recovery was rapid and complete after administering steroids in case 1 and with no therapy in case 2. We conclude that RALI may occur in stable non-immunocompromised patients with nephrotic syndrome and its frequency may be higher than expected. Clinical presentation may be mild and resolve after steroids, suggesting hypersensitivity as the main mechanism. Rapid recognition and prompt FR194738 free base steroid therapy, if needed, are mandatory for resolution. Background The chimeric anti-CD20 monoclonal antibody, rituximab (IgG1/ human/murine), has been historically used to treat oncohaematological conditions such as non-Hodgkin’s lymphoma, lymphocytic leukaemia, large B-cell non-Hodgkin’s lymphoma and autoimmune diseases (thrombotic thrombocytopenic purpura, rheumatoid arthritis, etc).1 2 It binds to CD20 expressed by B Mouse monoclonal to FLT4 cells and causes cell lysis via activation of the complement cascade and natural killer cells.3 Thus, rituximab infusion results in significant depletion of peripheral blood B lymphocytes that last 6C9?months after treatment. More recently, rituximab has been introduced in the therapeutic approach to nephrotic syndrome and, based on clinical trials, its use was limited to patients having proven sensitivity to steroids and cyclosporine. 4C6 Resistance to both drugs is now considered a contraindication to rituximab use. 7 Safety is a crucial point prior to considering more widespread use. Although this drug is generally well tolerated and has an acceptable toxicity profile, mild and severe complications have both been reported. Rituximab-associated lung injury (RALI) is included in the second group of conditions since it is considered potentially life-threatening.8 This is a clinically and histologically polymorphic entity that may present as cryptogenic organising pneumonia (previously known as bronchiolitis obliterans organising pneumonia) and/or as interstitial and hypersensitivity pneumonia with or without fibrosis. Alveolar haemorrhage and acute respiratory distress can result in fatal outcomes. It is a diagnosis of exclusion based on clinical presentation and radiological CT features, and on exclusion of other possible causes, the first being of a primarily infective aetiology (bronchoscopy with bronchoalveolar lavage is required to rule out an infection). RALI has been described mainly in a oncohaematological and/or rheumatological context, while it is very rare in patients with renal disease.8C10 It has been reported in three cases with renal transplant, one FR194738 free base received rituximab for post-transplant lymphoproliferative disease, whereas the other two patients were treated for post-transplant recurrence of focal segmental glomerulosclerosis.11C13 Only two patients treated with rituximab for primary nephrotic syndrome have been reported (table 1). One had a fatal outcome, the other recovered with immunoglobulin infusion.14 15 Table?1 Clinical, radiological and histological features of nephrotic patients with RALI thead valign=”bottom” th rowspan=”1″ colspan=”1″ /th th align=”left” rowspan=”1″ colspan=”1″ Chaumais em et al /em 15 /th th align=”left” rowspan=”1″ colspan=”1″ Bitzan em et al /em 14 /th th align=”left” rowspan=”1″ colspan=”1″ Case 1 /th th align=”left” rowspan=”1″ colspan=”1″ Case 2 /th /thead DiagnosisMRNSFSGSFSGSINSSexFMFMAge at RALI (years)9141615Therapy for RALICsACsA, MMFTacCsAYears therapyNone 1243RTX pulse1634RTX doses (mg/m2)375375375375Presenting symptomsRespiratory distress, hypoxiaFever, cough, tachypnoea, hypoxiaFatigue, weakness, palpitations, hypotension, feverFatigue, weakness, dyspnoeaTime from last RTX, days3191440CT lung findingsBilateral opacities, pleural effusionBilateral ground glassBilateral ground glassBilateral ground glassTreatmentAntibiotics, ECMO, Ig anti-RSVIVIGAntibiotics, steroidsNoneHistological findingsExtensive fibrosisNot performedNot performedNot performedOutcomeDeadFully recoveredFully recoveredFully recoveredCommentsDeath caused by RSV infection and pulmonary haemorrhageNoneNoneNone Open in a separate window CsA, cyclosporine A; ECMO, extracorporeal membrane oxygenations; F, female; FSGS, focal segmental glomerulosclerosis; INS, idiopathic nephrotic syndrome; IVIG, intravenous immunoglobulins; M, male; MMF, mycophenolate mofetile; MRNS, multidrug resistant nephrotic syndrome; RALI, rituximab-associated lung injury; RSV, respiratory syncytial virus; RTX, rituximab; Tac, tacrolimus. We describe here the third and the fourth cases of RALI, occurring in two adolescents, in very good clinical condition, with nephrotic syndrome, who presented with full blown RALI after rituximab infusion; both patients had complete recovery, one with a simple steroid course (case 1), and the other with no therapy (case 2), suggesting variability in clinical presentation of an otherwise potentially life-threatening illness. The time course of rituximab sequelae and rapid response to therapy prompts some considerations on possible mechanisms. Cases presentation Case 1 A 12-year-old girl presented with clinical onset of nephrotic syndrome because of steroid resistance; cyclosporine (4?mg/kg q12?h, orally) first and then tacrolimus (0.1?mg/kg q12?h, orally) were added to therapy and a renal biopsy was performed, showing a pattern compatible with focal segmental glomerulosclerosis. The association of steroids and FR194738 free base tacrolimus-induced stable remission of proteinuria reappeared, however, when the steroids were tentatively suspended. For this reason, starting from 2?years after the clinical onset, three rituximab doses were given at intervals of 12?months (1 dose/year). FR194738 free base No problems occurred after the first two rituximab infusions, with the exception of a mild cough, which resolved with an additional dose of antihistamine. Two weeks later, after the third pulse (375?mg/m2), the patient began to report fatigue, weakness, palpitations, hypotension and fever; chest X-ray showed bilateral basal thickening, later confirmed.