Annie-Pierre Jonville-Bera

A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock

IntroductionWe aimed to establish whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during evolving bacterial community-acquired infection in adults is associated with severe sepsis or septic shock.MethodsWe conducted a multicentre case-control study in eight intensive care units. Cases were all adult patients admitted for severe sepsis or septic shock due to a bacterial community-acquired infection. Control individuals were patients hospitalized with a mild community-acquired infection. Each case was matched to one control for age, presence of diabetes and site of infection.ResultsThe main outcome measures were the proportions of cases and controls exposed to NSAIDs or aspirin during the period of observation. In all, 152 matched pairs were analyzed. The use of NSAIDs or aspirin during the observation period did not differ between cases and controls (27% versus 28; odds ratio = 0.93, 95% confidence interval [CI] = 0.52 to 1.64). If aspirin was not considered or if a distinction was made between acute and chronic drug treatment, there remained no difference between groups. However, the median time to prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02).ConclusionsIn this study, the use of NSAIDs or aspirin during evolving bacterial infection was frequent and occurred in one-quarter of the patients with such infection. Although the use of NSAIDs by patients with severe sepsis or septic shock did not differ from their use by those with mild infection at the same infected site, we observed a longer median time to prescription of effective antibiotic therapy in NSAID users.

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross‐sectional study

To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimers disease (AD) or other dementia in France.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009–2013 French PharmacoVigilance assessment

BACKGROUND Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS This study suggests different ADR patterns between romiplostim and eltrombopag.

Pharmacovigilance en pédiatrie

Drug safety in children must take into account the frequency of « off label » prescriptions, childrens growth dynamics, and possible long-term consequences (growth, neurodevelopment). The pharmacovigilance methodology is based on spontaneous notification and pharmacoepidemiology studies usually included the in risk management plan. Despite an increased drug risk (pharmacokinetic and pharmacodynamic specificities), drug safety is better in children than in adults. The incidence of drug side effects depends on the country, the type of study (in or out of the hospital), and age. Antibiotics, central nervous, respiratory and dermatologic drug systems are most often involved. The target organs are gastrointestinal and neurologic. In neonates, the most frequent side effects are due to pregnancy exposure to psychotropic drugs, beta-blockers, and antiepileptics. Some studies have shown an increased risk of off-label prescriptions in children. During the last 6 years in France, pediatric alerts (desmopressin, metoclopramide, bronchial mucolytic drugs, first-generation anti-H1, Uvesterol D(®), and Uvesterol A.D.E.C(®), rotavirus vaccines, growth hormone, cisapride) have been less frequent than in adults.

Prescription of drugs contraindicated in children: a national community survey

Many drugs are prescribed off-label, which means outside the terms of the summary of product characteristics (SPC) i.e. indication, dosage, contraindication, etc, in children. Among the numerous studies about off-label use, no data have focused on drug use despite contraindication in children. The aim of this survey was to assess the frequency of prescription despite a contraindication for age in France. Drugs were defined as contraindicated for age if the SPC (as quoted in the French compendium Le Dictionnaire Vidal), indicated clearly that the drug is contraindicated in the age group of the patient receiving the prescription [1]. For each drug contraindicated, the reason given in the SPC for the contraindication for age was classified as “toxic effects described in children”, “insufficient data for use in children”, “unsuitable dosage strength or formulation for the age” or no explanation given. Moreover, to investigate avoidability of a contraindication transgression we searched for an available alternative defined as a product with the same active substance, the same route of administration but in a dosage licensed for children. The study population was children younger than 16 years, affiliated to the French mandatory national health fund (Caisse Nationale d’Assurance Maladie), refunded for prescriptions from office-based practice over 2 months. The use of this database did not need parents’ consent or ethics committee agreement. A total of 276,472 prescriptions including 1,068,705 drugs were refunded for children younger than 16 years. Of these, 11,138 prescriptions (4%) included at least one drug contraindicated for age i.e. 12,333 drugs contraindicated for age (1.2%). This percentage of contraindicated drugs is slightly higher than that found in two other studies (0.9% [7] 0.04% [5]), but the aim of the latter was to assess offlabel use. We found that the rate of prescriptions contraindicated for age increased with age (Table 1), while the frequency of off-label prescription decreased with age in other studies [4, 6]. The lower rates of drugs contraindicated for age in younger children is probably partly due to a greater reluctance on the part of physicians to go beyond contraindication for age in this group. Among 5,911 prescribers, 48.4% prescribed at least one drug contraindicated for age. This rate was highest among general practitioners (78.6%) and paediatricians (74.4%). Therapeutic classes most frequently prescribed that were contraindicated for age were topical and systemic drugs for ear, nose and throat (ENT) symptoms (24.5%), topical Eur J Clin Pharmacol (2007) 63:99–101 DOI 10.1007/s00228-006-0227-7

Lack of association between rifampicin plasma concentration and treatment-related side effects in osteoarticular infections.

The aim of this study was to assess the frequency of gastrointestinal side effects (GSE) and hepatotoxicity in patients treated with rifampicin for an osteoarticular infection and to determine if there is an association between rifampicin plasma concentrations and side effects. Rifampicin plasma concentrations were prospectively measured before (trough concentration, C0) and 2 ± 0.5 h (peak concentration, C2) after drug intake. The presence of GSE, the alanine transferase (ALT) value, and concomitantly administered medications were recorded on the day rifampicin concentrations were measured. C0 and C2 were compared for differences regarding the presence or absence of side effects. Multivariate analysis was performed, with associated medications being taken into account. Seventy C0 and 57 C2 values were measured in 46 adults after a median treatment of 8 days (range, 1–179). Wide inter‐individual variability was observed for C0 and C2. Thirteen (28%) patients reported GSE at least once. When GSE occurred, C0 (median, 1 mg L−1; range, 0.1–9.9 mg L−1) and C2 (median, 10.3 mg L−1; range, 1.8–40.3 mg L−1) were similar to C0 (median, 0.6 mg L−1; range, 0.1–10.3 mg L−1) and C2 (median, 10.9 mg L−1; range, 2.9–29.0 mg L−1) without GSE. The ALT value was more than normal in only three patients (6.5%) after rifampicin treatment began. The patients received no different associated medications whether or not GSE were present. Multivariate analysis showed no association between rifampicin plasma concentrations and GSE. GSE occur frequently in patients receiving rifampicin for osteoarticular infection but without an association with rifampicin plasma concentrations. Thus, therapeutic drug monitoring of rifampicin is irrelevant in the management of GSE.

Periprandial administration of inhaled iloprost: a risk factor for digestive bleeding?

The role of inhaled iloprost should be suspected in cases of gastro-intestinal haemorrhage in patients suffering from pulmonary hypertension (PH) receiving this treatment, and the way the drug is administered should possibly be changed. Clinical, functional and haemodynamic deterioration of systemic scleroderma-PH in a 73-year-old Caucasian woman without any other past medical history, led to the introduction of aerosolized iloprost 5 µg six times a day in addition to her existing treatment of sitaxentan 100 mg once daily, sildenafil 20 mg three times daily, furosemide 40 mg once daily, bromazepam 6 mg one to two times daily, calcium 1000 mg once daily, cholecalciferol 880 IU once daily, monosodic alendronate 70 mg weekly, fluindione 20 mg once daily with an international normalized ratio (INR) maintained between 2 and 3. In the past, she had had occasional melaena, once a month, generally the day following alendronate ingestion. Two months after beginning aerosolized iloprost, the frequency of her melaena increased, becoming continuous, after each aerosolization (INR = 2.18). An oesogastroduodenal endoscopy revealed digestive angiomatosis, and the hypothesis that iloprost could play a role in causing this lesion to bleed was raised. As reassessment of pulmonary hypertension suggested the benefit of inhaled iloprost, it was decided to reduce the regimen to five aerosols a day, avoiding the first post-prandial hour. The frequency of melaena decreased and abdominal meteorism stopped completely. Reducing the dose of aerosols did not have any effect on the PH at the next reassessment. In a 79-year-old Caucasian man with a past medical history of ischaemic cardiomyopathy, inhaled iloprost aerosol 5 µg six times a day was initiated following deterioration of a PH secondary to a chronic obstructive pulmonary disease, in association with previous treatment with sildenafil 20 mg three times daily, bosentan 125 mg two times daily, fluindione 20 mg once daily (INR between 2 and 3 throughout follow-up), furosemide 40 mg once daily, amiodarone 200 mg once daily, pravastatin 40 mg once daily, ramipril 5 mg once daily, clopidogrel 75 mg once daily, tiotropium bromide 1 inhalation day−1, molsidomine 2 mg three times daily and potassium chloride 600 mg day−1. One month earlier, anaemia with iron deficiency had been diagnosed and treated by blood transfusion and ferrous sulphate supplements (80 mg two times daily). Oesogastroduodenal endoscopy had revealed millimetric bleeding angiodysplasias in the duodenal cap, which had been treated by argon plasma coagulation. Four months after beginning inhaled iloprost, haemoglobinaemia was 85 g l−1 with iterative digestive haemorrhages requiring several blood transfusions, despite ongoing ferrous supplementation. A colonoscopy found a 3 mm caecal angiodysplasia and two colic polyps requiring argon plasma coagulation therapy and polypectomy. In spite of this digestive procedure, gastro-intestinal haemorrhage continued and consequently clopidogrel was stopped and iloprost reduced to 5 aerosols a day, avoiding the immediate post-prandial period. There was no recurrence of digestive bleeding and haemoglobin stabilized. At the next reassessment, there had been no worsening of PH. These two cases suggest a possible link between digestive haemorrhage and iloprost aerosols. There was a temporal relationship between inhalation of iloprost and the onset or worsening of bleeding, and between the reduced dose of iloprost inhalation and improvement of bleeding symptoms. The digestive haemorrhage did not recur after the iloprost dosage was reduced and inhalation was avoided after meals. The role of fluindione can be excluded because the INR did not increase and because bleeding symptoms improved despite the continuation of fluindione treatment. In the second patient, stopping clopidogrel may have had a beneficial effect on gastro-intestinal haemorrhage, but the symptoms worsened when iloprost was started, requiring blood transfusion. The role of other drugs can be ruled out as bleeding symptoms improved despite the continuation of these drugs. Neither of these patients had any history of liver disease. The evidence for the effect of inhaled iloprost on digestive bleeding is strong and possibly multifactorial. Iloprost is an analogue of epoprostenol. Besides its vasodilatory effect, it inhibits platelet function in a dose-related manner and platelet aggregability returns to baseline levels after the end of the infusion [1]. Because its absolute bioavailability is approximately 80% [2], inhaled iloprost may induce sufficiently high serum concentrations to produce adverse systemic effects. Splanchnic blood flow increases after iloprost administration [3], which could promote the bleeding of an angioma. This pharmacodynamic effect could also explain why bleeding symptoms improved when iloprost was no longer inhaled close to meals. It is possible that part of the aerosolized iloprost is swallowed rather than truly inhaled and could have a direct action on the digestive cell wall. Prostaglandins inhibit secretion of histamine and pancreastatin by enterochromaffin-like cells of the gastric epithelium and therefore decrease gastric acidity, making the hypothesis that digestive haemorrhage is related to gastro-duodenal ulcers highly improbable [4]. In conclusion, these observations suggest that patients with a risk of digestive bleeding should avoid inhaled aerosols during peri-prandial periods as far as possible, and that patients with a history of digestive bleeding should be monitored clinically and biologically during the months following the introduction of inhaled iloprost.

Chronic spontaneous urticaria in children - a systematic review on interventions and comorbidities

Chronic spontaneous urticaria (CSU) is not frequent in children. Management guidelines have been developed for adults and randomized controlled trials (RCTs) included teenagers aged 12‐18, but data for children under age 12 are limited. We performed a systematic review to assess comorbidities in children <12 years old with CSU and the efficacy and safety of treatments.

Interstitial Nephritis Secondary to Vedolizumab Treatment in Crohn Disease and Safe Rechallenge Using Steroids: A Case Report

Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the α4 β7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year-old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report.

Lettre à la RédactionPhotoallergie au gel depiroxicam :quefaut-il contre-indiquer ?Photoallergy to Piroxicam: What Should be Contraindicates?

Les anti-inflammatoires non stéroïdiens (AINS) par voie topique permettent de limiter le risque d’effet indésirable systémique, en particulier digestif et rénal, mais ils exposent le patient à un risque d’effet indésirable cutané, parmi lequel figure le risque d’éruption photo-induite.[1] Si cette complication est très largement rapportée avec le kétoprofène par voie cutanée,[2] les cas sont moins nombreux avec les autres AINS, en particulier avec le piroxicam. Ainsi, la conduite à tenir vis-à-vis du risque de réaction croisée et les contre indications spécifiques aux photosensibilités induites par cet AINS sont moins bien connues des professionnels de santé. Nous rapportons un cas d’éruption photo-induite compliquée d’eczéma d’évolution prolongée au décours de l’application cutanée de piroxicam (Geldène®) en précisant les conseils qui doivent être donnés au patient lorsque cet AINS est en cause.