key: cord-0851078-qternis4 authors: Yasuda, Hajime; Tsukune, Yutaka; Watanabe, Naoki; Sugimoto, Kazuya; Uchimura, Ayana; Tateyama, Misa; Miyashita, Yosuke; Ochi, Yusuke; Komatsu, Norio title: Persistent covid-19 pneumonia and failure to develop anti-SARS-CoV-2 antibodies during rituximab maintenance therapy for follicular lymphoma date: 2020-08-22 journal: Clin Lymphoma Myeloma Leuk DOI: 10.1016/j.clml.2020.08.017 sha: 486bb6d0ec4e218ad43f388563842b668a683351 doc_id: 851078 cord_uid: qternis4 nan The global covid-19 pandemic has been reported to inflict higher death rates in patients with hematological malignancies compared to the general population. 1 Proposed theoretical mechanisms include lymphopenia which is often seen in this patient group, and suppressed immune function due to the hematological malignancy itself or due to treatment. We report the first case of persistent covid-19 pneumonia which was still ongoing at two months after onset in a follicular lymphoma (FL) patient undergoing rituximab maintenance therapy. The patient failed to develop anti-SARS-CoV-2 IgG and IgM antibodies which was most probably the result of prior rituximab therapy, and thus provoked this unusual chronic state of covid-19 pneumonia. A 61-year-old woman was admitted to our hospital in April 2020 due to covid-19 pneumonia diagnosed by two sequential positive RT-PCR results from nasopharyngeal swabs performed on different days. Four other family members were simultaneously diagnosed with covid-19. In September 2018, she was diagnosed with concurrent uterine cancer and FL involving the small intestine, multiple lymph nodes, and bone marrow. Serum IgG, IgA, and IgM were 504mg/dl, 31mg/dl, and 39mg/dl, respectively. She underwent ovariohysterectomy and resection of the small intestine FL lesion, followed by G-CHOP therapy. However, after the second course of CHOP and fourth administration of obinutuzumab, chemotherapy was withheld due to a sustained decrease of platelet counts around 60 × 10 9 /L which was thought to be a side effect of obinutuzumab. Platelet counts gradually rose, but approximately six months were required for the platelet count to return to baseline. Because of the long-term treatment interruption, a PET scan was carried out in August 2019 and showed complete metabolic response (CMR). Six courses of CHOP were originally planned, but because of the long-term interruption and because she was in CMR, CHOP therapy was discontinued and rituximab maintenance therapy was initiated from September 2019. Three bimonthly administrations of rituximab maintenance therapy had been carried out before the patient developed covid-19 pneumonia. Upon admission for covid-19 pneumonia, the patient presented with fever, cough, and multiple bilateral ground glass opacities on CT scans. Serum IgG, IgA, and IgM were suppressed at 225mg/dl, 14mg/dl, and 30mg/dl, respectively. After admission, repetitive immunoglobulin replacement therapy was carried out and IgG levels were maintained at approximately 500mg/dl. Covid-19 pneumonia was treated according to the protocols of a clinical trial from day 1 of hospitalization, and disappearance of the pneumonia was confirmed by chest radiographs on day 16 along with a CRP peak-out after topping at 6.0mg/dl on day 17, and fever resided on day 19. However, a new lung lesion suddenly appeared in the right upper lung region around day 22, and the lesion migrated to the right middle lung region on day 28. Fever, cough, and CRP elevation also recurred around day Anti-CD20 monoclonal antibodies including obinutuzumab and rituximab not only deplete malignant B-lymphocytes but also their normal counterparts, and therefore impair humoral immunity. In fact, patients with prior rituximab treatment are known to be poor responders to various types of vaccinations including influenza viruses, Haemophilus influenzae, and Streptococcus pneumoniae. 2, 3 Despite the long-term exposure to the virus, our case also failed to develop anti-SARS-CoV-2 antibodies. Rituximab has also been reported to provoke other serious viral conditions such as hepatitis B reactivation and progressive multifocal leukoencephalopathy caused by the JC virus. 4 Not only viral, but infections in general were found to be increased in FL patients undergoing rituximab maintenance therapy in the PRIMA study, and the association of increased infections and rituximab therapy is a well established concept. 5 The presented case initially tested positive for nasopharyngeal SARS-CoV-2 RNA on two occasions at disease onset, but tested negative on six follow up nasopharyngeal swabs despite the persisting symptoms and lung lesions. Later on, on day 46, the patient finally tested positive for SARS-CoV-2 RNA on BAL specimen. The sensitivity of RT-PCR done on BAL has been reported to be highest at 93%, follow by sputum at 72%, nasal swab at 63%, and pharyngeal swab at 32%. 6 In patients with a high clinical suspicion of covid-19 who test negative on nasopharyngeal swabs, additional testing on BAL specimens may be a rational approach. It has been reported that covid-19 patients with hematological malignancies show prolonged persistence of SARS-CoV-2 RNA in respiratory samples, 1 but this case demonstrates that actual clinical manifestations can also persist. Above all, anti-SARS-CoV-2 IgG and IgM antibodies are likely to be absent throughout the disease course in patients with prior anti-CD20 therapy as seen in J o u r n a l P r e -p r o o f this case, and provides one explanation for the worse prognosis of covid-19 patents with hematological malignancies. The European Society for Medical Oncology (ESMO) currently recommends avoidance of anti-CD20 antibody-based maintenance therapy for FL during the covid-19 pandemic, and the clinical course of the presented case strongly supports this recommendation. Other than B-cell malignancies, rituximab is currently used in a wide range of other disorders including rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris, and awareness of its increased risk for use during the covid-19 pandemic is necessary across the entire medical community. Patients undergoing recent rituximab therapy are likely to fail to develop anti-SARS-CoV-2 antibodies, which may lead to severe and prolonged covid-19 infections. Rituximab therapy should be avoided whenever possible during the covid-19 pandemic. The authors have no conflict of interest to disclose. infections. ・ Rituximab therapy should be avoided whenever possible during the covid-19 pandemic. J o u r n a l P r e -p r o o f Poor Outcome and Prolonged Persistence of SARS-CoV-2 RNA in COVID-19 Patients with Haematological Malignancies; King's College Hospital Experience Rituximab-treated Patients Have a Poor Response to Influenza Vaccination The Effect of Rituximab on Vaccine Responses in Patients with Immune Thrombocytopenia Rituximab-associated Infections Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial Detection of SARS-CoV-2 in Different Types of Clinical Specimens