Low risk of relapse in aplastic anemia patients after SARS‐CoV‐2 omicron infection: A prospective NICHE cohort

To the Editor, Aplastic anemia (AA) is an auto-activated T cell-mediated bone marrow failure, characterized by pancytopenia and hypocellular marrow. With the worldwide spread of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, patients with AA are at high risk for infection due to disease-related neutropenia and enduring immunosuppressive therapy (IST). Furthermore, AA patients often do not receive the SARS-CoV-2 vaccination due to an ineffective protective specific antibody response to viral antigens and potential immune system activation that may worsen underlying marrow failure. Prior studies have evaluated the clinical manifestation of SARS-CoV-2 infection in severe or very severe AA (SAA/VSAA) patients through case reports or case series, but the severity and long-term prognosis of SARS-CoV-2 infection in AA is still not clear. To better explore whether patients with AA experienced more severe symptoms of infection or demonstrated higher relapse rate after infection, we prospectively collected 175 AA patients enrolled in National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and described the clinical features and outcomes of AA after infecting Omicron SARS-CoV-2 between December 2022 and January 2023. This study demonstrated a low risk of relapse in AA after Omicron infection. In this study, SARS-CoV-2 illness severity was evaluated by the National Institutes of Health COVID-19 Treatment Guidelines. Severe illness was defined as individuals who had SpO2 < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen <300 mmHg, a respiratory rate > 30 breaths/min, or lung infiltrates >50%. Hematological responses were evaluated based on established criteria. Robust response was defined as not only meeting standard response criteria, but fulfilling more than 50 10/L of platelet and 100 g/L of hemoglobin (Hb). A progressive and substantial decline in blood counts requiring reinitiation of highdose cyclosporine or androgen or thrombopoietin receptor agonists was defined as relapse. Paired t-tests were used to compare the hematological indices before and after Omicron infection, including Hb, platelet, neutrophil, and lymphocyte counts. The study engaged a total of 175 patients, comprising 90 males and 85 females, with a median age of 33 years (range, 10–72). Among these patients, 29.7% had SAA/VSAA, 14.3% had transfusiondependent AA, and 56.0% had transfusion-independent AA. Forty-six patients (26.3%) had been vaccinated against SARS-CoV-2, with a median interval of 18 (1–55) months between the last vaccine dose and Omicron infection. At the onset of infection, 64.0% (105/164) of AA patients achieved robust response, 20.1% (33/164) had inferior response, and 15.9% (26/164) were no response. Among the whole population, 136 patients received IST for at least 6 months before infection, with 36 (20.6%) of them accepting either antithymocyte or antilymphocyte globulin. As presented in Table S1, the most common initial symptoms were fever (78.9%), sore throat or cough (60.6%), headache (49.1%), fatigue (44.6%), and myalgia (40.0%). Approximately 47% of patients experienced symptoms beyond 2 weeks. A total of 11 patients developed pneumonia and required oxygen supplementation, and one of them needed admission to intensive care unit for invasive ventilation. Among these 11 patients, the median age was 34 years (range, 15–58), with four of them having SAA/VSAA and four being male. Furthermore, one of them had asthma as a complication, and one had a gastrointestinal tumor for whom the last chemotherapy was over 3 years ago. Four of these 11 patients had been vaccinated against SARS-CoV-2, with a median interval of 15 months (range, 12–16) between the last dose and infection. Nine individuals received IST before infection, with seven of them receiving IST for more than 6 months. At the onset of Omicron infection, three patients achieved robust response with a median lymphocyte of 1.45 10/L (range 0.9–3.61 10/L). All 11 patients recovered from Omicron infection following supportive therapies, including oxygen supplementation, antipyretic drugs, and a short course of broad-spectrum antibiotics. Only one case required steroids and intravenous immunoglobulin infusion to alleviate symptoms. To investigate the impact of Omicron infection on hematological profiles in AA patients, we analyzed the successive hematological indices during both the infection and convalescence periods (Figure 1A). During the 2-week infectious period, we observed a progressive decline in hematological profiles compared to preinfection levels, including Hb (112.4 vs. 107.4 g/L, p = .043), platelet (84.0 vs. 61.2 10/L, p < .0001), and neutrophil (2.11 vs. 1.73 10/L, p = .014). Nevertheless, no significant alteration was observed in lymphocyte count. During convalescence period of 2–4 weeks after infection, Hb (112.4 vs. 105.3 g/L, p < .001), platelet (84.0 vs. 69.7 10/L, p < .001), and neutrophil (2.01 vs. 1.70 10/L, p = .0084) were still significantly lower than those prior to the infection. However, the platelet count increased than that during 2-week infectious period (36 vs. 42 10/L, p = .018). Interestingly, the lymphocyte count increased from the preinfection level (1.75 vs. 1.87 10/L, p = .004). Within 4–8 weeks following Received: 11 April 2023 Revised: 29 June 2023 Accepted: 30 June 2023