Length of stay in at-risk areas and time to malaria attack on return.

BACKGROUND: Experimental infection with Plasmodium falciparum results in malaria attack within a few days of exposure. However, we have regularly observed malaria attack within a short time after return, regardless of the time spent in an endemic area. We therefore aimed to assess whether the time before return and malaria attack varies according to length of stay. METHODS: We used anonymized data from the French National Reference Centre for Malaria between 2006 and 2016. We analyzed 11,823 cases aged at least 1 year and diagnosed with P. falciparum malaria 1 day to 1 year after returning to France, after a stay of 1 day to 1 year in an at-risk area. RESULTS: Trips had a median duration of 31 days [IQR: 19-56]. Median time between return from the endemic area and onset of malaria symptoms was 5 days [IQR: 0-10], and the median between return and malaria diagnosis was 9 days [IQR: 5-14]. Times to symptom onset or diagnosis were longer for stays of fewer than 15 days vs 15 days or more (for symptoms: 7 vs 4 days for longer stays, for diagnosis: 11 vs 9 days). For stays longer than 15 days, no variation was observed according to length of stay. CONCLUSIONS: Aside from at-risk stays of fewer than 15 days, the time between return and malaria attack is constant and rather short, even after long stays. The 2 weeks following return should be considered as a risk period whatever the length of stay in an at-risk area.

The recent introduction of Angiostrongylus cantonensis and its intermediate host Achatina fulica into Guadeloupe detected by phylogenetic analyses.

BACKGROUND: Angiostrongylus cantonensis (rat lungworm) is the main pathogen responsible for eosinophilic meningitis in humans. One of its intermediate snail hosts, Achatina fulica, was already present in many countries around the world before it appeared in the West Indies in the late 1980s. In the French territories in the Caribbean and northern South America, the first cases of human neuroangiostrongyliasis were reported in Martinique, Guadeloupe and French Guiana in 2002, 2013 and 2017, respectively. In order to better characterize angiostrongyliasis in Guadeloupe, particularly its geographical origin and route of introduction, we undertook molecular characterization of adult worms of Angiostrongylus cantonensis and its intermediate host Achatina fulica. METHODS: Genomic DNA of adult Angiostrongylus cantonensis and Achatina fulica was extracted and amplified by polymerase chain reaction (PCR) targeting the mitochondrial genes cytochrome B and C for A. cantonensis and 16S ribosomal RNA for A. fulica. The PCR products were sequenced and studied by phylogenetic analysis. RESULTS: Cytochrome B and cytochrome C molecular markers indicate a monophyletic lineage of A. cantonensis adult worms in Guadeloupe. Two sequences of A. fulica were identified. CONCLUSIONS: These results confirm the recent introduction of both Angiostrongylus cantonensis and Achatina fulica into Guadeloupe. Achatina fulica in Guadeloupe shares a common origin with those in Barbados and New Caledonia, while Angiostrongylus cantonensis in Guadeloupe shares a common origin with those in Brazil, Hawaii and Japan.

Fatal HSV-2 primary infection most likely acquired by kidney transplantation: A case report.

Herpes simplex virus 2 (HSV-2) rarely causes severe disease, even in solid organ transplant recipients. This paper describes a fatal case of HSV-2 infection, probably transmitted from a donor to a kidney transplant recipient. The donor was seropositive for HSV-2 but not for HSV-1, whereas the recipient was seronegative for both viruses before transplantation, suggesting that the graft was the source of infection. The recipient received valganciclovir prophylaxis due to cytomegalovirus seropositivity. Three months after transplantation, the recipient presented with rapidly disseminated cutaneous HSV-2 infection with meningoencephalitis. The HSV-2 strain was resistant to acyclovir, probably acquired under valganciclovir prophylaxis. Despite early initiation of acyclovir therapy, the patient died. This fatal case of HSV-2 infection, probably transmitted by the kidney graft with acyclovir-resistant HSV-2 from the onset, is uncommon.

Correction: A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

[This corrects the article DOI: 10.1371/journal.pntd.0009144.].

Tocilizumab Evaluation in HLA-Desensitization before Kidney Transplantation as an Add-On Therapy to Apheresis: The TETRA Study.

BACKGROUND: Desensitization strategies improve access to transplantation in highly sensitized kidney transplant candidates. Tocilizumab could be a valuable addition to more traditional desensitization regimens. We investigated the effect of tocilizumab as an add-on therapy to our standard of care (SoC) desensitization strategy based on rituximab and apheresis. METHODS: In this study, we prospectively included highly sensitized patients to receive monthly tocilizumab infusions for 6 months before our SoC regimen (Toci + SoC group). We compared the reductions in the mean fluorescent intensity (MFI) rebound at post-transplantation and kidney function at 1-year post-transplantation to patients treated by SoC (based on apheresis and two doses of rituximab). RESULTS: Twenty-six patients were included in the SoC group; seven in the Toci + SoC group. Reductions in pre-transplantation MFI were similar between groups. At 1-year post-transplantation, there was no absolute difference in overall MFI rebounds, including donor-specific antibodies. Toci + SoC helped lower the rebound of antibodies with more elevated baseline MFIs. Graft function and survival rates were similar at one-year post-transplantation (median eGFR 62.8 vs. 65.6 mL/min/1.73 m2 for SoC and Toci + SoC, respectively). CONCLUSIONS: Tocilizumab as an add-on to SoC desensitization may help control the post-transplantation rebound of antibodies with elevated baseline MFIs. However, reductions in pre-transplantation MFIs were similar with or without tocilizumab. Further studies are needed to validate this pilot study.

Early Blood Transfusion After Kidney Transplantation Does Not Lead to dnDSA Development: The BloodIm Study.

Outcomes after kidney transplantation are largely driven by the development of de novo donor-specific antibodies (dnDSA), which may be triggered by blood transfusion. In this single-center study, we investigated the link between early blood transfusion and dnDSA development in a mainly anti-thymocyte globulin (ATG)-induced kidney-transplant cohort. We retrospectively included all recipients of a kidney transplant performed between 2004 and 2015, provided they had >3 months graft survival. DSA screening was evaluated with a Luminex assay (Immucor). Early blood transfusion (EBT) was defined as the transfusion of at least one red blood-cell unit over the first 3 months post-transplantation, with an exhaustive report of transfusion. Patients received either anti-thymocyte globulins (ATG) or basiliximab induction, plus tacrolimus and mycophenolic acid maintenance immunosuppression. A total of 1088 patients received a transplant between 2004 and 2015 in our center, of which 981 satisfied our inclusion criteria. EBT was required for 292 patients (29.7%). Most patients received ATG induction (86.1%); the others received basiliximab induction (13.4%). dnDSA-free graft survival (dnDSA-GS) at 1-year post-transplantation was similar between EBT+ (2.4%) and EBT- (3.0%) patients (chi-squared p=0.73). There was no significant association between EBT and dnDSA-GS (univariate Cox's regression, HR=0.88, p=0.556). In multivariate Cox's regression, adjusting for potential confounders (showing a univariate association with dnDSA development), early transfusion remained not associated with dnDSA-GS (HR 0.76, p=0.449). However, dnDSA-GS was associated with pretransplantation HLA sensitization (HR=2.25, p=0.004), hemoglobin >10 g/dL (HR=0.39, p=0.029) and the number of HLA mismatches (HR=1.26, p=0.05). Recipient's age, tacrolimus and mycophenolic-acid exposures, and graft rank were not associated with dnDSA-GS. Early blood transfusion did not induce dnDSAs in our cohort of ATG-induced patients, but low hemoglobin level was associated with dnDSAs-GS. This suggests a protective effect of ATG induction therapy on preventing dnDSA development at an initial stage post-transplantation.

Crossing of the Cystic Barriers of Toxoplasma gondii by the Fluorescent Coumarin Tetra-Cyclopeptide.

FR235222 is a natural tetra-cyclopeptide with a strong inhibition effect on histone deacetylases, effective on mammalian cells as well as on intracellular apicomplexan parasites, such as Toxoplasma gondii, in the tachyzoite and bradyzoite stages. This molecule is characterized by two parts: the zinc-binding group, responsible for the binding to the histone deacetylase, and the cyclic tetrapeptide moiety, which plays a crucial role in cell permeability. Recently, we have shown that the cyclic tetrapeptide coupled with a fluorescent diethyl-amino-coumarin was able to maintain properties of cellular penetration on human cells. Here, we show that this property can be extended to the crossing of the Toxoplasma gondii cystic cell wall and the cell membrane of the parasite in its bradyzoite form, while maintaining a high efficacy as a histone deacetylase inhibitor. The investigation by molecular modeling allows a better understanding of the penetration mechanism.

[Biobanking in a histocompatibility laboratory. Guidelines from the Francophone Society of Histocompatibility and Immunogenetics (SFHI)]. / Critères de conservation des échantillons biologiques dans un laboratoire d'histocompatibilité Les recommandations de la Société francophone d'histocompatibilité et d'immunogénétique (SFHI).

Histocompatibility laboratories perform the biological analyses linked related to organ transplant, hematopoietic stem cells transplant, some immune dysfunction diseases and immuno-allergy after therapeutic treatment. Most of these analyses are prospectively or retrospectively performed on sera and DNA. The Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) has made some recommendations in order to define storage conditions and storage lifetime of the samples required in a histocompatibility laboratory. These recommendations have been drawn up by a working group of ten biologists. They have been established on literature review and data from method validation, which has been already performed within French laboratories (collected through a national questionnaire sent to participant laboratories). The recommendations made by the SFHI for the storage of samples for immunogenetics analyses facilitate the harmonization of practices among histocompatibility laboratories.

[How to deal with an unexpected event that could alter the normal activity of cellular therapy? Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Comment faire face à un événement inattendu pouvant modifier l'activité normale de thérapie cellulaire ? Recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

The SARS-CoV-2 (COVID-19) pandemic has rapidly impacted cell therapy activities across the globe. Not only was this, unexpected event, a threat to patients who had previously received hematopoietic cell transplantation or other cell therapy such as CAR-T cells, but also, it was responsible for a disruption of cell therapy activities due to the danger of the virus and to the lack of solid scientific data on the management of patients and donors. The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) devoted a workshop to issue useful recommendations in such an unexpected event in order to harmonize the actions of all the actors involved in cellular therapy programs so that we can collectively face, in the future, the challenges that could threaten our patients. This work is not specifically dedicated to the SARS-CoV-2 outbreak, but the latter has been used as a concrete example of an unexpected event to build up our recommendations.

Characterization of the novel HLA-C*01:214 allele by sequencing-based typing.

HLA-C*01:214 differs from HLA-C*01:02:01:01 by one nucleotide substitution in codon -10 in exon 1.

Characterization of the novel HLA-A*26:208 allele by sequencing-based typing.

The novel HLA-A*26:208 allele was characterized using two next generation sequencing technologies.

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.

A brain cyst load-associated antigen is a Toxoplasma gondii biomarker for serodetection of persistent parasites and chronic infection.

BACKGROUND: Biomarker discovery remains a major challenge for predictive medicine, in particular, in the context of chronic diseases. This is true for the widespread protozoan Toxoplasma gondii which establishes long-lasting parasitism in metazoans, humans included. This microbe successively unfolds distinct genetic programs that direct the transition from high to low replicative potential inside host cells. As a slow-replicating cell, the T. gondii bradyzoite developmental stage persists enclosed in a cyst compartment within tissues including the nervous system, being held by a sustained immune equilibrium which accounts for the prolonged clinically silent phase of parasitism. Serological surveys indicate that nearly one third of the human population has been exposed to T. gondii and possibly host bradyzoites. Because any disruption of the immune balance drives the reverse transition from bradyzoite to fast replicating tachyzoite and uncontrolled growth of the latter, these people are at risk for life-threatening disease. While serological tests for discriminating recent from past infection are available, there is yet no immunogenic biomarker used in the serological test to allow ascertaining the presence of persistent bradyzoites. RESULTS: Capitalizing on genetically engineered parasites induced to produce mature bradyzoites in vitro, we have identified the BCLA/MAG2 protein being restricted to the bradyzoite and the cyst envelope. Using laboratory mice as relevant T. gondii host models, we demonstrated that BCLA/MAG2 drives the generation of antibodies that recognize bradyzoite and the enveloping cyst structure. We have designed an ELISA assay based on a bacterially produced BCLA recombinant polypeptide, which was validated using a large collection of sera from mice of different genetic backgrounds and infected with bcla+ or bcla-null cystogenic and non-cystogenic T. gondii strains. To refine the design of the ELISA assay, we applied high-resolution BCLA epitope mapping and identified a specific combination of peptides and accordingly set up a selective and sensitive ELISA assay which allowed the detection of anti-BCLA/MAG2 antibodies in the sera of human patients with various forms of toxoplasmosis. CONCLUSIONS: We brought proof of principle that anti-BCLA/MAG2 antibodies serve as specific and sensitive serological markers in the perspective of a combinatorial strategy for detection of persistent T. gondii parasitism.

Characterization of the novel HLA-B*15:514 allele in a French hematopoietic stem cell donor.

The novel HLA-B*15:514 allele was characterized using two next-generation sequencing technologies.

Chronic toxoplasmosis and sleepiness in obstructive sleep apnea: Is there a link?

INTRODUCTION: Sleepiness is the main clinical expression of obstructive sleep apnea (OSA) syndrome resulting from upper airway collapse. Recent studies have discussed the fact that the presence of T. gondii cysts in the brain and the resulting biochemical and immunological mechanisms could be linked to neurobehavioral disorders. The aim of the present study was to explore the potential impact of chronic toxoplasmosis on sleepiness and on obstructive sleep apnea (OSA) severity in OSA obese patients. MATERIALS AND METHODS: A case control study on obese patients screened for OSA was performed. According to the sleep disorder and matched based on gender, age and body mass index (BMI), two groups of obese patients were selected from our sample collection database. All patients were tested for toxoplasmosis serological status measuring anti-Toxoplasma IgG and IgM levels. Univariable and multivariable logistic regression models were performed to assess the impact of chronic toxoplasmosis on sleepiness and OSA severity. RESULTS: 107 obese patients suffering from OSA were included in the study (median age: 53.3 years Interquartile range (IQR): [41.9-59.9]; median BMI: 39.4 kg/m2 IQR: [35.5-44.1], apnea-hypopnea index = 27.5 events/h [10.7-49.9]). Chronic toxoplasmosis was present in 63.4% and 70.7% of patients with or without sleepiness (p = 0.48), respectively and was not associated either to sleepiness (OR: 0.76, 95% CI: [0.52; 2.33], p = 0.64) or OSA severity (OR = 1.75, 95% CI: [0.51; 5.98] p = 0.37). CONCLUSION: Although chronic Toxoplasma infection in immunocompetent humans has been associated to several behavioral disorders or pathologies in recent literature, we demonstrate here that chronic toxoplasmosis is not associated to sleepiness and to sleep apnea syndrome severity in obese patients suspected of sleep apnea syndrome.

First cases of Angiostrongylus cantonensis infection reported in Martinique, 2002-2017.

Neuroangiostrongyliasis is a parasitic disease caused by the accidental ingestion of the nematode Angiostrongylus cantonensis in its larval form. Human infection can lead to eosinophilic meningitis, sometimes complicated by life-threatening radiculomyelitis or encephalitis. Although some cases have been reported from other Caribbean Islands, no cases have been diagnosed in Martinique so far. Here, we report the first eight laboratory-confirmed cases of neuroangiostrongyliasis on the island of Martinique, French West Indies, between 1 January 2002 and 31 December 2017. One case was fatal and five resulted in neurological sequelae. The medical community should consider the risk of A. cantonensis infection in patients living in or returning from Martinique.

TITLE: Premiers cas d'angiostrongylose à Angiostrongylus cantonensis à la Martinique, de 2002 à 2017. ABSTRACT: L'angiostrongylose neuroméningée est une maladie parasitaire causée par l'ingestion accidentelle du nématode Angiostrongylus cantonensis sous sa forme larvaire. L'infection humaine peut conduire à une méningite à éosinophiles, pouvant évoluer en radiculomyélite ou encéphalite menaçant le pronostic vital. Bien que des cas aient été rapportés dans d'autres îles des Caraïbes, aucun cas n'avait été diagnostiqué à la Martinique jusqu'à présent. Dans cet article, nous caractérisons les huit premiers cas d'angiostrongylose neuroméningée biologiquement diagnostiqués à la Martinique, Antilles françaises, entre le 1er janvier 2002 et le 31 décembre 2017. Un cas s'est révélé mortel et cinq ont engendré des séquelles neurologiques. La communauté médicale doit désormais considérer le risque d'infection à A. cantonensis chez les patients vivant ou revenant d'un voyage à la Martinique.

Characterization of the novel HLA-DQB1*03:01:46 variant allele in a French hematopoietic stem cell donor.

HLA-DQB1*03:01:46 differs from HLA-DQB1*03:01:01:01 by one nucleotide substitution at codon 142.3 in exon 3.

Characterization of the novel HLA-DQB1*05:236N null allele in a French hematopoietic stem cell donor.

HLA-DQB1*05:236N differs from HLA-DQB1*05:03:01:01 by one nucleotide substitution at codon 34.1 in exon 2.

Characterization of two novel HLA alleles, C*03:03:58 and DQB1*06:288, in a French hematopoietic stem cell donor.

Two novel HLA alleles were detected using two next generation sequencing technologies.