Exposure to ammonia solution due to substance use: a retrospective study from the French poison centres database (2009-2018).

INTRODUCTION: Ammonia solution (ammonium hydroxide) is used to convert cocaine hydrochloride to freebase cocaine. Due to its causticity, unintentional exposure to ammonia in a substance use context can result in injury. The objective of this study was to describe the characteristics of unintentional oral and buccal ammonia solution exposure in a substance use context. METHODS: A retrospective study was conducted using the French poison centres database over a 10-year period (2009-2018). RESULTS: A total of 1,546 files were extracted, and 263 substance users were included. There was a significant increase in the number of these exposures between 2009 and 2018. Unintentional ingestion of ammonia solution was linked to product decanting in 89 per cent of cases. Substance use prior to the exposure and a festive context, such as free parties or teknivals, were identified in 25 per cent and 21 per cent of cases, respectively. Patients received a hospital examination in 87 per cent of cases. The severity of intoxication in substance users was graded as moderate (33 per cent) or severe (15 per cent) using the Poisoning Severity Score. DISCUSSION: The increased number of ammonia solution cases reported was consistent with an increase in the number of crack users in Europe in the same period. Ammonia solution exposure can suggest the possibility of substance use disorders. In such cases, patients can be referred to receive appropriate treatment and support. This study had some limitations, such as the lack of available information due to the retrospective nature of the study and the non-standardized questions asked by the poison centre during the medical phone interviews. CONCLUSION: Oral and buccal ammonia solution exposure in known substance users in France increased between 2009 and 2018. These users were mostly young men. A festive context and decanting were frequent. Patients were mainly referred to emergency departments to receive clinical examination and care. The potential severity of oral or buccal ammonia solution exposure in substance users requires increased vigilance among all healthcare professionals involved in the management of these intoxication cases.

Application to several suspected poisoning cases of a validated analytical method for the determination of muscarine in human biological matrices using liquid chromatography with high-resolution mass spectrometry detection.

Despite prevention efforts, many cases of mushroom poisoning are reported around the world every year. Among the different toxins implicated in these poisonings, muscarine may induce parasympathetic neurological damage. Muscarine poisonings are poorly reported in the current literature, implying a lack of available data on muscarine concentrations in human matrices. A validated liquid chromatography with high-resolution mass spectrometry detection (Orbitrap technology) method was developed to determine muscarine concentrations in human urine, plasma, and whole blood samples. Muscarine was determined using 100 µL of biological fluids, and precipitation was used for sample preparation. Liquid chromatography-mass spectrometry was performed using an Accucore Phenyl-X analytical column with the electrospray source in positive ion mode. Muscarine was quantitated in parallel reaction monitoring (PRM) mode with D9-muscarine as the internal standard. The method was validated successfully over the concentration range 0.1-100 µg/L for plasma and whole blood and 1-100 µg/L for urine, with acceptable precision and accuracy (<13.5%), including the lower limit of quantification. Ten real cases of suspected muscarine poisoning were successfully confirmed with this validated method. Muscarine concentrations in these cases ranged from 0.12 to 14 µg/L in whole blood,

Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database.

PURPOSE: To characterize clinical profile of pediatric local anesthetic (LA) systemic toxicity (LAST) and to identify determinants of life-threatening outcomes. METHODS: Spontaneous reports notified to the French Pharmacovigilance Network were retrieved and followed by a case-by-case review, according to the following criteria: LA as suspected drug, age < 18 years, adverse drug reactions related to nervous system, cardiac, respiratory, psychiatric or general disorders. Multivariate logistic regression analysis was performed to identify factors leading to life-threatening reaction (i.e. continuous seizures or cardiorespiratory arrest). RESULTS: Among 512 cases retrieved, 64 LAST cases were included (neonates 11%, infants 30%, children 36%, adolescents 23%) mainly involving lidocaine (47%), lidocaine + prilocaine (22%) and ropivacaine (14%). Toxicity profiles were neurological (58%), cardiac (11%) or mixed (20%) and 7 patients (11%) developed methemoglobinemia. LAST was life-threatening for 23 patients (36%) and 2 patients died. Doses were above recommendations in 26 patients (41%) and were not different between life-threatening and non-life-threatening cases. The context of use (general and orthopedic surgery, p = 0.006) and the type of LA agent (lidocaine, p = 0.016) were independently associated with a life-threatening outcome. CONCLUSION: In this national retrospective analysis, LAST in children appear to be a rare event. Neurological and cardiac signs were the most frequently reported reactions. LAST in children can be life-threatening, even at therapeutic doses. Although a fatal outcome may anecdotally occur, the vast majority of patients recovered after appropriate medical care.

Determination of Orellanine in Human Biological Matrices Using Liquid Chromatography with High-Resolution Mass Spectrometry Detection: A Validated Method Applied to Suspected Poisoning Cases.

Consumption of mushrooms can become unsafe for the consumer in case of confusion. Some fungi of Cortinarius genus contain the nephrotoxic mycotoxin orellanine responsible for their toxicity. Related case poisoning diagnosis is a challenge for both clinicians and analysts because of a long latency period between intake and toxic syndrome, the lack of available information in literature and the numerous pitfalls of orellanine identification/quantification in biological samples. In this situation, we propose an analytical method designed for the orellanine detection and/or quantification in biological matrices such as plasma, urine and whole blood, in a context of related intoxication suspected case. Using 1 mL biological sample volume, this liquid chromatographic with high-resolution mass spectrometry detection method (i) exhibits a limit of quantification for orellanine of 0.5 µg/L in plasma and urine and (ii) enables orellanine detection in whole blood with a limit of detection of 0.5 µg/L. This validated analytical method was successfully applied to 10 suspected intoxication cases.

Poison control centres and alternative forms of communication: comparison of response rates between text message and telephone follow-up.

INTRODUCTION: In recent years, the number of patients managed by poison control centres (PCCs) has increased without a proportional increase in the number of physicians. To improve efficiency without neglecting patient follow-up, some PCCs have begun using text messages. We evaluated the difference in response rates between text messaging and traditional telephone follow-up. MATERIALS AND METHODS: This retrospective, monocentric, non-randomised cohort study was conducted using data from calls made by the New Aquitaine PCC between February 27, 2019, and March 31, 2019. Patients were contacted up to three times by a phone call or short message service (SMS). RESULTS: For the analysis, 823 patients were included. At the end of follow-up, the response rates were similar in the phone call and SMS group (94 vs. 94%; p = 0.76) with median [interquartile range] response times of 0 min [0; 27 min] and 29 min [6; 120 min], respectively. The response rates did not differ in subgroups stratified according to sex, self-poisoning vs. relative response, age class, and solicitation during working hours vs. outside of working hours (all p > 0.5). Moreover, health practitioners required 2.4-fold more time to call than to send text messages (p < 0.001), and all practitioners were satisfied or very satisfied with text messaging implementation. CONCLUSION: Patients had good adherence to text messages. Text messages are easy to use, rapid, and allow the physician to easily prioritise follow-up without occupying the emergency line. Additionally, the costs of installation and maintenance are low for text message systems; these low costs facilitate the implementation of such services in various medical situations.

Human poisonings by neurotoxic phycotoxins related to the consumption of shellfish: study of cases registered by the French Poison Control Centres from 2012 to 2019.

CONTEXT: In June 2019, a paralytic shellfish poisoning (PSP) case related to the consumption of mussels contaminated by saxitoxins at a concentration below the regulatory threshold came to the attention of the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). This pointed to probable undetected human cases of poisoning by neurotoxic phycotoxins. METHODS: We conducted a retrospective study of poisoning cases by bivalve shellfish (oysters, mussels and scallops) recorded by the French Poison Control Centres (PCC) from 2012 to 2019. All medical records were reviewed by a toxicologist.Cases that could be related to neurotoxic phycotoxins were selected and described. Diagnosis was based on symptoms compatible with ingestion of contaminated shellfish and on contamination data for the shellfish production area (analysed by the French Research Institute for Exploitation of the Sea, Ifremer), or notifications to the European Rapid Alert System for Food and Feed when the origin of the shellfish was known. RESULTS: Among the 619 shellfish poisoning cases recorded by the PCCs from 2012 to 2019, 22% (n = 134) had reported at least one neurological symptom (headache, dizziness or paraesthesia). Review of medical records for the 134 patients led to suspicion of 14 cases of PSP and one case of amnesic shellfish poisoning. Five patients experienced persistent neurological symptoms. Marine toxins were not tested for in the blood or urine of these patients. CONCLUSION: This retrospective identification of cases strongly suspected of being related to neurotoxic phycotoxins led ANSES, PCCs and Ifremer to develop a specific questionnaire and to recommend actions to take when neurological symptoms related to shellfish consumption are reported to a PCC. Daily monitoring of shellfish poisoning cases registered in the national PCCs database was also implemented in order to rapidly detect any suspicious cases, alert the competent authorities, and warn the general population.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children.

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

Bowel obstruction following ingestion of superabsorbent polymers beads: literature review.

RATIONALE: Superabsorbent polymers are marketed as toys, and cases of ingestion in children are increasingly reported. Even if these cases are usually considered benign, bowel obstruction has been reported. OBJECTIVE: To investigate the exposure characteristics, clinical presentation, management, and outcome of patients who developed bowel obstruction following ingestion of superabsorbent polymer-made products. METHODS: Databases were searched (no start date - 2020/01/31) using the following keywords: ("superabsorbent" OR "polymer" OR "hydrogel" OR "crystal" OR "jelly" OR "Orbeez" OR "beads") AND ("ingestion" OR "obstruction" OR "perforation") AND ("intestinal" OR "bowel"). All cases of bowel obstruction following superabsorbent polymer-made product ingestion were included. RESULTS: Report selection: We found 25 reports reporting 43 cases of bowel obstruction following superabsorbent polymer-made product ingestion. All the reports were retrospective, including 20 case reports and 4 case series. Patient characteristics and clinical presentation: Age ranged from 6 to 36 months, and the female/male sex ratio was 1.3. The median delay between the ingestion of the product and the onset of the first symptoms (available in only four reports) was 1.0 [0.7;1.8] day (from 15 h to 2 days). The median delay between the onset of gastrointestinal symptoms and hospital admission, available for all but 15 patients, was 3 [2;4] days (from 15 h to 30 days). The reported symptoms were persistent vomiting in all cases, associated with constipation (11/43), diarrhea (1/43), abdominal pain (1/43), and clinically assessed dehydration (14/43). Abdominal palpation found abdominal tenderness or distension in 11/43 and 28/43 patients, respectively. An abdominal mass was palpated in 3/43 patients. Two patients presented with fever, and three patients developed seizures. Characteristics of exposure: Ingestion of superabsorbent polymer-made products was reported by relatives on hospital admission in only 10/43 cases. Based on imaging and/or surgically/endoscopically removed products, all were bead-shaped objects. The median number of beads removed (available in 27/43) was 1 [1-2] (range from 1 to 6). Their median diameter (available in 21/43 patients) at the time of the diagnosis of bowel obstruction - i.e., at hydrated state - was 30 [30;36] mm (range from 25 to 65 mm). Imaging findings: Abdominal radiography, performed in 31/43 patients, never showed evidence of foreign body ingestion Abdominal computed tomography scanning, performed in 10/43 patients, visualized an intraluminal mass in 5/10 cases. Abdominal ultrasound performed in 34/43 patients allowed visualization of a rounded intraluminal image that corresponded to a bead in 28/34 patients but led to a correct diagnosis of foreign body-induced bowel obstruction in only 15/34 cases. One case reported the contributory use of abdominal MRI. Beads were always located in the small bowel (from the duodenum to the terminal ileum). Removal of beads: Bead removal required endoscopy in 2/43 cases and surgery in 41/43 cases (enterotomy or resection in 36/43 and 5/43 cases, respectively). In 3/36 cases, additional enterotomy was performed to remove beads that had not been found during the first surgery. The delay between the onset of gastrointestinal symptoms and removal procedures ranged from 1 to 7 days. Outcome: Except for two fatal cases, the outcome was favorable. CONCLUSIONS: Ingestion of superabsorbent polymer-made beads can be responsible for fatal bowel obstruction in children related to the increase in bead size within the intestinal tract. Diagnosis is made difficult by the radiolucent properties of the beads. The management of bowel obstruction probably most often requires endoscopic or surgical procedures. Children under 4 years of age are probably the most at risk of developing bowel obstruction.

Poisoning during the COVID-19 outbreak and lockdown: retrospective analysis of exposures reported to French poison control centres.

INTRODUCTION: The aim was to assess the impact of the COVID-19 pandemic on French Poison Control Centre (PCC) call characteristics. METHODS: Reported cases of xenobiotic exposures from 1 March to 30 April in 2018, 2019, and 2020 were extracted from the French National Database of Poisonings. The collected data included call, patient, and exposure characteristics for both general calls and for calls involving sentinel xenobiotic categories related to the COVID-19 pandemic. The 2020 exposures were compared to 2018-2019 exposures by using simple logistic models in order to provide effect size with odds ratios. RESULTS: From March to April 2020, 32,182 exposures were reported to French PCCs with an overall increase of 5.6% compared to exposures in the same time frame in 2018-2019. A similar increase in calls was observed in non-epidemic and epidemic COVID-19 areas with an increase in calls from the public (+13.6%) while calls from health-professionals decreased (-7.5%). Despite the increase in exposures, the incidence of symptomatic exposures remained stable (-0.4%) with a decrease in severity (moderate/severe -17.2%). A significant increase in exposures to home cleaning products containing biocides, essential oils, and alcohol-based hand sanitizers (odds ratio >1.3, p < .0001) was observed. DISCUSSION AND CONCLUSION: The COVID-19 pandemic altered calls to French PCCs with a small increase in calls during the study period and changes in the pattern of exposure. These changes possibly reflected the indirect consequences of the COVID-19 pandemic i.e., limited access to primary care, fear of contracting COVID-19 and anxiety related to home isolation.

Relationship between adverse drug reactions and unlicensed/off-label drug use in hospitalized children (EREMI): A study protocol.

INTRODUCTION: To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. METHODS: In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients' electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. STRENGTH AND LIMITATIONS OF THIS STUDY: For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

Ciguatera fish poisoning in France: experience of the French Poison Control Centre Network from 2012 to 2019.

INTRODUCTION: Ciguatera fish poisoning (CFP) is a common Poisoning in the tropical countries. France is directly concerned with French tourists in endemic area and with French citizens living in the French overseas territories. METHOD: Retrospective, descriptive study of CFP cases handled by the French Poison Control Centre Network from 2012 through 2019. RESULTS: Fifty-two events were studied concerning 130 patients. The fish species was identified for 41 events, mainly belonging to five fish families: 14 groupers, 11 snappers, 5 jacks, 4 parrotfishes, 4 barracudas. The origin of the fish was the Atlantic Ocean (23 events), the Indian Ocean (17 events) and the Pacific Ocean (12 events). 91% of the poisonings occurring in the Atlantic Ocean began with gastrointestinal effects while in 44% of events occurring in the Pacific Ocean, the patients had no gastrointestinal effects (onset with neurological symptoms: paraesthesia and dysesthesia). The evolution of the 130 patients has been classic for CFP with persistent symptoms during 1 to 45 weeks. Numerous patients reported exacerbation of neurological signs several months after poisoning following consumption of alcoholic beverages (23 patients) or seafood (19 patients). DISCUSSION: Medical practitioners in Europe must be trained to manage CFP as cases are reported with tourists returning from endemic areas but also with poisoned patients far from tropical areas after consumption of imported fish.

Snake bites by European vipers in Mainland France in 2017-2018: comparison of two antivenoms Viperfav® and Viperatab®.

Context: Today, immunotherapy with Fab or F(ab')2 fragments is considered as a gold standard treatment for patients bitten by vipers. We compared the efficiency of two antivenoms, Viperfav® and Viperatab®, in mainland France in 2017-2018 with data provided by the French poison control centre (PCC).Methods: Patients with a moderate (2a and 2b) or severe (3) envenomation after a European viper bite and treated with immunotherapy were included and the markers chosen were the risk of post-antivenom treatment worsening, duration of hospital stay and persistent functional discomfort on day 15. Statistical studies were based on multivariate data analysis.Results: Two hundred and ninety-seven cases were recorded. One hundred and eighty-two (61.3%) patients received Viperfav® and 115 (38.7%) received Viperatab®. Compared to Viperfav®, use of Viperatab® significantly increased the risk of post-antivenom treatment worsening (OR* 12.05; 95%CI [3.11; 46.70]; p < .001). No significant difference between these antivenoms was recorded with respect to the duration of hospital stay and persistent functional discomfort on day 15. Viperfav® and Viperatab® have a similar tolerance (p > .21). Otherwise, duration of hospitalisation was significantly increased by a delay of immunotherapy infusion of more than 12 h (OR 2.70; 95%CI [1.45-5.06]; p = .002) or a preventive administration of LMWH (OR 6.55; 95%CI [1.58-27.13]; p=.02).Discussion: While Viperfav® and Viperatab® have a similar tolerance, our data show that Viperatab® was associated with a higher risk of post-antivenom treatment worsening compared to Viperfav®. Furthermore, this study confirms that the antivenom should be used as soon as possible. Indeed, patients receiving the immunotherapy infusion from the grade 2b presented significantly more frequent exacerbated symptoms (OR 3.99; 95%CI [1.16-13.73]; p=.028) after the antivenom infusion compared to grade 2a group.Conclusions: Whereas no significant difference between these antivenoms was recorded with respect to the duration of hospital stay and persistent functional discomfort on day 15, use of Viperatab®, compared to Viperfav®, significantly increased the risk of post-antivenom treatment worsening (OR* 12.05; 95%CI [3.11; 46.70]; p < .001). Taken together, these data show that Viperfav® is the treatment of choice for the management of snake bites in France.

[Medication errors in Auvergne-Rhône-Alpes: A prospective pilot study led in collaboration by regional vigilance and support structures]. / Erreurs médicamenteuses en Auvergne Rhône-Alpes : étude pilote descriptive collaborative entre structures régionales de vigilance et d'appui (SRVA).

Medication errors (ME) are frequently encountered and present at every step of the therapeutic process. This study's aims were to take stock of the ME reported to the region's pharmacovigilance (CRPV) and poison control centers (CAPTV) and to identify potential regional actions. A 2-months (January and February 2017) prospective gathering of the calls to the CAPTV regarding the ME and of the ME declarations to the region's CRPV (Clermont-Ferrand, Grenoble, Lyon, Saint-Etienne) has been carried out. The place of occurrence, the event's description and its consequences and data regarding the patient were collected. In addition to that, the regional drug observatory OMEDIT analysis has allowed to determine the ME's types (REMED characterization, never event?) and to look for the results of a potential thorough analysis. The study reported 580 calls for 590 ME and 583 patients. ME mostly affected the ambulatory/domicile sector (76%), the medico-social sector (14%) and the healthcare facilities sector (7%). It usually was about dose errors, medication errors and patient errors with a different profile in each sector. The majority of errors (85%) occurred at the administration step. Almost all the observed ME were confirmed errors having reached the patient (99.5%) but only a few had serious consequences. One out of 5 ME was eligible for a thorough analysis but even less were subjected to that kind of analysis. The main never event concerned the unidose in the ambulatory sector. The health products involved were mostly a single medication (75%) and then the patient's full treatment (12%). The CRPV/CAPTV/OMEDIT's skills are complementary for the gathering, the analysis and the management of the ME. Training campaigns and support are to be considered for the professionals and especially within the medico-social facilities.

Risperidone medication errors in children: an analysis of French poison centres data.

OBJECTIVES: To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose. METHODS: All cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact. RESULTS: One hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment. CONCLUSIONS: Risperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose ≤0.15 mg/kg.

Decrease in factor V activity in patients treated with azathioprine or 6-mercaptopurine.

BACKGROUND AND OBJECTIVE: A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care. METHODS: Cases of decrease in prothrombin (PT) or factor V activity involving purine analogs were extracted from the French pharmacovigilance database. Reports with evidence of disseminated intravascular coagulation, signs of acute hepatocellular failure, liver cirrhosis or concomitant vitamin K antagonist treatment were excluded. RESULTS: Twenty-four cases (azathioprine: 13 and 6-mercaptopurine: 11) were retained. Therapeutic indications were inflammatory bowel diseases in 11 patients, acute leukemia in eight, and other autoimmune diseases in five. PT activity before treatment was normal in all nine tested patients. The decrease in PT or factor V activity occurs after a median of 10 weeks of treatment and all patients were asymptomatic. The median PT and factor V activities values were 51.5% and 36.4%, respectively. Other coagulation factors were inconsistently decreased. Full recovery was observed within 3-60 days following purine analogs discontinuation. In four patients, drug rechallenge was associated with recurrence of the coagulation disorders. CONCLUSIONS: Although the mechanism remains unknown, this series that includes cases with positive drug reintroduction strongly suggests the causative role of these drugs. As all patients remained asymptomatic, treatment discontinuation should be carefully considered in patients who clearly benefits from this treatment.