<scp>SARS‐CoV</scp>‐2 vaccination in patients with autoimmune cytopenias: The experience of a reference center

Abstract

Both SARS-CoV-2 infection and vaccination have raised concern in immune mediated diseases, including autoimmune cytopenias (AIC, ie, autoimmune hemolytic anemia, AIHA; immune thrombocytopenia, ITP; autoimmune neutropenia, AIN; aplastic anemia, AA; and their combination, termed Evans syndrome, ES). Autoimmune cytopenias are highly heterogeneous conditions with variable severity and a clinical course. They are marked by several relapses often triggered by immune-activating events (infections, traumas, surgery) including vaccines.1, 2 Some reports of ITP and AIHA exacerbations after SARS-CoV-2 vaccines (mRNA vaccines Pfizer-Biontech and Moderna, and Adenovirus based vaccine AstraZeneca) have been described,3-16 but evidence-based indications for their management are lacking. Here we prospectively studied a large series of 108 patients with AIC (56 AIHA, 41 warm type, wAIHA and 15 cold, cAIHA, 38 ITP, 7 AIN, and 7 AA) prospectively followed at a reference hematologic center in Milan, Italy, who underwent SARS-CoV-2 vaccination from March, 24 until the end of June 2021. The study was conducted in accordance with Helsinki Declaration and each participant had given a written informed consent for data collection. Patients (median age 62 years, range 25–89 years, female/male ratio 1.7) were monitored with whole blood counts (and LDH levels in AIHA) the week before and the week after each vaccination dose. Importantly, ongoing AIC therapy (38% of cases, including steroids, cyclosporine, eltrombopag, and complement inhibitor sutimlimab) were kept stable within the 2 weeks before the first dose. Table 1 summarizes hematologic trends and side effects observed after each dose in patients with ITP, AIHA, AIN, and AA. Seven patients had ES, of whom four ITP plus AIHA and one ITP plus neutropenia. Patients mainly received Pfizer-BioNtech vaccine (N = 90), followed by Moderna (N = 16), and Astra-Zeneca (N = 2). Hematological parameters showed a wide distribution both at baseline and after vaccines. To better investigate intra-patient variation we calculated the delta% change of Hb and LDH for AIHA and of PLT in ITP patients, after the first and the second vaccine dose (supporting information Figure S1). Regarding AIHA, four elderly patients experienced a clinically significant Hb reduction requiring treatment adjustment. In detail, patient number one was a 79-year-old female with warm type AIHA (wAIHA) who experienced an Hb decrease from 10.4 to 9.1 g/dL (LDH 1.2 to 1.7 × ULN) after the first dose of Pfizer vaccine; she required a slight increase of steroid dose (to 5 mg day prednisone) and remained stable after the second dose. Patient number two was a 73-year-old male with wAIHA, off-therapy; he had a frank relapse 1 week after the first dose of Moderna vaccine (Hb 13.9 to 9.1 g/dL, LDH 1.1 to 1.6 × ULN), requiring prednisone 0.5 mg/kg day with prompt response. The patient refused to receive the second dose. Patient number three was a 77-year-old male suffering from cold type AIHA (cAIHA), who had an Hb drop from 9.3 to 7.2 g/dL 1 week after after the first dose of Moderna vaccine, requiring steroids, rituximab, and recombinant erythropoietin. The second dose was administered without adverse events. Patient number four was a 73-year-old man suffering from multi-relapsing wAIHA on low-dose steroids, who experienced a severe relapse (Hb 14 to 7.4 g/dL, LDH 1.1 to 2.3 × ULN) 5 days after the second dose of Pfizer vaccine. He required high dose intravenous steroids and hemolysis improved in about 1 week. Concerning ITP, 4 patients experienced a clinically significant platelets (PLT) reduction. Patient number five and number six were two elderly male subjects (81-year-old and 78-year-old) on low-dose eltrombopag who experienced a severe relapse (PLT 21 and 29 × 109/L, 80% and 90% decrease from pre-vaccine, respectively) with mucosal bleeding, 9 days after the first and 7 days after the second dose of Pfizer vaccine, respectively. Patient number six had a concomitant reactivation of his chronic bronchitis. Both were rescued by increasing eltrombopag dose and with the addition of prednisone 1 mg/kg day. Patient number five deferred the second dose due to hip fracture requiring surgery. Patient number 7 was a 63-year-old man on low-dose steroids plus eltrombopag and rivaroxaban for a previous pulmonary embolism. He experienced a PLT drop to 40 × 109/L (40% reduction) 10 days after the first dose of Pfizer vaccine and required eltrombopag and steroid increase. The second dose was administered without adverse events. Patient number eight was a 70-year-old woman on steroid therapy for persistent ITP. Her PLT decreased to 20 × 109/L (70% reduction) after the second dose of Pfizer vaccine and the patient was rescued with intravenous immunoglobulin and steroids increase. Patients with AIN and AA had no significant changes in their hematologic values (one AIN had a neutrophil decrease by 30% but was consistent with previous oscillations) and required no treatment changes. Finally, the following non-hematologic adverse events were observed (all grade I): fever (11%), pain at the injection site (21%), arthralgia (3%), headache (2%), and vomiting (1%), without significant differences between the first and the second dose. Our data show that SARS-CoV-2 vaccination may be associated with a clinically significant decrease of hematologic values in 7.4% of AIHA and ITP cases that were rapidly rescued by treatment adaptation. Mild decrease was observed in about 10% of AIHA and 20% of ITP, requiring no treatment change. Notably, AIC recrudescences were not predictable, since they occurred in both patients on active treatment and off therapy, independently from AIHA type, after either the first or the second dose, and regardless vaccine type. Regarding available literature, three AIHA patients developing/reactivating AIHA after SARS-CoV-2 vaccine have been reported so far: one cAIHA exacerbation after the first and second dose of Pfizer vaccine16 and two severe wAIHAs developing after the first and the second dose of Pfizer vaccine. All cases have been successfully managed with steroids and transfusion support.14, 15 More data are available for ITP, including 21 patients (15 Pfizer, four Moderna, two Johnson&Johnson) from nine case reports/series.3-11 Most patients rapidly improved with steroids or adjustment of ongoing treatment, including TPO-RA that may reduce the need of immunosuppression. The latter may abate the immune response to vaccines,17 although further studies are needed to assess vaccination efficacy under immunosuppressive treatment. Additionally, two large epidemiological studies in Scotland and USA12, 13 estimated an incidence of ITP of 0.8 million doses with Pfizer BioNTech, and of 1.71 million doses of AstraZeneca. This incidence was inferior to that expected for primary ITP in the general population (3.3 cases per 100 000 adults per year).12, 13 In conclusion, our study along with the evidence above, underlines that post-vaccine AIC flares are manageable and that the benefits of vaccination greatly outweigh the risks. The hematologic monitoring adopted in our survey (1 week before, 1 week after the first and the second dose) appears appropriate to promptly intercept and manage AIC reactivations. We also avoided modifications of the ongoing AIC treatment in the 2–3 weeks preceding vaccine to prevent AIC exacerbations unrelated to vaccination. One of the main concerns is whether to administer the second dose after an AIC flare following the first one. Apart from patients' refusal, the second dose should be carefully weighed, and may be feasible upon close monitoring of blood counts and therapy adjustment. All these measures will ensure a safe vaccination campaign in this patient population. No funding sources to declare. The authors declare that they have no conflict of interest. B.F., J.A.G., N.C., and W.B. designed the study, collected data and wrote the paper. Further data will be available upon request to the corresponding author. Figure S1: Change of hematologic parameters after SARS-CoV-2 vaccine in patients with autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Box plots represent the delta percentage change of hemoglobin (Hb) and lactate dehydrogenase (LDH) for AIHA, and of platelets (PLT) for ITP patients, after the first and the second vaccine dose (gray area represents the interquartile range; white areas represent the higher and the lower quartiles). Dots represent patients (Pt) number one to eight Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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