Dermatological adverse effects of anti-glaucoma eye drops: a review.

Many patients are treated for glaucoma. Like other drugs, anti-glaucoma eye drops may induce dermatological adverse effects. We aim to review the dermatological adverse effects secondary to the active agents in anti-glaucoma eye drops through a literature review. In January 2020, we queried PubMed using the following MeSH terms: glaucoma/drug therapy or glaucoma, open angle/drug therapy cross-referenced with parasympathomimetics/adverse effects or adrenergic agonists/adverse effects or carbonic anhydrase inhibitors/adverse effects or prostaglandins F, synthetic/adverse effects or adrenergic beta antagonists/adverse effects or ophthalmic solutions/adverse effects. The initial search identified 1128 studies, of which 49 were excluded for being in a foreign language, 15 for not involving eye drops, 968 for not focusing on adverse dermatological effects, and 11 for insufficient documentation or redundancy. After adding 38 linked studies, we finally analyzed 123 studies. The ocular and periocular dermatological adverse effects of eye drops are contact dermatitis, hyperpigmentation, prostaglandin analog periorbitopathy, mucous membrane pemphigoid, eyelash depigmentation, skin hypertrichosis, and rare cases of melanoma and skin depigmentation. The reported distant dermatological adverse effects are psoriasis, excessive sweating, lichen planus, alopecia, toxic epidermal necrolysis, erythema multiforme, erythroderma, subacute cutaneous lupus erythematosus, nail pigmentation, and bullous pemphigoid. Most of the cutaneous adverse effects of anti-glaucoma eye drops are ocular and periocular and induced by prostaglandin analogs. Distant adverse effects are rare and sometimes questionable but should be kept in mind, especially mucous membrane pemphigoid, which could lead to blindness. The role of preservatives, such as benzalkonium chloride, should also be considered.

[Eosinophilic pneumonia: A rare complication of sodium divalproate]. / Pneumopathie à éosinophiles : une complication rare du divalproate de sodium.

INTRODUCTION: Eosinophilic pneumonias are characterized by an increase in lung eosinophils. These disorders can be induced by drug reactions. CASE REPORT: A 57-year-old woman suffering from bipolar disorder and treated by sodium divalproate for more than 2 years was hospitalised in the department of respiratory medicine for dyspnoea and cough. The investigations showed severe hypoxaemia, airflow limitation, multiple ground-glass opacities and crazy paving on the chest CT-scan and a blood eosinophilia. A significant alveolar eosinophilia was found in the broncho-alveolar lavage. A complete assessment of possible causes was made. Finally, we made the diagnosis of eosinophilic pneumonia secondary to sodium divalproate. The treatment was stopped and systemic corticosteroid therapy was not introduced. The patient showed an improvement of her dyspnoea in a few days. Lung function and the CT-scan were normal within a few months. CONCLUSIONS: Sodium divalproate, frequently used in the treatment of bipolar disorder, is a rare cause of eosinophilic lung disease, even years after its introduction. Rapid diagnosis and withdrawal of treatment led to complete resolution in the reported case.

[Drug-induced interstitial pneumonitis due to avelumab: A case report]. / Pneumopathie interstitielle médicamenteuse à l'avelumab : à propos d'un cas.

INTRODUCTION: The anti programmed death-1 (PD-1) and the programmed death ligand 1 (PD-L1) antibodies are used as immunotherapies in the treatment of many solid tumours. Cases of interstitial pneumonitis induced by anti PD-1 have been widely described, but there are fewer data with anti PD-L1. Avelumab is a new immunotherapy of the anti PD-L1 class. CASE REPORT: A 66-year-old woman, ex-smoker, had been treated with avelumab and axitinib since November 2016 for renal cell cancer. Interstitial pneumonitis was discovered accidentally 4 months after the beginning of the treatment, with ground glass opacities, intra-lobular crosslinking and adenopathy of the 4R zone on the CT scan. An exhaustive assessment did not reveal any respiratory function defect or an infectious or immunological cause. The radiological abnormalities regressed spontaneously after cessation of treatment confirming the diagnosis of drug-induced pneumonitis. CONCLUSION: Avelumab can induce interstitial lung disease. The mechanism is uncertain and requires further studies. Monitoring of respiratory function and CT scanning are necessary for its early management.

Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012.

BACKGROUND: Perioperative anaphylaxis mainly involves neuromuscular blocking agents (NMBAs) with an IgE-mediated mechanism. In France, this life-threatening condition is reported by anesthetists and allergologists, and two safety alerts concerning suxamethonium were raised in 2011 and 2012. This led to start a national survey over the 2000-2012 period which objectives were to provide a descriptive analysis, to estimate incidence rates, and to analyze the trends over this period. METHODS: The French pharmacovigilance database was retrospectively queried for all the available NMBAs. Anaphylaxis cases with elevated tryptase and positive skin tests were qualified as "confirmed cases." Subgroup analysis compared atracurium and cisatracurium vs suxamethonium and rocuronium. RESULTS: A total of 680 confirmed cases and 944 nonconfirmed cases were identified. Suxamethonium was the most implied NMBA (64%). Incidence rates (according to sales data) of suxamethonium and rocuronium were, respectively, 10- and 13-folds higher than those of the others NMBAs, regardless the confirmed/nonconfirmed status. Cisatracurium incidence rates remained stable over the period, while suxamethonium and atracurium increased and rocuronium first decreased but re-increased after 2006. Male patients were more frequent in the subgroup "atracurium-cisatracurium" (P = .019), whereas obesity and emergency setting were more frequent in the subgroup "rocuronium-suxamethonium." Shared characteristics were the poorly documented previous exposure to NMBA(s) and an insufficient adherence of patients to perform skin tests, showing the need to improve this procedure. CONCLUSION: Suxamethonium and rocuronium are markedly more involved in perioperative anaphylaxis than the other available NMBAs. Patients should be more informed about their perioperative anaphylaxis and its consequences.

Reversible drug-induced antiphospholipid syndrome.

We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antiß2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-ß2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-ß2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks.

[Intracranial hemorrhage and oral anticoagulants of patients treated between 2011 and 2013 at the Nancy Regional University Hospital]. / Hémorragies intracrâniennes et anticoagulantes orales de patients traités entre 2011 à 2013. Étude descriptive au CHRU de Nancy.

OBJECTIVE: To perform a descriptive analysis of intracranial hemorrhages of patients treated with an antivitamin K (fluindione, acenocoumarol or warfarin) or a direct oral anticoagulant (dabigatran, rivaroxaban or apixaban) at the Nancy Regional University Hospital. MATERIAL AND METHOD: The study period was from January 2011 to December 2013 and the computerized data (Programme de Médicalisation des Systèmes d'Information) of our hospital was accessed to identify the patients. Clinical data were obtained from the patients' files. Regional healthcare system was queried for reimbursement data. RESULTS: Among the 157 identified cases of intracranial hemorrhage, 153 were related to antivitamin K, primarily fluindione (n=127), and only 4 to a direct oral anticoagulant (3 dabigatran and 1 rivaroxaban). During the same period, regional data indicated that 65,345 patients had had at least one reimbursement of antivitamin K and 20,983 patients one reimbursement of an oral direct anticoagulant. In our series, the most frequent intracranial hemorrhages were subdural hematoma (chronic in 65 cases, acute in 50 cases) and intraparenchymal hemorrhage (20 cases). The global mortality rate was 20.2% but varied with the site of hemorrhage. In multivariate analysis, the two risk factors of fatal outcome were coma on admission (OR 6.2; 95%CI: 2.6-15.0) and a history of previous intracranial hemorrhage (OR 13,4; 95% CI: 1,6-114,9). CONCLUSION: During the 2011-2013 period, antivitamin K, especially fluindione, was the most frequently involved anticoagulants in intracranial hemorrhages with hospitalization at our Regional University Hospital. Coma on admission and a history of previous intracranial hemorrhage were the two main risk factors for fatal outcome.

[Erysipelas without fever or biologic inflammation during tocilizumab therapy]. / Érysipèle sans fièvre ni syndrome inflammatoire lors d'un traitement par tocilizumab.

BACKGROUND: Tocilizumab (TCZ) is a monoclonal antibody that inhibits the interleukin 6 (IL-6) signalling pathway. This treatment is extremely effective in rheumatoid arthritis (RA), which may well be accompanied by serious infections presenting misleading clinical pictures. Herein we report a case of a typical bacterial dermo-hypodermitis in a female patient treated with TCZ. PATIENTS AND METHODS: An 80-year-old woman treated with methotrexate (MTX) and TCZ for RA presented dermo-hypodermitis on her left leg 8 days after receiving her 13th infusion of TCZ. She exhibited neither fever nor biological inflammatory syndrome. Oral amoxicillin (3g/d) was initiated on an outpatient basis. Two weeks later, the patient was apyretic and her laboratory results were normal, although local inflammatory signs persisted. TCZ infusion was postponed and she was given intravenous amoxicillin (4g/d) for 2days, followed by oral amoxicillin, resulting in rapid recovery. Subsequent courses of TCZ were administered without incident. DISCUSSION: During the course of treatment with TCZ, this patient presented delineated bacterial cellulitis in the form of erysipelas, which was noteworthy on account of the absence of fever and of biological inflammatory syndrome. While there have been reports of severe cases of cellulitis during TCZ treatment, to our knowledge, there have been none of erysipelas. Attenuation of local and systemic inflammatory symptoms is widely reported, and is directly associated with the anti-IL-6 action of TCZ. Patients with RA are especially susceptible to opportunistic or severe infections as a result of the disease itself and of associated treatments, and increased vigilance is called for with regard to infections that may be transformed and potentially more severe as a result of TCZ.

Anaesthetic hypersensitivity reactions in France between 2011 and 2012: the 10th GERAP epidemiologic survey.

BACKGROUND: Immediate hypersensitivity reactions during anaesthesia are rare but potentially life-threatening. The epidemiology changes with time and evolving professional practice, and hence needs to be monitored. Our objective was to follow this epidemiology. METHODS: This was a retrospective, observational study in French hospital clinics, conducted by GERAP members (Groupe d'Étude des Réactions Anaphylactoïdes Périopératoires). Consecutive patients seen in allergo-anaesthesia outpatient clinics, who had experienced a hypersensitivity reaction during anaesthesia between 1 January 2011 and 31 December 2012, were included. Demographic data, allergy history, drugs received before the reaction, symptoms of the reaction, results of blood samples (histamine, tryptase, IgE-specific assays), and results of the allergy assessment were recorded. RESULTS: The most common causes of allergic reactions were (Neuromuscular Blocking Agents) NMBAs (N = 302; 60.6%), antibiotics (N = 91, 18.2%, Cephalosporin N = 49, 10%) and dyes (N = 27; 5.4%). Latex as an allergic agent was involved in 26 cases (5.2%), hypnotics in 11 cases (2.2%) and opioids in seven cases (1.4%). Of the NMBAs, Rocuronium had the highest proportion of reactions (13.8 reactions/100,000 vials sold) followed by Suxamethonium (13.3/100,000 vials sold). Cisatracurium had the lowest proportion of reactions (0.4/100,000 vials sold). Patients were sensitized to two or more NMBAs in 48.9% of cases and without testing, cross-sensitivity cannot be predicted. CONCLUSIONS: When compared with the previous GERAP studies, NMBAs are still the most frequently triggering allergens, with marked differences between individual NMBAs, but they are now followed by antibiotics (of which greater than 50% were cephalosporins) and dyes. Anaesthetists must be aware of the differences between drugs and of the pattern of emerging allergens. For the future of safe anaesthesia, allergy assessment is essential.

Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis.

BACKGROUND: Anaphylactic reactions to neuromuscular blocking agents (NMBAs) can be severe and even fatal. Our aim was to evaluate mortality rate in France from anaphylactic reactions to NMBAs, to identify risk factors for a fatal outcome, and to describe management of the cases that proved fatal. METHODS: The French National Pharmacovigilance Database was queried for reports of NMBA anaphylaxis that occurred between January 2000 and December 2011. A questionnaire was sent to regional pharmacovigilance centers to obtain further information on the management of cases with a fatal outcome. RESULTS: Two thousand and twenty-two cases of NMBA hypersensitivity were retrieved, of which 84 were fatal (4.1%). Among the 1247 cases of severe NMBA anaphylaxis (grades 3 and 4), independent risk factors associated with a fatal outcome in a multivariate analysis were male gender (female gender: OR = 0.4; 95% CI 0.2-0.7; P = 0.0004), an emergency setting (OR = 2.6; 95% CI 1.5-4.6; P = 0.0007), a history of hypertension (OR = 2.5; 95% CI 1.5-4.4; P = 0.0010) or of other cardiovascular disease (OR = 4.4; 95% CI 2.4-8.1; P < 0.0001), obesity (OR = 2.4; 95% CI 1.1-5.3; P = 0.0376), and ongoing beta-blocker treatment (OR = 4.2; 95% CI 1.8-9.8; P = 0.0011). All 31 patients with a fatal outcome received epinephrine in a titrated manner according to international guidelines. CONCLUSION: Obese males with a history of cardiovascular disease receiving ongoing beta-blocker treatment and undergoing surgery in an emergency setting were at high risk of a fatal outcome after NMBA-induced anaphylaxis. Some epinephrine-resistant cases may play a role in our high mortality rate. New therapeutic approaches need to be developed to treat these cases.

Hypersensitivity reactions during anesthesia. Results from the ninth French survey (2005-2007).

BACKGROUND: Hypersensitivity reactions occurring during anesthesia remain a major cause of concern for anesthesiologists. We report the results of the ninth consecutive survey of hypersensitivity reactions observed during anesthesia in France. This report will be used as an epidemiologic reference prior to this intervention. METHODS: Between January 1, 2005 to December 31, 2007, 1253 patients who experienced an immune-mediated (IgE-mediated) or non-immune-mediated (non-IgE-mediated) hypersensitivity reaction were referred to one of the 40 participating centers. Diagnosis was established on the basis of clinical history, skin tests and/or specific IgE assay. RESULTS: An IgE-mediated or non-IgE-mediated reaction was diagnosed in 786 cases (63%) and 467 cases (37%), respectively. The most common causes of anaphylaxis were neuromuscular blocking agents (NMBA) (N.=373, 47.4%), latex (N.=158, 20%), and antibiotics (N.=141, 18.1%). Succinylcholine (N.=226, 60.6%) was the most frequently incriminated NMBA, whereas the low frequency of reactions involving cis-atracurium was confirmed (N.=22, 5.9%) when market shares of each NMBA were taken into account. An increased number of reactions involving vital dyes was recorded (N.=34, 4.4%). CONCLUSION: These changes in the epidemiology of allergic reactions confirm the need for regular epidemiologic surveys of anaphylaxis in the perioperative period.

[Glycopeptide-induced cutaneous adverse reaction: results of an immunoallergic investigation in eight patients]. / Toxidermies aux glycopeptides : résultats des explorations immunoallergologiques dans une série de huit cas.

BACKGROUND: Vancomycin (V) and teicoplanin (T) are glycopeptides used in severe infections and can induce different kinds of cutaneous adverse reactions (CAR). AIMS: To determine the value of immunoallergic investigations in CAR in which glycopeptides are suspected. METHODS: Retrospective study (2000-2007) in eight patients with CAR suspected of being caused by glycopeptides. Six weeks after abatement of the reaction, in accordance with ESCD's guideline for drug testing, immunoallergic skin tests investigations were carried out (drug patch-tests, prick-tests and intradermal tests) in succession for all the drugs taken during the CAR. If negative, a glycopeptide challenge was proposed. RESULTS: The study included eight patients (five women, three men; mean age=53); three patients presented a reaction to vancomycin, four reacted to teicoplanin and one reacted to both drugs. CARs consisted of six maculopapular rashes, one case of DRESS and one of urticaria. Skin tests confirmed involvement of glycopeptides in four of eight cases with cross-reactivity between V and T in two patients. Four patients exhibited good tolerance to rechallenge tests with glycopeptides. CONCLUSIONS: This study shows that skin tests may be useful in glycopeptide-induced CAR in determining the responsible drug and also in the event of rechallenge. Allergic cross-reactivity (V and T), observed in two of our patients, although already been reported in the literature, but does not occur systematically.

[Severe neuropsychiatric disorders in an asthmatic infant who received repeated glucocorticoid treatment: the importance of associated factors]. / Troubles neuropsychiatriques sévères chez un nourrisson asthmatique au décours de cures itératives de corticoïdes oraux : analyse des facteurs favorisants.

Children and adults may experience neuropsychiatric disorders during glucocorticoid treatment, most of which are reversible upon drug withdrawal. Whereas the occurrence of these disorders is well documented in teenagers, only a few cases have been reported in children under 3 years of age. We report on severe neuropsychiatric disorders that occurred in a 27-month-old child during glucocorticoid treatment for asthma that did not regress when treatment was stopped. The psychiatric symptoms suggested autism and were associated with deterioration of the child-mother relationship. This led the medical staff to initiate a dual therapy (conducted by a psychiatrist and a speech therapist) focused on the restoration of the maternal bond. A dramatic improvement in both the child's and the mother's behavior was observed within a few months. Severe psychiatric disorders induced by glucocorticoids can occur in young children and be worsened by environmental factors. The quality of the child-parent relationship should be kept in mind during the management of drug-induced psychiatric disorders.