Hoi Y. Tong

Proton pump inhibitors are associated with hypersensitivity reactions to drugs in hospitalized patients: a nested case-control in a retrospective cohort study.

Previous research has shown that gastric acid suppression by antacid drugs can promote allergic reactions to acid‐labile food proteins. No data are available about whether antacid drugs can promote drug hypersensitivity reactions. The most potent and longer lasting inhibition of gastric secretion is provided by proton pump inhibitors (PPIs). We hypothesized that gastric acid suppression by proton pump inhibitors could be causative of drug hypersensitivity reactions during hospitalization.

Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: Results from a retrospective cohort study

AIMS To estimate the incidence and predictors of symptomatic arterial and venous thromboembolic events (TEE) from intravenous immunoglobulin (IVIg) therapy according to its indications. METHODS We performed a retrospective cohort study of patients seen at our institution and treated with IVIg over a 36-month period. Indications, comorbility and comedication associated with TEE were identified by a stepwise logistic regression analysis. RESULTS Of 303 patients included with at least one infusion of IVIg over three years, TEE were identified in a total of 50 patients treated with IVIg, for an incidence of 16.9% (CI 95%: 13.0-21.6); 27 (54%) arterial (9.1%;CI 95%: 6.3-13.0%) and 23 (46%) venous TEE (7.8%; CI95%: 5.2-11.4%), overall mortality was 32%. Per indication there were more patients with autoimmune conditions, secondary immunodeficiency, dysimmune neuropathies, acute rejection of solid organ transplantation and sepsis. Patients with TEE were significantly older, were more likely to be men, they had more comorbid conditions; the doses of IVIg were high (589.4mg/kg/day vs 387.0mg/kg/day, p<0.001) and differences in comedication were found. The stepwise logistic regression analysis retained high doses of IVIg (OR 3.03; CI 95%: 1.49-5.67) and diuretics therapy (OR 1.69; CI 95%: 1.06-3.97) when combined with the usual comorbid confounders. CONCLUSIONS The incidence of TEE from IVIg therapy remains high at one in six patients treated. The most remediable factor is a high daily IVIg load. Decreasing the daily IVIg dose together with carefully weighing diuretics therapy and comorbid risk factors may be the keys to saving lives.

Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.

Graphical abstract Figure. No caption available. ABSTRACT Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens‐Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class‐I and AED‐induced SCARs in the Spanish population. HLA class‐I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])‐induced SJS/TEN (n = 15) or DRESS (n = 12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA‐A*02:01/Cw15:02 alleles were significantly associated with PHT‐cases compared to control groups B and C [(B)odds ratio(OR):14.75, p = 0.009;(C)OR:27.50, p < 0.001], and were close to significance with respect to control group A (p = 0.060). The genotype frequency of the HLA‐B*38:01 was significantly associated with PHT‐LTG‐cases compared with the 3 groups of controls [(A)OR:12.86, p = 0.012;(B)OR:13.81; p = 0.002;(C)OR:14.35, p < 0.001], and with LTG‐cases [(A)OR:147.00, p = 0.001;(B)OR:115.00, p < 0.001;(C)OR:124.70, p < 0.001]. We found the HLA‐B*15:02 allele in a Spanish Romani patient with a CBZ‐case. The HLA‐A*11:01 was significantly associated with CBZ‐cases [(A)OR:63.89, p = 0.002;(B)OR:36.33, p = 0.005;(C)OR:28.29, p = 0.007]. For DRESS, the HLA‐A*24:02 genotype frequency was statistically significant in the PHT‐LTG‐cases [(A)OR:22.56, p = 0.003;(B)OR:23.50. p = 0.001; (C)OR:33.25, p < 0.001], and in the LTG‐cases [(A),OR:49.00, p = 0.015;(B)OR:27.77, p = 0.005; (C)OR:34.53, p = 0.002]. HLA‐A*31:01 was significantly associated with the CBZ‐cases [(A)OR:22.00, p = 0.047;(B)OR:29.50, p = 0.033;(C)OR:35.14, p = 0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA‐A*02:01/Cw*15:02 combination as a risk factor for PHT‐induced SJS/TEN, HLA‐B*38:01 for LTG‐ and PHT‐ induced SJS/TEN, HLA‐A*11:01 for CBZ‐induced SJS/TEN, and HLA‐A*24:02 for LTG‐ and PHT‐ induced DRESS. The strong association between HLA*31:01 and CBZ‐DRESS in Europeans was confirmed in this study.

Two cases of overlap severe cutaneous adverse reactions to benznidazole treatment for asymptomatic Chagas disease in a nonendemic country.

Chagas disease is a parasitosis endemic to South America. It is normally treated with benznidazole as first choice, which has been associated with numerous cutaneous reactions. However, very few benznidazole‐associated severe cutaneous adverse reactions have been reported to date. The rise of Chagas disease in nonendemic countries represents a growing public health challenge. We report two patients who met the criteria for drug reaction with eosinophilia and systemic symptoms syndrome and Stevens–Johnson syndrome/toxic epidermal necrolysis according to the RegiSCAR scoring systems. They were thus deemed overlapping cases, with a lymphocyte transformation test positive for benznidazole. Both required intensive care unit admission and both survived. Considering the rising application of this drug for trypanosomiasis in immigrant populations, clinicians should be aware of this newly reported, potentially life‐threatening risk.

Hepatotoxicity induced by acute and chronic paracetamol overdose in adults. Where do we stand

Paracetamol (Acetaminophen) poisoning data can reveal the potential deficiencies of paracetamol poisoning management guidelines. We conducted a retrospective cohort study of patients >18years who were attended in the emergency department (ED) of a Spanish tertiary hospital, from 2005 to 2010 for suspected paracetamol overdose and who had measurable paracetamol concentrations. 208 patients suspected of paracetamol poisoning were identified. The annual incidence in the ED increased from 2.0 (95%-CI: 0.2-7.2) cases per 10,000 patients in 2005 to 3.4 (95%-CI: 1.1-8.8) in 2010. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity signs, 4 (57.1%) of whom presented acute liver failure (ALF) criteria, while 8 of 10 patients (80%) with chronic paracetamol poisoning at toxic doses presented hepatotoxicity and 3 (37.5%) with ALF criteria. The time required to find medical care was 9.0h for acute poisoning and 49.6h for chronic poisoning (p<0.001). We conclude that the incidence of suspected cases of paracetamol poisoning at our hospital is increasing. The majority of toxicity cases, including ALF, associated with the ingestion of paracetamol were due to chronic poisoning. This finding constitutes an important warning regarding paracetamol chronic poisoning, and clinicians should have a higher index of clinical suspicion for this entity.

Clinical Implementation of Pharmacogenetic Testing in a Hospital of the Spanish National Health System: Strategy and Experience Over 3 Years

In 2014, we established a pharmacogenetics unit with the intention of facilitating the integration of pharmacogenetic testing into clinical practice. This unit was centered around two main ideas: i) individualization of clinical recommendations, and ii) preemptive genotyping in risk populations. Our unit is based on the design and validation of a single nucleotide polymorphism (SNP) microarray, which has allowed testing of 180 SNPs associated with drug response (PharmArray), and clinical consultation regarding the results. Herein, we report our experience in integrating pharmacogenetic testing into our hospital and we present the results of the 2,539 pharmacogenetic consultation requests received over the past 3 years in our unit. The results demonstrate the feasibility of implementing pharmacogenetic testing in clinical practice within a national health system.

Nonchemotherapy drug-induced agranulocytosis in children detected by a prospective pharmacovigilance program

ABSTRACT Objectives: A prospective evaluation of nonchemotherapy drug-induced agranulocytosis (DIA) cases, which are infrequent in the pediatric population. We characterize agranulocytosis cases and assess lab test differences between drug- and nondrug-induced agranulocytosis. Methods: Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital we detected pediatric agranulocytosis cases from July 2007 to December 2010. This program estimates the incidence, drug causality, clinical features, outcomes of DIA pediatric cases, and assesses laboratory differences with respect to non-DIA. Results: We detected 662 agranulocytosis in 308 pediatric patients, of which 14 were caused by nonchemotherapy drugs. The incidence rate of DIA for 10,000 pediatric patients was 3.92 (Poisson 95% confidence interval 1.09–8.77); 78.6% of DIA cases occurred in patients younger than 3 years. The final outcome was recovery without sequela in all cases. The pharmacologic group most frequently implicated was antimicrobial drugs (11 drugs), 7 of which were beta-lactams. The drugs most frequently suspected were cefotaxime and vancomycin (3 cases each). We found 3 drugs (cloperastine, codeine, and enoxaparin) not previously described to induce DIA. Automatic linear modeling (n = 56, R2 = 45.2%) showed a significant inverse association with platelets (R2 = 17.5%), hemoglobin, and alanine transaminase, and a direct association with red cell distribution (R2 = 16.2%). A generalized linear model (Type III, n = 1188; DIA, n = 86; likelihood ratio chi-squared = 156.16) retained eosinophils (p <.001), platelets (p <.001), total serum proteins (p <.001), and hemoglobin (p =.039). Conclusions: We found a higher incidence of DIA in children than previously described. Our findings also suggest an immune-mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure.

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the livers function is highly recommended.

Non‐Chemotherapy‐Induced Agranulocytosis Detected by a Prospective Pharmacovigilance Program in a Tertiary Hospital

We conducted a prospective evaluation of non‐chemotherapy‐induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features and outcomes of NIA cases and assesses laboratory differences with respect to non‐NIA. We detected 1349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non‐chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 [Poisson confidence interval (CI)‐95%: 0.62–7.22]. The mean (S.D.) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (one case of toe amputation) or death (three cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 defined daily doses was for cefepime (83.85; Poisson‐CI 95%: 67–102.89). Automatic linear modelling (n = 75, R2 = 77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C‐reactive protein, fibrinogen, lactate dehydrogenase; and direct association with mean corpuscular haemoglobin, and haematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and haemoglobin. The findings suggest an immune‐mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such as nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug.