key: cord-1051659-8ytrv8if authors: Pengo, Vittorio; Del Ross, Teresa; Tonello, Marta; Andreoli, Laura; Tincani, Angela; Gresele, Paolo; Silvestri, Elena; Simioni, Paolo; Campello, Elena; Hoxha, Ariela; Falanga, Anna; Ghirarduzzi, Angelo; Denas, Gentian title: Impact of COVID-19 and COVID-19 vaccination on high-risk patients with Antiphospholipid Syndrome: a nationwide survey date: 2022-04-12 journal: Rheumatology (Oxford) DOI: 10.1093/rheumatology/keac224 sha: 37b8be3408dc6008b34ee4df9eb8562707f1145e doc_id: 1051659 cord_uid: 8ytrv8if OBJECTIVES: Patients with antiphospholipid syndrome (APS) and triple-positive for antiphospholipid antibodies (aPL) are at high-risk of recurrent events. As COVID-19 and COVID-19 vaccination may induce thrombotic complications, the objective of the study was to assess the course of COVID-19 and adverse events after vaccination in these patients. METHODS: This is a nationwide multicentre survey conducted in nine APS referral centres by means of a questionnaire. Included patients are thrombotic APS with triple-positive aPL confirmed 12 weeks apart. Reference specialist physicians used a four-graded scale of severity for COVID-19 [from 0 (asymptomatic) to 3 (hospitalization in intensive care unit)] and a six-graded scale for adverse reactions to vaccination [from 0 (transient local injection site sign/symptoms) to 5 (potentially life-threatening reactions)]. Outcomes were considered within a 30-days period. RESULTS: Out of 161 patients interviewed, 18 (11%) had COVID-19. All of them fully recovered without any progression to severe disease nor thromboembolic event. One-hundred-forty-six patients received the first (92%) and 129 (80%) the second dose of vaccine; side effects were minimal and, in most cases, (83% after the first and 68% after the second shot) limited to a sore arm. Fifteen patients (9%) were unvaccinated. Most of them raised doubts on the need for vaccination, complained for poor safety and in general were reluctant on COVID-19 vaccination. CONCLUSION: Patients with triple-positive thrombotic APS did not suffer from severe COVID-19 outcomes. Importantly, COVID-19 vaccination was well tolerated. These data may reassure patients and physicians and contribute in reducing hesitancy in unvaccinated patients. COronaVIrus Disease 19 (COVID-19) caused by the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic associated with a remarkably high rate of morbidity and mortality (1, 2) . There is strong evidence supporting a major pathogenic role of a procoagulant state associated with mortality in severe COVID-19 (3) and autopsy studies have extensively reported the presence of macro-and micro-embolism (4) . This clinical phenotype has similarities with thrombotic antiphospholipid syndrome (APS) and its catastrophic variant (5, 6) . Indeed, there are reports that at least three patients with infection caused by SARS-CoV-2 had cerebral infarcts associated with the presence of antibodies to β2-Glycoprorein I (β2GPI) and cardiolipin(7). Moreover, some authors detected Lupus Anticoagulant (LAC), a risk factor for thromboembolic events, in 45% of 56 patients with COVID-19(8). Thus, hypothetically, COVID-19 patients may develop thrombotic APS, although detected antibodies are apparently different from those of genuine APS (9) . Patients with thrombotic APS are at high-risk of thrombosis recurrence both in arterial and venous circulation when positive in all the three tests for antiphospholipid antibodies (aPL) (10) . Secondary prevention with warfarin is mandatory while direct oral anticoagulants are not recommended (11) as they failed to provide non-inferiority versus warfarin in randomized clinical trials (12) (13) (14) . However, thromboembolic events may occur despite anticoagulation (10) . In the same way, the risk of thromboembolism remains high in hospitalized COVID-19 patients despite anticoagulation prophylaxis. Indeed, the incidence of thrombotic events in COVD-19 complications is 9.5% (15) , but in those requiring intensive care, thrombosis rates can be remarkably high (31%)(16). In March 2021, concerns developed regarding the occurrence of a feared complication, the Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) mainly related to the use of ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine(17). Some authors raised concerns that COVID-19 vaccines, at least theoretically from a pathophysiologic point of view, Page 5 of 19 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 could induce full-blown APS in aPL carriers(18). However, to our knowledge, there is no patientinvolving study assessing the impact of SARS-CoV-2 infection or vaccination against SARS-CoV-2 in high-risk thrombotic APS. Despite the general advice to undergo vaccination, some physicians may be reluctant on vaccination due to fear of thrombotic events in this high-risk group of patients. Based on these premises, we sought to answer the widespread concern among patients and physicians on the impact of SARS-CoV-2 infection and vaccination in APS patients. We performed a survey on the occurrence of COVID-19 and adverse reactions following vaccination against SARS-CoV-2 in APS patients at high-risk of thromboembolic events. This survey was conducted in centres participating in the TRAPS trial (12) where high-risk triplepositive thrombotic APS patients agreed to be followed up for trial extension outcomes (19). All thrombotic APS patients were positive for Lupus Anticoagulant (LA), anti-cardiolipin (aCL) and anti β2-Glycoprotein I (aβGPI) antibodies confirmed 12 weeks apart. All participants gave written informed consent and the study was performed in accordance with the principles of the Declaration of Helsinki. Research ethics approval was not required: the information was obtained as part of routine clinical management in such a manner that the identity of the human subjects cannot readily be ascertained, directly or through identifiers linked to the subjects. In order to ensure respect for data protection and privacy, data were completely anonymized. Patients were interviewed in person during on-site follow-up visits or by means of a phone call. A dedicated physician completed the survey questionnaire. All patients agreed to be interviewed (absence of nonresponse bias). General questions exploring demographics and clinical status were routinely collected or retrieved from the TRAPS database (12) ; mandatory items were the past APS clinical history, the index thrombotic event (arterial, venous, catastrophic) and the presence of associated autoimmune disease. We specifically collected data on possible prior SARS-CoV-2 infection, date, type of diagnosis and on vaccination status and possible side effects or established thrombotic events within a 30-day period. Patients were required to indicate the clinical evolution of previous SARS-CoV-2 infection using a four-graded scale of severity: 0= asymptomatic; 1=mild symptoms treated at home; 2= hospitalization in non-intensive ward; 3=hospitalization in intensive care unit (ICU). We specifically collected data on the type of vaccine administered (Pfizer/BioNTech, Moderna and AstraZeneca), the timing and number of administrations given. Adverse events included all local and systemic reactions in the first month following the injection. Local adverse reactions included injection-site pain or inflammation. Systemic adverse reactions comprised flulike symptoms (fever, chills, headache, cough, muscle pain and body aches, fatigue and weakness, nausea or vomiting, diarrhoea). Allergic reactions such as angioedema, urticaria, wheezing, and skin rash were also assessed. The severity of adverse reactions was graded according to the following criteria: 0=no adverse reaction apart from transient local injection site signs/symptoms; 1=flu-like signs/symptoms of less than one-day duration; 2=flu/like sign/symptoms of more than one-day duration; 3=symptoms requiring medical intervention; 4= hospitalization; 5=potentially life-threatening reaction requiring assessment in the emergency department. In case patients did not get vaccination, the reason was noted, even if this was related to disbelief towards vaccines, fear, hesitancy, and advice from relatives or their general practitioner. The survey included 161 eligible patients and all accepted to answer the questionnaire. Patients' characteristics are reported in Table 1 . Mean age was 47.1 years and the majority were females (68%). All the patients experienced venous and /or arterial thromboembolic events that were catastrophic in 2 cases and 60 (37%) had associated autoimmune diseases. The study flow is 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Vaccination was generally well tolerated as shown in Figure 2 . One-hundred twenty-one (83%) had no adverse reaction or minimal signs/symptoms at the site of injection, 17 (12%) had flu-like symptoms lasting less than 1 day, six (4%) had these symptoms for more than 1 day, and two (1%) asked for medical intervention/counselling. No patient had severe adverse events that needed hospitalization. No case of VITT was reported during the 30 days following the first dose. One-hundred twenty-nine patients (80%) received the second dose after a mean of 24 days from the first one. Of these, 88 (68%) had minimal transient reaction at the injection site. Twenty-eight (22%) had flu-like signs/symptoms lasting less than one day. Ten (8%) had flu-like signs/symptoms lasting more than one day. Three (2%) asked for the intervention of General Practitioner and one of them had a deep vein thrombosis 39 days after the second shot. Thirty patients with no or minimal local adverse reaction after the first shot had a worse reaction after the second shot. On the other hand, of 19 patients with some reaction after the first shot, nine had better, six no change and four a worse reaction after the second dose. No patients were hospitalized nor had severe allergic reactions after both shots. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 At the time of survey, all patients were on oral anticoagulant treatment with warfarin (except two patients who refused to switch from rivaroxaban to warfarin after the premature closure of the TRAPS trial) (12) . Whether prior oral anticoagulant treatment may protect patients from severe COVID 19 complications is still a matter of debate (28) (29) (30) . Limitations of the study. In this retrospective survey, recollection and perceptions of symptoms 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 World Health Organization. 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