key: cord-0710622-mld3q7x8 authors: Schioppo, Tommaso; Argolini, Lorenza Maria; Sciascia, Savino; Pregnolato, Francesca; Tamborini, Francesco; Miraglia, Paolo; Roccatello, Dario; Sinico, Renato Alberto; Caporali, Roberto; Moroni, Gabriella; Gerosa, Maria title: Clinical and peculiar immunological manifestations of SARS-CoV-2 infection in systemic lupus erythematosus patients date: 2021-08-05 journal: Rheumatology (Oxford) DOI: 10.1093/rheumatology/keab611 sha: 15be3ff860e4adfc6cc4c5939229e2a10fb29c36 doc_id: 710622 cord_uid: mld3q7x8 OBJECTIVES: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with systemic lupus erythematosus (SLE) remains unclear and data on clinical manifestations after infection are lacking. The aim of this multicentre study is to describe the effect of SARS-CoV-2 in SLE patients. METHODS: SLE patients referring to 4 Italian centres were monitored between February 2020 and March 2021. All patients with SARS-CoV-2 infection were included. Disease characteristics, treatment, disease activity, and SARS-CoV-2 related symptoms were recorded before and after the infection. RESULTS: Fifty-one (6.14%) SLE patients were included among 830 regularly followed-up. Nine (17.6%) had an asymptomatic infection. Five (9.8%), out of 42 (82.6%) symptomatic, developed interstitial pneumonia (no identified risk factor). The presence of SLE major organ involvement (particularly renal involvement) was associated with asymptomatic SARS-CoV-2 infection (p-value = 0.02). Chronic corticosteroid therapy was found to be associated with asymptomatic infection (p-value = 0.018). Three SLE flares (5.9%) were developed after SARS-CoV-2 infection: one of them was characterized by MPO-ANCA positive pauci-immune crescentic necrotizing glomerulonephritis and granulomatous pneumonia. CONCLUSIONS: SARS-CoV-2 infection determined autoimmune flares in a small number of our patients. Our data seem to confirm that there was not an increased risk of SARS-CoV-2 in SLE. Patients with asymptomatic SARS-CoV-2 infections were those having major SLE organ involvement. This may be explained by the high doses of corticosteroids and immunosuppressive agents used for SLE treatment. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, in December 2019, and then spread worldwide. The World Health Organization (WHO) declared SARS-CoV-2 a pandemic in March 2020. SARS-CoV-2 has so far infected more than 139 millions of people and caused the death of almost 3 millions of them(1). In the following months, some risk factors for SARS-CoV-2 infection were identified in the general population (e.g. older age, male sex, non-white race, obesity)(2). It is well established that patients with inflammatory rheumatic diseases (RDs) are at higher risk of infections than the general population because of associated comorbidities, underlying disease activity and concomitant immunosuppressive therapies(3). SARS-CoV-2 was shown to cause endothelitis resulting in vascular manifestations (e.g., thrombosis) and immune system activation via toll-like receptors and complement system(4,5). At the beginning, the current pandemic aroused many questions for patients with RDs, such as systemic lupus erythematosus (SLE). In these patients, many factors associated with the disease were matter of concern, such as the well-establish role of viruses (e.g., Epstein-Barr virus) in SLE pathogenesis(6-8), the higher susceptibility to infections(9), the risk of SLE flares after viral and bacterial infections (10) , the presence of organ damage directly caused by SLE, the use of glucocorticoids (GCs), and immunosuppressive regimens. Few new SLE cases, triggered by SARS-CoV-2 infection, have been so far reported (11) . Conversely, as of today, studies were not able to detect an increased risk of SARS-CoV-2 in SLE patients (12) . This could be explained by the fact that SLE patients could have adopted more protective behaviour than the general population and therefore this could have protected them from the infection (13, 14) . Besides GCs (more than 10 mg daily), no SLE-related risk factors have been identified (15) . Moreover, some data about mortality in patients with RDs suggest caution about rituximab (15) . 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 Retrospective observational multi-centre cohort study. 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 after SAR-CoV-2 infection, possible treatment modifications related to nasal swab positivity and comorbidities were collected and gathered in a database for statistical analysis. Moreover, when available, laboratory parameters (protein C reactive -CRP, erythrocyte sedimentation rate -ESR, ferritin, gamma globulins, interleukin 6 -IL-6) were collected at last follow-up visit before the SARS- (20) . SARS-CoV-2 infection severity was assessed as previously defined (21) . Descriptive statistic was used to summarize the patients' demographic and clinical data by using median, interquartile range, absolute numbers, and percentages. All these variables were then investigated as risk factors of the following outcomes: SARS-CoV-2 symptoms, COVID-19 pneumonia, and SLE flare after SARS-CoV-2 infection. The comparisons of continuous variables between groups of patients were assessed through Welch two sample t-test or Mann Whitney nonparametric test, as appropriate. The association between categorical variables was assessed by performing Chi square or Fisher's exact test, as appropriate. In order to identify subjects with similar profile and the association among the categorical variables, multiple correspondence analysis (MCA) was carried out (22) . This multivariate analysis can also be seen as a generalization of principal component analysis (PCA) when the variables to be analysed are categorical instead of quantitative (23) . No further modelling was conducted because of the limited number of individuals in each level of the investigated outcomes. A p value lower than 0.05 was considered as significant. All analyses were performed using R software, version 3.5.2, with package Rcmdr (version 2.5-1). Fifty-one patients, who had SARS-CoV-2 infection, were included in the study among 830 regularly followed-up patients. Disease history, laboratory parameters, demographic characteristics and therapy, collected at the last visit of follow-up before the SARS-CoV-2 infection, are reported in The clinical manifestations of SARS-CoV-2 infection and its impact on SLE disease activity are reported in table 2. Nine (17.6%) patients had an asymptomatic SARS-CoV-2 infection, while 34 (66.7%) patients had a mild COVID-19, and 8 (15.7%) a severe-moderate COVID-19. Out of 42 symptomatic patients, 5 (9.8%) developed interstitial pneumonia(21) and 3 (5.9%) of them were hospitalized. In all patients with pneumonia the steroid dose was increased. Outpatients were treated with an oral course of antibiotics (macrolide). Among hospitalized patients, 2 received conventional oxygen therapy and 1 needed non-invasive positive pressure ventilation. Moreover, all 3 were treated with low molecular weight heparin and antibiotics. 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 infection (4 and 23 out of 34 patients with organ involvement underwent GCs and/or immunosuppressive therapy, respectively). On the contrary, the remaining variables seem not to represent distinctive characteristics of the SARS-CoV-2 symptomatic profile. In this regard and on a strictly descriptive level, the multivariate analysis allowed to have an overall view of the relationships among all the clinical characteristics and to identify patients with similar profile (Supplementary Figure S1 , available at Rheumatology online). A substantial biologic variability of our cohort was explained by 2 underlying dimensions: the disease-related characteristics and the ongoing therapy. In this context, the major organ involvement and the treatment clearly defined the two profiles of SARS-CoV-2 infection. In our cohort, only 5 patients (9.8%) developed SARS-CoV-2 related interstitial pneumonia. None of the considered parameters (e.g., gender, age, disease duration, SLE organ involvement, serological SLE characteristics, SLE therapy, SLEDAI-2K score before the infection, or comorbidities) correlated with the risk of COVID-19 pneumonia. In the considered parameters, no difference was found between hospitalized and non-hospitalized patients. 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 Table 4) . Kidney biopsy was then performed with evidence of diffuse pauci-immune extra-capillary necrotizing glomerulonephritis (Figure 2) . The patient received three intravenous methylprednisolone pulses of 750 mg each and rituximab (1 gr 14 days apart) followed by oral prednisone 0.5mg/kg/day with rapid resolution of the fever and of the other symptoms. One month after discharge, the patient was asymptomatic with a good control of blood pressure and a noticeable improvement on laboratory tests. Our data seem to confirm that there is not an increased risk of SARS-CoV-2 in SLE patients. In this cohort, SLE patients with major organ involvements (with lupus nephritis being the most frequently observed) were those who experienced more often an asymptomatic form of the infection. SARS-CoV-2 infection determined flares in a small number of patients. Particularly, a patient with long-standing SLE developed a renal and pulmonary syndrome, atypical for SLE, more closely resembling a vasculitis. Although statistically significant, the difference found between IL-6, ferritin and ESR levels before and after the infection did not seem biological relevant. Moreover, although increased with respect to pre-SARS-CoV-2 infection, ESR and ferritin values were still in the range of normality. Considering the SLE intrinsic immunological abnormalities along with immunosuppressant therapies, the question of whether patients with SLE might have a different clinical SARS-CoV-2 infection outcome than the general population has risen among clinicians worldwide. It seems now evident that SARS-CoV-2 infection is characterized by a viral phase and a subsequent immunological response, supporting the hypothesis that the clinical spectrum of COVID-19 is a result of the heterogeneity in the immune reaction to the virus itself. The critical aspect of the most severe form of COVID-19 is the loss of the immune tolerance, leading to an exacerbation of the inflammatory components (the so-called cytokine storm) (24) . In this regard, several therapeutic immunomodulatory approaches (e.g., tocilizumab), usually administered in RDs, have been considered in the context of COVID-19 (25) . While overall results are still inconclusive, probably due to variability in dosing and heterogeneous inclusion criteria, it seems that some anti-rheumatic agents could have a role in the management of the immune response to SARS-CoV-2 infection. In our cohort, patients with major organ involvement taking immunosuppressive regimens tended to experience asymptomatic SARS-CoV-2 infections; this fact might be explained by the concomitant ongoing SLE treatment (e.g., high dose GCs) that could possibly have altered the immunological response to infection. This is only partially in line with what have been described in Page 13 of 27 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 Our data suggest a need to pay close attention to SLE patients with mild form, considering that they usually do not take immunosuppressant therapy and therefore they could be more exposed The authors have declared no conflicts of interest. 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 Funding: No specific funding was received from any bodies in the public, commercial or not-forprofit sectors to carry out the work described in this article. 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 Data availability statement Data have been collected anonymously in an excel file that can be available upon request. Data about the case report could be subjected to some limitations due to privacy reasons. 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 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 Table 1 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 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 60 Influenza A/H1N1 septic shock in a patient with systemic lupus erythematosus. 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