Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

Erythroblastic synartesis associated with lymphoproliferative disorder: There can be more than meets the eye.

Erythroblastic synartesis is a rare cause of acquired dyserythropoiesis. Only 9 cases have been previously reported. We hereby report 3 cases of patients diagnosed with erythroblastic synartesis associated with monoclonal immunoglobulin and an overt malignant lymphoid disorder. A different B-cell clone may produce the monoclonal immunoglobulin, forming a biclonal disorder. In light of these data and literature review, treatment targeting the paraprotein seems to be efficient to control synartesis and correct anemia. In the case of monoclonal gammapathy associated with chronic lymphocytic leukemia, therapeutics should be adapted to control both chronic lymphocytic leukemia and monitored monoclonal immunoglobulin titer.

Persistent IgG anticardiolipin autoantibodies are associated with post-COVID syndrome.

Persistence of various symptoms in patients who have recovered from coronavirus disease 2019 (COVID-19) was recently defined as 'long COVID' or 'post-COVID syndrome' (PCS). This article reports a case of a 58-year-old woman who, although recovering from COVID-19, had novel and persistent symptoms including neurological complications that could not be explained by any cause other than PCS. In addition to a low inflammatory response, persistence of immunoglobulin G anticardiolipin autoantibody positivity and eosinopenia were found 1 year after acute COVID-19 infection, both of which have been defined previously as independent factors associated with the severity of COVID-19. The pathophysiological mechanism of PCS is unknown, but the possibility of persistence of the virus, especially in the nervous system, could be suggested with a post-infectious inflammatory or autoimmune reaction.

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation.

Sources of solutes and carbon cycling in perennially ice-covered Lake Untersee, Antarctica.

Perennially ice-covered lakes that host benthic microbial ecosystems are present in many regions of Antarctica. Lake Untersee is an ultra-oligotrophic lake that is substantially different from any other lakes on the continent as it does not develop a seasonal moat and therefore shares similarities to sub-glacial lakes where they are sealed to the atmosphere. Here, we determine the source of major solutes and carbon to Lake Untersee, evaluate the carbon cycling and assess the metabolic functioning of microbial mats using an isotope geochemistry approach. The findings suggest that the glacial meltwater recharging the closed-basin and well-sealed Lake Untersee largely determines the major solute chemistry of the oxic water column with plagioclase and alumino-silicate weathering contributing < 5% of the Ca2+-Na+ solutes to the lake. The TIC concentration in the lake is very low and is sourced from melting of glacial ice and direct release of occluded CO2 gases into the water column. The comparison of δ13CTIC of the oxic lake waters with the δ13C in the top microbial mat layer show no fractionation due to non-discriminating photosynthetic fixation of HCO3- in the high pH and carbon-starved water. The 14C results indicate that phototrophs are also fixing respired CO2 from heterotrophic metabolism of the underlying microbial mats layers. The findings provide insights into the development of collaboration in carbon partitioning within the microbial mats to support their growth in a carbon-starved ecosystem.

Genetic Diversity and Population Structure of Leishmania infantum from Southeastern France: Evaluation Using Multi-Locus Microsatellite Typing.

In the south of France, Leishmania infantum is responsible for numerous cases of canine leishmaniasis (CanL), sporadic cases of human visceral leishmaniasis (VL) and rare cases of cutaneous and muco-cutaneous leishmaniasis (CL and MCL, respectively). Several endemic areas have been clearly identified in the south of France including the Pyrénées-Orientales, Cévennes (CE), Provence (P), Alpes-Maritimes (AM) and Corsica (CO). Within these endemic areas, the two cities of Nice (AM) and Marseille (P), which are located 150 km apart, and their surroundings, concentrate the greatest number of French autochthonous leishmaniasis cases. In this study, 270 L. infantum isolates from an extended time period (1978-2011) from four endemic areas, AM, P, CE and CO, were assessed using Multi-Locus Microsatellite Typing (MLMT). MLMT revealed a total of 121 different genotypes with 91 unique genotypes and 30 repeated genotypes. Substantial genetic diversity was found with a strong genetic differentiation between the Leishmania populations from AM and P. However, exchanges were observed between these two endemic areas in which it seems that strains spread from AM to P. The genetic differentiations in these areas suggest strong epidemiological structuring. A model-based analysis using STRUCTURE revealed two main populations: population A (consisting of samples primarily from the P and AM endemic areas with MON-1 and non-MON-1 strains) and population B consisting of only MON-1 strains essentially from the AM endemic area. For four patients, we observed several isolates from different biological samples which provided insight into disease relapse and re-infection. These findings shed light on the transmission dynamics of parasites in humans. However, further data are required to confirm this hypothesis based on a limited sample set. This study represents the most extensive population analysis of L. infantum strains using MLMT conducted in France.

Human leptospirosis: an emerging risk in Europe?

Leptospirosis has been reemerging in both developed and developing countries including Europe, where, this phenomenon has notably been associated with urban transmission. However, the comprehensive data that are needed to fully understand the ongoing epidemiological trends are lacking. In this article, we report surveillance data from throughout Europe, especially in France, to have an overview of this neglected disease in temperate countries. Our results underline the important role of wild rodents as reservoir of leptospirosis, and highlight the potential danger of a reemergence of this under-reported infectious disease in European cities, associated with the important expansion of the rat population in urban areas.

Environmental determinants of cholera outbreaks in inland Africa: a systematic review of main transmission foci and propagation routes.

Cholera is generally regarded as the prototypical waterborne and environmental disease. In Africa, available studies are scarce, and the relevance of this disease paradigm is questionable. Cholera outbreaks have been repeatedly reported far from the coasts: from 2009 through 2011, three-quarters of all cholera cases in Africa occurred in inland regions. Such outbreaks are either influenced by rainfall and subsequent floods or by drought- and water-induced stress. Their concurrence with global climatic events has also been observed. In lakes and rivers, aquatic reservoirs of Vibrio cholerae have been evocated. However, the role of these reservoirs in cholera epidemiology has not been established. Starting from inland cholera-endemic areas, epidemics burst and spread to various environments, including crowded slums and refugee camps. Human displacements constitute a major determinant of this spread. Further studies are urgently needed to better understand these complex dynamics, improve water and sanitation efforts, and eliminate cholera from Africa.

Cholera in coastal Africa: a systematic review of its heterogeneous environmental determinants.

According to the "cholera paradigm," epidemiology of this prototypical waterborne disease is considered to be driven directly by climate-induced variations in coastal aquatic reservoirs of Vibrio cholerae. This systematic review on environmental determinants of cholera in coastal Africa shows that instead coastal epidemics constitute a minor part of the continental cholera burden. Most of coastal cholera foci are located near estuaries, lagoons, mangrove forests, and on islands. Yet outbreaks often originate in coastal cities, where cholera is more likely to be imported from distant areas. Cholera outbreaks also may intensify in densely populated slum quarters before spreading to adjacent regions. Frequent seasonality of cholera incidence appears driven by the rainfall-induced contamination of unprotected water sources through latrine overflow and sewage, as well as by the periodicity of human activities like fishing or traveling. Lulls in transmission periods of several years are repeatedly recorded even in high-risk coastal areas. To date, environmental studies have failed to demonstrate a perennial aquatic reservoir of toxigenic V. cholerae around the continent. Finally, applicability of the cholera paradigm therefore appears questionable in Africa, although available data remain limited. Thorough surveys with microbiological analyses of water samples and prospective genotyping of environmental and clinical strains of V. cholerae are needed to understand determinants of cholera in coastal Africa and better target prevention and control measures.

Family compliance with counseling for children traveling to the tropics.

BACKGROUND: The number of people, both adults and children, traveling abroad, is on the rise. Some seek counseling at travel medicine centers before departure. METHODS: A prospective study was conducted among children <16 years visiting a travel medicine center in Marseille, France, from February 2010 to February 2011. Parents were contacted by telephone 4 weeks after their return, and asked about compliance with pre-travel advice. RESULTS: One hundred sixty-seven children were evaluated after their trip. Compliance with immunizations, malaria chemoprophylaxis, and food-borne disease prevention was 71, 66, and 31%, respectively. Compliance with malaria chemoprophylaxis varied significantly with destination, and was higher for African destinations. Significant features associated with poor compliance with chemoprophylaxis were a trip to Asia or the Indian Ocean, age <5 years, and a monoparental family. Compliance with prevention of food- and water-borne diseases was higher in children < 2 years of age. CONCLUSIONS: A ≥ 80% compliance with pre-travel counseling in children traveling overseas was achieved only for drinking bottled water, using repellents, a routine vaccine update, and yellow fever immunization.

Spatio-temporal dynamics of cholera during the first year of the epidemic in Haiti.

BACKGROUND: In October 2010, cholera importation in Haiti triggered an epidemic that rapidly proved to be the world's largest epidemic of the seventh cholera pandemic. To establish effective control and elimination policies, strategies rely on the analysis of cholera dynamics. In this report, we describe the spatio-temporal dynamics of cholera and the associated environmental factors. METHODOLOGY/PRINCIPAL FINDINGS: Cholera-associated morbidity and mortality data were prospectively collected at the commune level according to the World Health Organization standard definition. Attack and mortality rates were estimated and mapped to assess epidemic clusters and trends. The relationships between environmental factors were assessed at the commune level using multivariate analysis. The global attack and mortality rates were 488.9 cases/10,000 inhabitants and 6.24 deaths/10,000 inhabitants, respectively. Attack rates displayed a significantly high level of spatial heterogeneity (varying from 64.7 to 3070.9 per 10,000 inhabitants), thereby suggesting disparate outbreak processes. The epidemic course exhibited two principal outbreaks. The first outbreak (October 16, 2010-January 30, 2011) displayed a centrifugal spread of a damping wave that suddenly emerged from Mirebalais. The second outbreak began at the end of May 2011, concomitant with the onset of the rainy season, and displayed a highly fragmented epidemic pattern. Environmental factors (river and rice fields: p<0.003) played a role in disease dynamics exclusively during the early phases of the epidemic. CONCLUSION: Our findings demonstrate that the epidemic is still evolving, with a changing transmission pattern as time passes. Such an evolution could have hardly been anticipated, especially in a country struck by cholera for the first time. These results argue for the need for control measures involving intense efforts in rapid and exhaustive case tracking.

Babesia microti: an unusual travel-related disease.

BACKGROUND: Human babesiosis is a rare tick-borne infectious disease. The clinical presentation ranges from an asymptomatic form to a life threatening infection with severe hemolysis. Human babesiosis due to Babesia microti is the most common and is endemic in North America. CASE PRESENTATION: We report a European patient with severe pancytopenia and reactive hemophagocytosis related to a Babesia microti infection. Babesia infection was acquired during a travel in the USA. CONCLUSION: Babesiosis should be considered in patients who traveled in endemic areas, especially North America for the most common agent Babesia microti.

Epidemiology of urban dog-related injuries requiring rabies post-exposure prophylaxis in Marseille, France.

BACKGROUND: Dog bites are a serious public health concern. Besides injuries and the adverse psychological impacts, dog bites can be complicated by infections including rabies, which has the highest case-fatality rate of all infectious diseases. METHODS: Dog-associated injuries occurring in the city of Marseille, France were investigated in 245 individuals among patients presenting to the rabies treatment center over a 4-year period. RESULTS: Male patients were more likely to report dog bites compared to female patients (66.5% vs. 33.5%; odds ratio 2.25, 95% confidence interval 1.72-2.93). The mean age of injured patients was 32 years (range 1-85 years). Children and young adults under 30 years of age were more than four times more likely to report dog bites compared to others. Most cases occurred outdoors (73.0%) - in public areas (38.0%) - and involved animals of unknown owners in 56.3% of the cases. Only 28.2% of dogs were available for observation. Most patients (63.7%) received complete rabies post-exposure prophylaxis. The distribution of dog bites in the city was not homogeneous and the incidence of bites was significantly higher in some areas. Eleven percent of patients declared having been bitten by dogs whose owner was a street beggar, and a clustered distribution was evidenced for these cases in one area of the city. CONCLUSIONS: Programs offering low-cost rabies vaccination and veterinary care to pets belonging to the group of street beggars should be considered. Such programs may be implemented in other large cities in France and Europe where street beggars are frequently seen.

Acute cerebral vasculopathy in systemic sclerosis.

Systemic sclerosis is an autoimmune disease characterized by skin and deep organ fibrosis and obliterative microvasculopathy. Cerebral involvement is currently not recognized as a manifestation of the disease, although several morphologic and functional studies suggested a frequent cerebral involvement in systemic sclerosis. We report a new case of acute cerebral vasculopathy in a patient suffering from systemic sclerosis together with five historical cases identified through a literature review. Cerebral acute vasculopathy most often revealed the disease. Affected patients suffered often from limited or diffuse cutaneous systemic sclerosis. Reversibility of arterial lesions, absence of specific histologic findings, and association with severe peripheral vascular involvement plead for a major role of vasospasm. However, the apparent efficacy of immunosuppressive treatments suggests an association with inflammatory or immune mechanisms. Awareness should be raised because of the severity of the disease, the risk of relapse, and the possible occurrence early in the course of systemic sclerosis.

Heterogeneity of environments associated with transmission of visceral leishmaniasis in South-Eastern France and implication for control strategies.

BACKGROUND: Visceral leishmaniasis due to Leishmania infantum is currently spreading into new foci across Europe. Leishmania infantum transmission in the Old World was reported to be strongly associated with a few specific environments. Environmental changes due to global warming or human activity were therefore incriminated in the spread of the disease. However, comprehensive studies were lacking to reliably identify all the environments at risk and thereby optimize monitoring and control strategy. METHODOLOGY/FINDINGS: We exhaustively collected 328 cases of autochthonous visceral leishmaniasis from 1993 to 2009 in South-Eastern France. Leishmaniasis incidence decreased from 31 yearly cases between 1993 and 1997 to 12 yearly cases between 2005 and 2009 mostly because Leishmania/HIV coinfection were less frequent. No spread of human visceral leishmaniasis was observed in the studied region. Two major foci were identified, associated with opposite environments: whereas one involved semi-rural hillside environments partly made of mixed forests, the other involved urban and peri-urban areas in and around the region main town, Marseille. The two neighboring foci were related to differing environments despite similar vectors (P. perniciosus), canine reservoir, parasite (L. infantum zymodeme MON-1), and human host. CONCLUSIONS/SIGNIFICANCE: This unprecedented collection of cases highlighted the occurrence of protracted urban transmission of L. infantum in France, a worrisome finding as the disease is currently spreading in other areas around the Mediterranean. These results complete previous studies about more widespread canine leishmaniasis or human asymptomatic carriage. This first application of systematic geostatistical methods to European human visceral leishmaniasis demonstrated an unsuspected heterogeneity of environments associated with the transmission of the disease. These findings modify the current view of leishmaniasis epidemiology. They notably stress the need for locally defined control strategies and extensive monitoring including in urban environments.

Comparison of mother and child antibodies that target high-molecular-mass Toxoplasma gondii antigens by immunoblotting improves neonatal diagnosis of congenital toxoplasmosis.

This retrospective study proposes a new reading of immunoblotting (IB) in the diagnosis of congenital toxoplasmosis. Our findings demonstrate that a three-IgM-band association at 75, 90, and 100 kDa called the IgM triplet increases the sensitivity to 95.8% when combined with prenatal and serological neonatal tests.