Infectious Complications of High-Dose Cyclophosphamide Treatment in Autoimmune Disease.
Authors: Sehgal Ajay , Ahlers Christoph M. , Jha Asit , de Almeda Kleper , Styler Michael , Topolsky David , Crilley Pamela A. , Brodsky Isadore 
Published: April 2020

Abstract
Immunoablative high-dose cyclophosphamide has recently been used in the treatment of a variety of autoimmune diseases, including but not limited to systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), rheumatoid arthritis, refractory autoimmune hemolytic anemia (AIHA), Myasthenia Gravis (MG), and severe aplastic anemia. Few studies to date detail infectious complications of high-dose cyclophosphamide in the treatment of autoimmune disorders.We performed a retrospective analysis of patients with autoimmune diseases treated with high-dose cyclophosphamide between 1996 and 2004. Medical records of each patient were reviewed for the type of autoimmune disease, presence or absence of infection, type of infection, use of prophylactic antibiotics, presence and duration of fever, mucositis, neutropenia, and hematuria. Data analysis allowed identification of common infections associated with cyclophosphamide therapy and event free survival. Patients were treated with cyclophosphamide (50 mg/kg body weight per day) intravenously for four consecutive days. GCSF (5 mg/kg per day) was started 6 days after the last dose of cyclophosphamide and was continued until the absolute neutrophil count reached 109 cells/L. A total of 25 patients were studied and the diseases represented were as follows: CIDP (n= 8), SLE (n= 8), (including 3 patients with lupus cerebritis), MS (n= 4), MG (n= 2), alloantibodies in pre renal transplant patient (n=1), AIHA (n=1), Cold agglutinin disease(n=1). All patients were prophylaxed with Acyclovir, Fluconazole, and Bactrim. From the patients studied, 96% (n= 24) developed neutropenic fever of which 68% (n=17) developed a clinical infectious complication. All patients were neutropenic at the time of diagnosis of the infection. The median duration of fever was 4 days. The median duration of neutropenia was 11 days. The infectious complications included: Hickman catheter infection 28% (n= 7) of which 3 patients were culture positive with (Strep. Pneum, fungal, and St. Maltophila), Bacteremia not related to Hickman catheter infection 12% (n=3) (Strep. Viridans, VRE, and Staph. Epidermidis), C. difficile infection 8% (n=2), Uncomplicated urinary tract infection 12% (n=3) (Enterococcus Faecalis, Polyoma virus, VRE), fungal pneumonia 4% (n=1), and herpes zoster 4% (n=1). Neutropenic fever also developed in 7 patients (32%) who were culture negative and no obvious source was found. Mucositis Grade 2 was seen (n=4) 16%, and Grade 3–4 (n=2) 8% of the patients. The median duration of mucositis was 6 days. Hematuria was seen in 1 patient which spontaneously resolved after 2 days. One patient had no neutropenic fever or any clinical infectious complication. In conclusion we report here our experience with the infectious complications of high dose cyclophosphamide in the treatment of autoimmune disorders. No deaths occurred related to toxicity or otherwise and all patients recovered and were discharged. Our study suggests that the type of infectious complications and the duration of neutropenia are not very different from those patients treated with other immunoablative regimens for transplantation. Further studies need to evaluate the role of different antibiotic prophylaxis to prevent the common infections in neutropenic patients.