key: cord-0770314-642bi0fz
authors: Berte', Roberto; Mazza, Stefano; Stefanucci, Marta Rachele; Noviello, Daniele; Costa, Stefania; Ciafardini, Clorinda; Mileti, Erika; Mapelli, Marina; Pasqualato, Sebastiano; Pinto, Sergio; Favale, Agnese; Vecchi, Maurizio; Neurath, Markus F; Atreya, Raja; Fantini, Massimo Claudio; Facciotti, Federica; Caprioli, Flavio
title: Seroprevalence of SARS-CoV2 in IBD patients treated with biological therapy
date: 2020-11-19
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjaa237
sha: 0596872603d719f0343995883b8c7977746db12c
doc_id: 770314
cord_uid: 642bi0fz

BACKGROUND AND AIMS: A similar course of COVID-19 in patients with inflammatory bowel diseases (IBD) and in the general population has been reported. However, disease prevalence in IBD patients is presently unknown. In this prospective observational study we aimed at determining SARS-CoV2 infection prevalence in IBD patients treated with biological therapy. METHODS: 354 sera from IBD patients under biological therapy recruited from three different locations in Italy and Germany were evaluated for antibody presence by RBD ELISA. Control groups were i) age-matched healthy subjects tested in the same time period in Milan, Italy; ii) healthy subjects collected in the pre-COVID era; iii) IBD patients under biological therapy collected in the pre-COVID era. RESULTS: 8 out of 354 patients tested positive for the anti-RBD-SARS-CoV2 IgG antibody (prevalence 2.3%). IgG positive patients’ percentage recruited from Milan was significantly higher than those recruited from other locations (prevalence 5.4% vs. 0.4% p < 0.005). IgG positive patients reported a significantly higher incidence of fever, anosmia and ageusia, and were more likely to have entered in close contact with COVID-19 positive subjects before the study enrolment. CONCLUSIONS: Seroprevalence of SARS-CoV2 in IBD patients treated with biological therapy reflects values measured in the local general population. Specific symptoms and contact history with SARS-CoV2-infected individuals strongly increase the likelihood of SARS-CoV2 seropositivity.

Infection by the novel SARS-CoV2 betacoronavirus [1] induces the immune system activation, finalized to the clearance of infected cells [2] . The impact of COVID-19 on IBD patients, especially those on immunosuppressive therapy, is not fully understood [3] . Recent reports described a rate of serious disease and death comparable to general population [4, 5] , but the real prevalence and clinical manifestations of infection among IBD patients remain largely unknown.

Humoral immune response against SARS-CoV2 proteins, including the receptor binding domain (RBD) of the spike (S) protein, leads the production of antibodies of different classes [6, 7] . Thus, serological tests represent a useful tool to identify patients who contracted the infection [8] .

Here, we prospectively collected data regarding the prevalence of SARS-CoV2 infection in patients treated with intravenous (i.v.) or subcutaneous biological therapy (e.g. infliximab, IFX; adalimumab, ADA; golimumab, GOL, vedolizumab, VDZ; ustekinumab, UST) in different geographical areas of Italy (Milan and Cagliari) and in Germany (Erlangen) through the detection of anti-SARS-CoV2 specific IgG and IgA by an home-made validated ELISA assay [9] [10] [11] . Risk factors and clinical variables linked with SARS-CoV2 seropositivity were investigated, and kinetic of SARS-CoV2 circulating antibodies over time was assessed.

From April to June 2020, sera from 354 IBD patients under biological therapy (Table 1) were   prospectively collected. 129 patients were recruited from Milan, Italy, 48 from Cagliari, Italy, and 177 from Erlangen, Germany. Sera from a control group of 129 otherwise healthy subjects matched for A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa237 5 age and sex were collected in the same period in Milan. Additional controls were sera from a cohort of 50 IBD patients under biological therapy and from a group of 63 healthy subjects, both collected in Milan during the pre-COVID era (2018).

Overall, 8 out of 354 patients tested positive for anti-RBD IgG antibodies (prevalence 2.3%, 95% CI 0.8-3.8%, Figure 1 ). The percentage of IgG-positive patients recruited from Milan was significantly higher than those recruited from other locations (prevalence 5. Table 2 and Supplementary Table 2 ). The presence of a COVID-19 infected relative was identified as an independent predictor of IgG seropositivity at multivariate analysis (RR 52.4, 95%CI 1.5-1769.2; p=0.027). Concomitant antiTNF therapy was associated with a significantly reduced seroprevalence of IgG at univariate, but not at multivariate, analysis. Positive history of fever and anosmia/ageusia in the last two months were significantly associated with IgG A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa237 6 seropositivity at univariate analysis (p<0.0001 for all variables) (Table 3) . Notably, history of anosmia/ageusia was confirmed as an independent predictor of IgG seropositivity at multivariable analysis (RR 54.5, 95%CI 2.1-1434.9; p=0.016) Predictors of IgA seropositivity were similar to IgG ones, including close/family contacts with a COVID-19 infected individual, and positive history for fever and anosmia/ageusia, even if these factors were not confirmed at multivariate analysis (Supplementary Tables 1 and 2 (Table 4 ). In no patient biological treatment for IBD was interrupted, and the majority of patients remained in clinical remission two months following enrolment. In one 70 year old UC female patient, receiving maintenance vedolizumab treatment for 24 months, a clinical relapse of the disease was observed following infection, successfully treated with dose optimization. Active infection of IgG-positive patients was confirmed SARS-CoV2 nasopharingeal swab testing.

The current work is, to our knowledge, the first report on SARS-CoV2 seroprevalence in IBD patients treated with biological therapy. Previous reports suggested, on the basis of symptom reporting, an extremely low SARS-CoV2 infection rate in IBD patients [14] . We observed that SARS-CoV2 IgG seroprevalence in IBD closely reflects values measured in background populations, whose prevalence was of 7% in Milan. This result is in line with an Italian nationwide study indicating SARS- To note, biological therapy did not prevent the mounting of efficient humoral responses in infected IBD patients, including those treated with anti-integrin molecules, for which an interference with IgA humoral responses following administration of oral vaccines has been previously reported [17] .

Confirming recent results [4, 5] , our data provide further reassurances over the benign course of COVID-19 in IBD patients under biological therapy.

The present study has several strengths, including a population cohort numerically relevant (almost 400 IBD patients treated with intravenous biologicals), and recruited from areas with different exposure to the SARS-CoV2 virus. Moreover, anti-SARS-COV2 seroprevalence was evaluated in highly homogeneous adult CD and UC patients. Additionally, different control populations were included in the study. Finally, the in-house ELISA test used has extremely high performance values (specificity 95.2% and sensitivity 97,64 for IgG, 99,8% and 71,4% for IgA) [9] . Conversely, a previous report [14] tested a mixed population of pediatric and adult IBD patients with a poorly perfoming not CE approved lateral flow rapid assay [18] . A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa237 12 

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