Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

The association between antiphospholipid antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: A critical review of the literature

In a previous systematic literature search, we demonstrated that the frequencies of antiphospholipid antibodies (aPL) in general-population patients with pregnancy morbidity (PM), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke (ST) are 6%, 10%, 11%, and 14%. To determine the association between aPL and clinical outcomes, we conducted a follow-up analysis of the 120 studies included in the original paper. Based on the analysis of 81 studies, a significant difference in the frequency of aPL criteria tests between patients and controls emerged considering all the outcomes together (10% versus 3%). In particular, a significant difference was reported for overall PM, pregnancy loss (PrL), late PrL, severe preeclampsia (PEC), ST, MI, and DVT. No difference emerged for early PrL, intrauterine growth restriction (IUGR), PEC, eclampsia (EC), and HELLP. A positive association was found in more than half of the studies for overall PrL, severe PEC, HELLP, ST, MI, and DVT and in less than half for early and late PrL, PEC, EC, and IUGR. The positive association between aPL and clinical outcomes included in the antiphospholipid syndrome classification criteria is not supported by every study, being particularly inconsistent for early PL, IUGR, PEC, EC, and HELLP

Clinical and laboratory characteristics of Brazilian versus non-Brazilian primary antiphospholipid syndrome patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) clinical database and repository

Background Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients. Methods We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS). Results We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ss2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white. Conclusions Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event

Immunosuppression use in primary antiphospholipid antibody-positive patients: Descriptive analysis of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry")

Background/Purpose APS ACTION Registry was created to study the outcomes of patients with persistently positive antiphospholipid antibodies (aPL) with or without other systemic autoimmune disease (SAIDx). Given that immunosuppression (IS) is used for certain aPL manifestations, for example, thrombocytopenia (TP), our primary objective was to describe the indications for IS in aPL-positive patients without other SAIDx. Secondly, we report the type of IS used in patients with selected microvascular or non-thrombotic aPL manifestations. Methods An online database is used to collect clinical data. The inclusion criteria are positive aPL based on the laboratory section of the APS Classification Criteria, tested at least twice within one year prior to enrollment. Patients are followed every 12 +/- 3 months. For this descriptive retrospective and prospective analysis, we included aPL-positive patients without other SAIDx and excluded those with new SAIDx classification during follow-up. For each patient, we retrieved clinical data at baseline and follow-up including selected aPL manifestations (diffuse alveolar hemorrhage [DAH], antiphospholipid-nephropathy [aPL-N], livedoid vasculopathy [LV]-related skin ulcers, TP, autoimmune hemolytic anemia [AIHA], cardiac valve disease [VD]), and IS medications. Results Of 899 patients enrolled, 537 were included in this analysis (mean age 45 +/- 13 years, female 377 [70%], APS Classification in 438 [82%], and at least one selected microvascular or non-thrombotic aPL manifestation in 141 (26%)). Of 537 patients, 76 (14%) were reported to use IS (ever), and 41/76 (54%) received IS primarily for selected aPL manifestation. In six of 8 (75%) DAH patients, 6/19 (32%) aPL-N, 4/28 (14%) LV, 25/88 (28%) TP, 6/11 (55%) AIHA, and 1/43 (2%) VD, the IS (excluding corticosteroids/hydroxychloroquine) indication was specific for selected aPL manifestation. Conclusion In our international cohort, 14% of aPL-positive patients without other SAIDx were reported to receive IS; the indication was at least one of the selected microvascular and/or non-thrombotic aPL-related manifestations in half. Thrombocytopenia was the most frequent among those selected aPL-related manifestations; however, approximately one-third received IS specifically for that indication. Diffuse alveolar hemorrhage was frequently treated with IS followed by AIHA and aPL-N. Systematic controlled studies are urgently needed to better define the role of IS in APS

Antiphospholipid Antibody Profile Stability Over Time: Prospective Results From the APS ACTION Clinical Database and Repository.

The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time. A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β2 glycoprotein-I (anti-β2-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis. Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate (P = 0.906) and multivariable analysis (P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, P = 0.002) the odds of an unstable aPL profile over time. Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry.

This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches