Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome

Extra-criteria manifestations such as thrombocytopenia and livedo are described associated with antiphospholipid syndrome (APS) but are not included in the current classification criteria. Their clinical expression might be important, as they may be associated with a high-risk profile of antiphospholipid antibodies (aPL) and thrombosis. We evaluated the association between the presence of extra-criteria manifestations in primary obstetric-APS (POAPS) and aPL profiles. We also evaluated whether the presence of extra-criteria manifestations in POAPS patients increases the risk of developing thrombosis during the follow-up period (median follow-up 5 years; range 3–9 years). We selected 79 women who were included in our study only if they were first diagnosed with POAPS (with no history of previous thrombosis) and reevaluated for the presence of thrombosis after the follow-up period. We evaluated the association between the aPL profile and extra-criteria manifestations. We also evaluated the relationship of thrombosis during the follow-up period with extra-criteria manifestations and other risk factors. Patients with three or more extra-criteria manifestations presented high rates of triple positivity for the aPL profile (75%) (p < 0.001). We also found a relationship between the presence of extra-criteria manifestations and the presence of high titers of aPL: 91.7% of patients with three or more extra-criteria manifestations had high titers of aPL (p < 0.01). We further evaluated the group of POAPS patients according to thrombotic events during the follow-up. Among these patients, 6 (7.6%) presented thrombosis. Notably, 100% of patients with a thrombotic event during the follow-up had more than three extra-criteria manifestations. POAPS patients with extra-criteria manifestations might have a high-risk aPL profile and a major risk of developing thrombosis.Fil: Udry, Sebastián. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Latino, José Omar. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Belizna, Cristina. Inserm; FranciaFil: Perés Wingeyer, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Fernández Romero, Diego Santiago. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: de Larrañaga, Gabriela Fernanda. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Risk factors for early severe preeclampsia in obstetric antiphospholipid syndrome with conventional treatment. The impact of hydroxychloroquine

Objective: The first aim was to retrospectively identify risk factors for the development of early severe preeclampsia (sPE) in patients with obstetric antiphospholipid syndrome (OAPS) who received conventional treatment (CT). The second aim was to evaluate the impact of hydroxychloroquine (HCQ) in preventing early sPE among a subgroup of patients considered at high risk. Methods: A total of 102 women diagnosed with OAPS and treated with CT since the diagnosis of pregnancy were selected. At the end of pregnancy, we identified risk factors associated with early sPE. According to these risk factors, we collected a new cohort of 42 patients who presented high-risk factors for developing early sPE and split them into two groups according to the treatment received: group A, CT (30 patients); and group B, CT+HCQ (12 patients). We evaluated and compared pregnancy outcomes in both groups. Results: According to the multivariate analysis, risk factors associated with early sPE and CT were triple positivity for antiphospholipid antibodies (aPL) (OR = 24.70, [4.27–142.92], p < 0.001) and a history of early sPE (OR = 7.11, [1.13–44.64], p = 0.036). A low-risk aPL profile was associated with a good response to CT in preventing early sPE (OR = 0.073, [0.014–0.382], p = 0.002). High-risk patients treated with CT+HCQ had a significantly lower early sPE rate than those treated with CT only (8.3% vs 40.0%; p = 0.03). Conclusion: Triple positivity for aPL and a history of early sPE are potential strong risk factors for the development of early sPE. HCQ might be an interesting therapeutic option for patients with high-risk factors for early sPE.Fil: Latino, José Omar. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Udry, Sebastian Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Aranda, Federico. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Peres Wingeyer, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Fernández Romero, Diego Santiago. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Belizna, Cristina. University Of Angers; FranciaFil: de Larrañaga, Gabriela Fernanda. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Risk factors for early severe preeclampsia in obstetric antiphospholipid syndrome with conventional treatment. The impact of hydroxychloroquine

Objective: The first aim was to retrospectively identify risk factors for the development of early severe preeclampsia (sPE) in patients with obstetric antiphospholipid syndrome (OAPS) who received conventional treatment (CT). The second aim was to evaluate the impact of hydroxychloroquine (HCQ) in preventing early sPE among a subgroup of patients considered at high risk. Methods: A total of 102 women diagnosed with OAPS and treated with CT since the diagnosis of pregnancy were selected. At the end of pregnancy, we identified risk factors associated with early sPE. According to these risk factors, we collected a new cohort of 42 patients who presented high-risk factors for developing early sPE and split them into two groups according to the treatment received: group A, CT (30 patients); and group B, CT+HCQ (12 patients). We evaluated and compared pregnancy outcomes in both groups. Results: According to the multivariate analysis, risk factors associated with early sPE and CT were triple positivity for antiphospholipid antibodies (aPL) (OR = 24.70, [4.27–142.92], p < 0.001) and a history of early sPE (OR = 7.11, [1.13–44.64], p = 0.036). A low-risk aPL profile was associated with a good response to CT in preventing early sPE (OR = 0.073, [0.014–0.382], p = 0.002). High-risk patients treated with CT+HCQ had a significantly lower early sPE rate than those treated with CT only (8.3% vs 40.0%; p = 0.03). Conclusion: Triple positivity for aPL and a history of early sPE are potential strong risk factors for the development of early sPE. HCQ might be an interesting therapeutic option for patients with high-risk factors for early sPE.Fil: Latino, José Omar. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Udry, Sebastian Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Aranda, Federico. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Peres Wingeyer, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Fernández Romero, Diego Santiago. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Belizna, Cristina. University Of Angers; FranciaFil: de Larrañaga, Gabriela Fernanda. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications

Purpose Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. Methods This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. Results No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. Conclusions The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications.Fil: Aranda, Federico. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Udry, Sebastián. Hospital General de Agudos"Dr Carlos G. Durand"; ArgentinaFil: Perés Wingeyer, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Amshoff, Lea Christina. University Hospital Munster; AlemaniaFil: Bogdanova, Nadja. University Hospital Munster; AlemaniaFil: Wieacker, Peter. University Hospital Munster; AlemaniaFil: Latino, José Omar. Hospital General de Agudos "Carlos G. Durand"; ArgentinaFil: Markoff, Arseni. University Hospital Munster; AlemaniaFil: de Larrañaga, Gabriela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentin

Obstetrical outcome and treatments in seronegative primary APS: data from European retrospective study

International audienceObjective: To compare characteristics, pregnancies and treatments during pregnancies of seronegative and seropositive antiphospholipid syndrome (APS), to analyse factors associated with obstetrical outcome.Patients and methods: Inclusion criteria were: (1) thrombotic and/or obstetrical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies (APL); (3) at least one persistent non-conventional APL among IgA anticardiolipin antibodies, IgA anti-B2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-phosphatidylethanolamine G/M and anti-phosphatidylserine/prothrombin G/M antibodies. The exclusion criteria were: (1) systemic lupus erythematosus ( SLE) or SLE-like disease; and (2) other connective tissue disease.Results: A total of 187 women (mean 33±5 years) with seronegative APS were included from 14 centres in Austria, Spain, Italy, Slovenia and France and compared with 285 patients with seropositive APS. Seronegative APS has more obstetrical rather than thrombotic phenotypes, with only 6% of venous thrombosis in comparison to seropositive APS. Cumulative incidence of adverse obstetrical events was similar in seronegative and seropositive APS patients, although higher rates of intrauterine deaths (15% vs 5%; p=0.03), of preeclampsia (7% vs 16%, p=0.048) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) were noted in seropositive APS. The cumulative incidence of adverse obstetrical events was significantly improved in treated versus untreated seronegative APS (log rank<0.05), whereas there was no difference between patients who received aspirin or aspirin-low-molecular weighted heparin combination.Conclusion: Several non-criteria APL can be detected in patients with clinical APS features without any conventional APL, with various rates. The detection of non-criteria APL and thus the diagnosis of seronegative APS could discuss the therapeutic management similar to seropositive APS, but well-designed controlled studies are necessary

Hydroxychloroquine For The Prevention Of Relapses In A Series Of 812 Patients With Primary Antiphospholipid Syndrome: The Hibiscus Retrospective Study

Wo

Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry

OBJECTIVES: To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS). METHODS: This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome. RESULTS: A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P &lt; 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P &lt; 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P &lt; 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C). CONCLUSION: Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients

In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

International audienceAzathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this fiel

Endometrial cancer in Puerto Rico: incidence, mortality and survival (1992-2003)

<p>Abstract</p> <p>Background</p> <p>Endometrial cancer is the most common gynecologic malignancy in Puerto Rico and the United States (US).</p> <p>Methods</p> <p>We compare the age-specific and age-adjusted incidence and mortality rates and the survival of endometrial cancer in Puerto Rico with that of non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Hispanics in the US. Data from the Puerto Rico Central Cancer Registry and the Surveillance, Epidemiology, and End Results program were analyzed from 1992-2003.</p> <p>Results</p> <p>Age-standardized incidence rates of endometrial cancer increased significantly (p < 0.05) in Puerto Rico (APC = 2.8%) and among NHB (APC = 1.9%) and remained constant (p > 0.05) for NHW (APC = -0.1%) and Hispanics in the US (APC = 0.4%). Mortality trends remained constant in all racial/ethnic groups (p > 0.05). For 1999-2003, women in Puerto Rico had similar incidence of endometrial cancer as Hispanics (Standardized rate ratio [SRR] = 0.94, 95% CI = 0.87-1.01), although their risk was lower than that of NHW (SRR = 0.56, 95% CI = 0.53-0.59) and NHB (SRR = 0.91, 95% CI = 0.84-0.98). Meanwhile, women in Puerto Rico had 15% higher risk of death than Hispanic women (SRR = 1.15, 95% CI = 1.03-1.30) similar risk than NHW (SRR = 0.93, 95% CI = 0.83-1.03), and lower risk than NHB (SRR = 0.51, 95% CI = 0.46-0.57). Puerto Rico (63.1%) and NHB (56.8%) had a lower 5-year survival than NHW (78.4%) and Hispanics (79.5%). An age-adjusted Cox proportional hazards model showed that compared with women in Puerto Rico, Hispanic women in the United States had 37% lower mortality risk (HR = 0.63, 95% CI = 0.56-0.71) and NHW had 53% lower mortality risk (HR = 0.47, 95% CI = 0.43-0.52) after 5 years of diagnosis; NHB women had 22% higher mortality risk than women in Puerto Rico (HR = 1.22, 95% CI = 1.09-1.36).</p> <p>Conclusions</p> <p>The lower burden of endometrial cancer in Puerto Rico suggests the presence of protective factors or lower exposure to risk factors in this population, although increases in incidence suggest changes in the occurrence of lifestyles and environmental risk factors. Meanwhile, the lower five-year survival from endometrial cancer among Puerto Ricans suggests a health disparity for this group in areas such as quality of care and/or differences in terms of stage at diagnosis and associated comorbidities. Assessment of disease risk factors and characteristics, and access and response to treatment is required to further understand these results.</p