**5. Antiphospholipid antibodies in infections**

It is known that aPL may be transiently elevated in sera during various infections, including skin infections (18%), human immunodeficiency virus infections (17%), pneumonia (14%), hepatitis C virus (13%), and urinary tract infections (10%) [32]. The presence of aPL in sera and also its clinical significance was first noted in patients with Treponema pallidum infection [33]. With the continued use of cardiolipin-based serologic tests for syphilis diagnosis, it became apparent that a small group of patients with autoimmune diseases, especially SLE, had "falsepositive" tests. In 1983, researchers recognized that the presence of aPL in SLE patients was associated with thromboembolic events and recurrent miscarriage, and the term anticardiolipin syndrome and later antiphospholipid syndrome (APS) were coined [34, 35].

Since the global COVID-19 pandemic, a possible link between the presence of aPL and infection with the SARS-CoV-2 virus has been investigated. Several groups have reported the presence of aPL in patients with COVID-19 and have suggested the possibility of SARS-CoV-2 virus-induced APS [36–38]. Coagulopathy and thrombotic events, including deep vein thrombosis, pulmonary embolism, and stroke, are serious manifestations in critically ill patients with COVID-19.

Currently, the role of aPL in thrombotic complications in COVID-19 is still unclear. Similar to the severe coagulopathies associated with COVID-19, patients with CAPS may develop thrombosis in multiple organs within a very short period of time [39]. Because of the similarity between the course of COVID-19 and CAPS, it was hypothesized that SARS-CoV-2 infection could be a possible trigger for APS. Detailed analysis of 23 studies (with a total of 250 patients) of aPL at COVID-19 showed that the presence of LA, aCL, and anti-β2GPI was 64%, 9%, and 13%, respectively [40]. However, none of the included studies reported re-examination of aPL after 12 weeks, so it is not clear whether the aPL presence in COVID-19 patients was transient or persistent. The only study in which aPL testing was repeated after 1 month and in which aPS/PT was also measured included 31 patients with COVID-19 [41]. In this study, elevated aPL levels were confirmed in 74% of patients, but 9/10 of the LA-positive patients retested were negative the second time. This observation supports the frequent single LA positivity during the acute phase of COVID-19 infection.

Later in the pandemic, two independent reviews were published that examined the prevalence of aPL in COVID-19 patients and its clinical significance [42, 43]. The prevalence of LA ranged from 35 to 92% in ICU patients, aCL IgG in 52%, and IgM in 40% of patients, and anti-β2GPI IgG and IgM were found in up to 39% and up to 34% of patients, respectively. Between 1 and 12% of patients had a triple-positive aPL profile [43]. In the second review, the authors primarily examined studies of aCL and anti-β2GPI but also addressed non-criteria aPL [42]. They concluded that aPL positivity may be a feature of COVID-19, at least in some patients, but in general the identified "solid-phase" aPL are of low titer and cannot be well associated with the thrombotic aspects of COVID-19. Also, in the few studies in which persistence was examined, the results seemed to indicate transient positivity of aPL that occurred only during infection. Importantly, high-titer aPL or multiple APL positivity (including double and triple positivity) was in the minority for COVID-19. There is also one important study where antigen specificity of aPL in COVID-19 has been investigated. These researchers have found that, contrary to APS, which is characterized by high aPL titers with specificity against domain 1 on β2GPI, patients with COVID-19 exhibit low titers of anti-β2GPI, with specificity against domains 4 and 5 [44].

The risk of a recurrent thrombotic event in patients with APS is greatly increased in those who have multiple subtypes of aPL (LA, aCL, anti-β2-GPI, aPS/PT), that is, double-, triple-positive patients. In patients with COVID-19, double or triple aPL positivity appears to be rare and aPL positivity appears to be transient. A well-designed, age- and sex-controlled observational study compared the aPL profile of hospitalized COVID patients with that of a) patients with thrombotic APS and b) patients with culturally/serologically proven infections [45]. Their data showed that positive aPL values can be found in half of the patients with infections, as 53% of patients with COVID-19 and 49% of patients with other viral/bacterial infections had positive aPL values. Importantly, however, the aPL profile was different when comparing patients with overt APS and patients with aPL detected in the setting of infections. Therefore, author conclude, caution is required in interpreting and generalizing the role of aPLs in the management of patients with COVID-19.
