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

Aplastic anemia (AA) is an auto-activated T cell-mediated bone marrow failure, characterized by pancytopenia and hypocellular marrow.1 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).2 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,3-8 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.9 Robust response was defined as not only meeting standard response criteria,9 but fulfilling more than 50 × 109/L of platelet and 100 g/L of hemoglobin (Hb). A progressive and substantial decline in blood counts requiring reinitiation of high-dose 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 transfusion-dependent 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 × 109/L (range 0.9–3.61 × 109/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 × 109/L, p < .0001), and neutrophil (2.11 vs. 1.73 × 109/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 × 109/L, p < .001), and neutrophil (2.01 vs. 1.70 × 109/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 × 109/L, p = .018). Interestingly, the lymphocyte count increased from the preinfection level (1.75 vs. 1.87 × 109/L, p = .004). Within 4–8 weeks following the infection, the hematological parameters including Hb (112.4 vs. 109.5 g/L, p = .213) and platelet (84.0 vs. 82.1 × 109/L, p = .933), showed a spontaneous return to their preinfection levels and remained stable thereafter. The neutrophil returned to the preinfection level after 8 weeks (2.11 vs. 1.95 × 109/L, p = .489). To evaluate the extent of the decline in hematological indices, a meaningful decrease was defined as a reduction in Hb of more than 30 g/L, in neutrophil count of more than 0.5 × 109/L, or in platelet count of more than 30 × 109/L, compared to preinfection levels. As shown in Figure 1B, less than 5% of patients experienced the meaningful reduction in Hb, but a meaningful decrease in neutrophil was observed over 30% of patients within 8 weeks after infection. The proportion of patients with a meaningful platelet decrease gradually reduced within 8 weeks, but 5.93% of patients still had a meaningful decrease in platelet count. Moreover, after at least 8 weeks of infection, 76 AA patients had successive blood indices and only three individuals (4.3%) experienced relapse, including one complicated with paroxysmal nocturnal hemoglobinuria. The patients were classified based on whether they received IST for at least 6 months before Omicron infection into long-course and short-course IST groups. The long-course group had significant declines in platelet (92.4 vs. 72.3 × 109/L, p < .001) and neutrophil (2.17 vs. 1.75 × 109/L, p = .012) after 2 weeks of infection. Meanwhile, the short-course group had a significant decrease in platelet (52.8 vs. 24.2 × 109/L, p = .005). Remarkable pancytopenia was observed in long-course group within 2–4 weeks following infection, including reduced level of Hb (114.5 vs. 107.5 g/L, p < .001), platelet (92.4 vs. 77.7 × 109/L, p < .001), and neutrophil (2.17 vs. 1.90 × 109/L, p = .039) as compared to counts before infection. However, no aggravated pancytopenia was observed in short-course IST group. Following a minimum of 8 weeks from infection, both groups exhibited a return of all hematological parameters to their prior levels (Figure 1C). To explore the relationship between response status and postinfection pancytopenia, patients were divided into robust group and inferior group based on their preinfection response status. The former was comprising those who achieved robust response, and the inferior group was consisting of patients who only achieved inferior response or no response. Within first 2 weeks of infection, notable declines of platelet (110.8 vs. 81.1 × 109/L, p < .001) and neutrophil (2.42 vs. 1.88 × 109/L, p = .008) were observed in robust group. Following 2–4 weeks of infection, Hb (124.5 vs. 119.9 g/L, p = .001), platelet (110.8 vs. 95.4 × 109/L, p < .001), and neutrophil (2.42 vs. 2.01 × 109/L, p = .002) were still significantly decreased in robust group. Hematological profiles returned to their baseline levels after a minimum of 8 weeks from the onset of infection (Figure 1D). Nevertheless, no significant pancytopenia was observed in the inferior group. This prospective cohort from NICHE provides detailed clinical data in the largest cohort of Omicron-infected AA patients. The initial symptoms were fever, dizziness or headache, muscle or body aches, and sore throat, which were consistent with those reported by the general population during the 2022 Omicron waves in Tianjin.10 The percentage of patients with severe/critical illness in AA patients was similar to that of the general population (0.6% vs. 0.5%, p > .05).10 However, it was significantly lower than that of patients with hematological malignancies11 (0.6% vs. 8.9%, p < .05), possibly due to fewer complications in the AA population. Our study found that Omicron infection did not result in a high proportion (less than 5%) of relapse in AA patients. Nevertheless, aggravated cytopenia was observed within 4 weeks of infection, which may be due to the aberrant immune response triggered by virus.12 It's worth noting that the lymphocyte count significantly increased during 2–4 weeks after infection, which may reflect an activated immune response. This abnormal immune response may not be sustained, as the hematological parameters spontaneously returned to the preinfection levels for more than 4 or 8 weeks. Furthermore, patients receiving a long course of IST were more likely to experience temporally aggravated pancytopenia compared to the short-course group. Additionally, patients with a robust response may have a fragile balance of immune condition, which can result in a significant decrease of hematological indices. In conclusion, infection of Omicron in AA did not result in higher mortality. Moreover, our data highlight true relapse after Omicron infection is rare in AA, but decrease on hematological parameters is common during acute infection and early convalescence. Lele Zhang and Jingyu Zhao designed the study, analyzed data, interpreted data, and wrote manuscript. Ruonan Li, Hong Pan, Zhen Gao, Weiwang Li, and Liwei Fang collected the clinical data and recruited patients. Jun Shi conceptualized the study, interpreted the data, and supervised the project. All authors critically edited and reviewed the manuscript. All authors have access to the raw data used for this study and they all approved the final manuscript. Authors declare that they have no competing interests. Data openly available in a public repository that issues datasets with DOIs. TABLE S1. Demographic and clinical characteristics of 175 AA patients infected with the SARS-CoV omicron. 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