Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database.

Phosphorus is an essential element for all living organisms and is involved in various biological pathways. A severe hypophosphatemia can lead to serious complications (acute heart or respiratory failure, rhabdomyolysis, hemolysis…) and increases mortality in patients at risk. Various drugs are known to induce hypophosphatemia through various mechanisms. The aim of this study was to highlight the main drugs associated with hypophosphatemia and to deduce the underlying mechanisms based on a descriptive analysis and a case/non-case analysis using the cases of drug-induced hypophosphatemia reported to the French Pharmacovigilance Network. A total of 368 cases of hypophosphatemia were included in the study. Patients' mean age was 52±18 years. One hundred and ninety-one cases (52%) were serious including 131 (36%) hospitalizations. The median value of serum phosphorus level was 0.54mmol/L [0.40-0.66] (n=309). Those 368 cases corresponded to 185 different suspected substances among which the most frequent drugs were tenofovir disoproxil (n=175; 48%), ferric carboxymaltose (n=29; 8%), denosumab (n=16; 4%), zoledronic acid (n=14; 4%) and hydrochlorothiazide (n=10; 3%). For these five drugs, a significant disproportionality was found. Tenofovir-disoproxil related hypophosphatemia occurred more than one year after its introduction, and a renal tubulopathy (Fanconi's syndrome) was reported in 44 cases (25%). Hypophosphatemia related to iron carboxymaltose occurred within a median of 20 days after injection and was mostly severe. Mechanism included the fibroblast growth factor 23 which can be measured to confirm drug origin. Concerning anti-osteoporosis treatments, hypophosphatemia could be explained by their mechanism of action (abrupt increase of parathormone induced by hypocalcemia) but the patient history (malignancy condition) was a major bias. For hydrochlorothiazide, hyphosphatemia was often moderate, associated with other electrolytic disturbances and occurred during a long-term treatment. Awareness of healthcare professionals is essential to detect as soon as possible hypophosphatemia and its complications related to these drugs.

Comprehensive description of adult-onset Still's disease after COVID-19 vaccination.

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management.

[Red yeast-rice-induced muscular injuries: Analysis of French pharmacovigilance database and literature review]. / Atteintes musculaires et levure de riz rouge : analyse des données de la base nationale de pharmacovigilance et revue de la littérature.

Red yeast rice (RYR) is a dietary supplement containing monacolins obtained by fermentation of Monascus purpureus strains. Because of its structural homology with lovastatin, monacolin K inhibits HMG-CoA reductase and shows hypocholesterolemic properties comparable to synthetic statins. We studied all cases of myopathy involving RYR reported in the French national pharmacovigilance database (6 cases) and in scientific literature (9 cases). Among these cases, 9 showed elevated creatine kinase, 3 rhabdomyolysis and 2 myalgia. Recent studies seem to show good efficacy of the RYR, however, our work reports the existence of related muscular disorders. In addition, dietary supplements currently available on the market may show considerable variability of formulation and/or the presence of contaminants. When clinicobiological disorders occur, physicians should consider the eventual use of an herbal treatment.

Fatal accidental lipid overdose with intravenous composite lipid emulsion in a premature newborn: a case report.

BACKGROUND: Tenfold or more overdose of a drug or preparation is a dreadful adverse event in neonatology, often due to an error in programming the infusion pump flow rate. Lipid overdose is exceptional in this context and has never been reported during the administration of a composite intravenous lipid emulsion (ILE). CASE PRESENTATION: Twenty-four hours after birth, a 30 weeks' gestation infant with a birthweight of 930 g inadvertently received 28 ml of a composite ILE over 4 h. The ILE contained 50% medium-chain triglycerides and 50% soybean oil, corresponding to 6 g/kg of lipids (25 mg/kg/min). The patient developed acute respiratory distress with echocardiographic markers of pulmonary hypertension and was treated with inhaled nitric oxide and high-frequency oscillatory ventilation. Serum triglyceride level peaked at 51.4 g/L, 17 h after the lipid overload. Triple-volume exchange transfusion was performed twice, decreasing the triglyceride concentration to < 10 g/L. The infant's condition remained critical, with persistent bleeding and shock despite supportive treatment and peritoneal dialysis. Death occurred 69 h after the overdose in a context of refractory lactic acidosis. CONCLUSIONS: Massive ILE overdose is life-threatening in the early neonatal period, particularly in premature and hypotrophic infants. This case highlights the vigilance required when ILEs are administered separately from other parenteral intakes. Exchange transfusion should be considered at the first signs of clinical or biological worsening to avoid progression to multiple organ failure.

Babesia divergens glycosylphosphatidylinositols modulate blood coagulation and induce Th2-biased cytokine profiles in antigen presenting cells.

Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs.

Adverse reactions related to brentuximab vedotin use: A real-life retrospective study.

Post-marketing data regarding brentuximab vedotin (BV) are sparse. The aim of this study was to assess the frequency and nature of significant adverse drug reactions (ADRs) in patients treated with BV in a real-world setting. We conducted a systematic retrospective study of patients treated with BV in a French university hospital. Significant ADRs were collected using the electronic patient records. Between January 2009 and December 2016, 39 patients received BV. Median age was 43.2 and 53.8% were males. Overall, 20 patients (51.3%) experienced at least one significant ADR and 24 reactions were reported in total. Twelve (50%) out of 24 ADRs were severe. The most frequently observed significant ADRs were peripheral sensory neuropathy and CMV reactivation. ADRs led to drug discontinuation for 4 patients and dose reduction for 6 patients. Only 29.2% of the events were spontaneously reported. Prospective monitoring is needed to better assess BV safety.

A targeted immunomic approach identifies diagnostic antigens in the human pathogen Babesia microti.

BACKGROUND: Babesia microti is a protozoan parasite responsible for the majority of reported cases of human babesiosis and a major risk to the blood supply. Laboratory screening of blood donors may help prevent transfusion-transmitted babesiosis but there is no Food and Drug Administration-approved screening method yet available. Development of a sensitive, specific, and highly automated B. microti antibody assay for diagnosis of acute babesiosis and blood screening could have an important impact on decreasing the health burden of B. microti infection. STUDY DESIGN AND METHODS: Herein, we take advantage of recent advances in B. microti genomic analyses, field surveys of the reservoir host, and human studies in endemic areas to apply a targeted immunomic approach to the discovery of B. microti antigens that serve as signatures of active or past babesiosis infections. Of 19 glycosylphosphatidylinositol (GPI)-anchored protein candidates (BmGPI1-19) identified in the B. microti proteome, 17 were successfully expressed, printed on a microarray chip, and used to screen sera from uninfected and B. microti-infected mice and humans to determine immune responses that are associated with active and past infection. RESULTS: Antibody responses to various B. microti BmGPI antigens were detected and BmGPI12 was identified as the best biomarker of infection that provided high sensitivity and specificity when used in a microarray antibody assay. CONCLUSION: BmGPI12 alone or in combination with other BmGPI proteins is a promising candidate biomarker for detection of B. microti antibodies that might be useful in blood screening to prevent transfusion-transmitted babesiosis.