Life-threatening Adverse Drug Reaction Research Articles

Serotonin Syndrome in ICU-A Road Less Traveled.

ABSTRACTA potentially life-threatening adverse drug reaction, serotonin syndrome (SS) may occur in patients on serotonin agonist medications. Medications responsible for SS include commonly prescribed antidepressants, anxiolytics, analgesics and antiemetics. This syndrome has been mentioned in various scenarios in perioperative setting but rarely acknowledged in intensive care unit (ICU) setting. Multiple comorbities leading to polypharmacy and serotoninergic medications place elderly patients, particularly at higher risk of SS. We wish to report a case of SS in an elderly male with depression who developed SS and required ICU admission. Most crucial point is to be able to recognize this entity whenever a patient on multiple drugs with altered sensorium is admitted to ICU.How to cite this articleJindal S, Gombar S, Jain K. Serotonin Syndrome in ICU—A Road Less Traveled. Indian J Crit Care Med 2019;23(8):376–377.

DRESS TO TEN: IS THIS A CONTINUUM?

Introduction Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a potentially life-threatening severe cutaneous adverse drug reaction (SCAR) that can be triggered by medications. Toxic Epidermal Necrolysis (TEN) is also a type of SCAR. To the best of our knowledge, we present a first known clear case of DRESS which progressed to clinical TEN and was successfully treated. Case Description A 17-year old female was started on Lamotrigine and Escitalopram for a mood disorder. One week later, she developed tender cervical lymphadenopathy, fevers, and abdominal discomfort. About 2.5 weeks after starting these two medications, she developed a raised, pruritic, erythematous rash on her arms. Although the medication was discontinued, she failed to improve and developed facial angioedema, hepatic failure, eosinophilia and atypical lymphocytosis - all concerning signs for DRESS. Skin biopsy confirmed perivascular lymphocytic infiltrate with scattered eosinophils supporting DRESS. She was treated with intravenous immunoglobulin and eventually discharged home with a resolving rash. As Prednisone was tapered, the patient was readmitted with concerns for relapsing DRESS. She went on to develop TEN with mucosal involvement as well as greater than 30 percent skin involvement. She was successfully treated with a combination of Cyclosporine and high dose Prednisone. Discussion There is paucity of literature on SCAR overlap syndromes and we acknowledge the ambiguity and difficulty with this diagnosis given the overlapping presentation with SCAR syndromes. Although the mortality rate tends to be quite high for SCAR overlap syndromes, our patient was successfully treated with a combination of IVIG, steroids and Cyclosporine. Progression towards TEN. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a potentially life-threatening severe cutaneous adverse drug reaction (SCAR) that can be triggered by medications. Toxic Epidermal Necrolysis (TEN) is also a type of SCAR. To the best of our knowledge, we present a first known clear case of DRESS which progressed to clinical TEN and was successfully treated. A 17-year old female was started on Lamotrigine and Escitalopram for a mood disorder. One week later, she developed tender cervical lymphadenopathy, fevers, and abdominal discomfort. About 2.5 weeks after starting these two medications, she developed a raised, pruritic, erythematous rash on her arms. Although the medication was discontinued, she failed to improve and developed facial angioedema, hepatic failure, eosinophilia and atypical lymphocytosis - all concerning signs for DRESS. Skin biopsy confirmed perivascular lymphocytic infiltrate with scattered eosinophils supporting DRESS. She was treated with intravenous immunoglobulin and eventually discharged home with a resolving rash. As Prednisone was tapered, the patient was readmitted with concerns for relapsing DRESS. She went on to develop TEN with mucosal involvement as well as greater than 30 percent skin involvement. She was successfully treated with a combination of Cyclosporine and high dose Prednisone. There is paucity of literature on SCAR overlap syndromes and we acknowledge the ambiguity and difficulty with this diagnosis given the overlapping presentation with SCAR syndromes. Although the mortality rate tends to be quite high for SCAR overlap syndromes, our patient was successfully treated with a combination of IVIG, steroids and Cyclosporine. Progression towards TEN.

Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.

Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B∗15:02.

Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.

Occurrence, Management, and Risk Factors for Adverse Drug Reactions in Multidrug Resistant Tuberculosis Patients.

Although Pakistan has a high burden of multidrug-resistant tuberculosis (MDR-TB), little is known about prevalence, management, and risk factors for adverse drug reactions (ADRs) in MDR-TB patients in Pakistan. To evaluate occurrence, management, and risk factors for ADRs in MDR-TB patients, and its impact on treatment outcomes, this observational cohort study was conducted at programmatic management unit for drug resistant TB of Lady Reading Hospital Peshawar, Pakistan. A total of 181 MDR-TB patients enrolled at the study site from January 1, 2012 to February 28, 2013 were included. Patients with drug resistant TB other than MDR-TB, transferred out patients and those who were still on treatment at the end of study duration (January 31, 2015) were excluded. Patients were followed until treatment outcomes were reported. ADRs were determined by laboratory data and/or clinical criteria. SPSS 16 was used for data analysis. A total of 131 patients (72.4%) experienced at least 1 ADR. Gastrointestinal disturbance was the most commonly observed adverse event (42%), followed by psychiatric disturbance (29.3%), arthralgia (24.3%), and ototoxicity (21%). Potentially life-threatening ADRs, such as nephrotoxicity (2.7%) and hypokalemia (2.8%) were relatively less prevalent. Owing to ADRs, treatment regimen was modified in 20 (11%) patients. On multivariate analysis, the only risk factor for ADRs was baseline body weight ≥ 40 kg (OR = 2.321, P-value = 0.013). ADRs neither led to permanent discontinuation of treatment nor adversely affected treatment outcomes. Adverse effects were prevalent in current cohort, but caused minimal modification of treatment regimen, and did not negatively impact treatment outcomes. Patient with baseline body weight ≥ 40 kg should be closely monitored.

Heparin-induced thrombocytopaenia

Heparin-induced thrombocytopaenia (HIT) is a severe and potentially life-threatening adverse drug reaction. Patients become extremely hypercoagulable, and this can lead to life-threatening and limb-threatening thrombosis with a mortality of 5%–10%....

Association Between HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions

Dapsone-induced hypersensitivity syndrome (DHS) is a life-threatening adverse drug reaction. Based on available epidemiologic studies, HLA genotypes may play an important role in DHS. To assess the association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions (cADRs). Human studies investigating associations between HLA-B*1301 and dapsone-induced cADRs were systematically searched without language restriction from the inception of each database until September 12, 2017, in PubMed, the Human Genome Epidemiology Network), and the Cochrane Library. Combinations of HLA genotypes, dapsone, and synonymous terms were used; reference lists were searched in selected articles. Two reviewers identified studies investigating the associations between HLA-B*1301 and dapsone-induced cADRs that reported sufficient data for calculating the frequency of HLA-B*1301 carriers among case and control patients, in which all patients received dapsone before HLA-B*1301 screening. An initial search of the databases identified 391 articles, of which 3 studies (2 in Chinese populations and 1 in a Thai population) met the inclusion criteria. Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine the association between HLA-B*1301 and dapsone-induced cADRs. Subgroup analyses by type of cADR were also performed. PRISMA guidelines were used to abstract and assess data. Primary outcomes were associations between HLA-B*1301 and dapsone-induced cADRs in dapsone-tolerant controls. The outcomes are reported as overall OR. Statistical heterogeneity was assessed using the Q statistic and I2 tests. From the 3 included studies, there were 111 unique patients with dapsone-induced cADRs (subsequently used in the meta-analysis), 1165 dapsone-tolerant patients, and 3026 healthy controls. The cases included 64 men and 49 women (2 patients were missing from the meta-analysis; 1 each from 2 of the 3 studies); mean age was 39.7 years. An association between HLA-B*1301 and dapsone-induced cADRs was identified (summary OR, 43.0; 95% CI, 24.0-77.2). Subgroup analyses among types of cADRs produced similar findings in DHS (OR, 51.7; 95% CI, 16.9-158.5), dapsone-induced severe cADRs (Stevens-Johnson syndrome and toxic epidermal necrolysis [SJS/TEN] plus drug rash [adverse skin reaction to a drug] along with eosinophilia and systemic symptoms [DRESS]) (OR, 54.0; 95% Cl, 8.0-366.2), dapsone-induced SJS/TEN (OR, 40.5; 95% CI, 2.8-591.0), and dapsone-induced DRESS (OR, 60.8; 95% CI, 7.4-496.2). There was no heterogeneity (I2 = 0%, P = .38). Associations between HLA-B*1301 and dapsone-induced cADRs were found in dapsone-tolerant and healthy control groups. For patient safety, genetic screening for HLA-B*1301 in Asian populations before dapsone therapy is warranted.

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

Carbamazepine-induced toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is an uncommon; however, life-threatening dermatological condition which occurs most frequently by the use of drugs. Some group of medications, such as antiepileptics, antibiotics as well as antivirals, can induce such adverse drug reaction (ADR). Among the antiepileptics, carbamazepine is widely prescribed in case of epilepsy and trigeminal neuralgia. Here, we report a case of 22-year-old male with seizure disorder with a history of carbamazepine-induced skin lesions. Patient along with caregiver had approached local physician for increased seizure episodes but did not mention about the allergic history, and he was restarted on carbamazepine. As a result, the patient again developed skin lesions for which he consulted the dermatology outpatient department of the hospital. After outpatient department consultation, he was admitted to the ward for further clinical management. On hospitalization, the patient was diagnosed with carbamazepine-induced TEN (body surface area >40%). The management included immediate withdrawal of carbamazepine and supportive therapy with corticosteroids, antibiotics, antiepileptics, and antiallergic medications. After 15 days of rigorous treatment and hospitalization, the patient was discharged, as erosions healed with reepithelization. Based on this case, it can be concluded that reinitiation of a medication with a history of known allergy can result in TEN which is a serious life-threatening ADR. For the prevention of such ADR, thorough patient medical history should be obtained on each consultation. In addition, the patient and caregiver have to be informed about the clinical condition and the drugs which can provoke such adverse reaction.

Under-reporting of adverse drug reactions, a problem that also involves medicines subject to additional monitoring. Preliminary data from a single-center experience on novel oral anticoagulants

Spontaneous reporting system is the most widely used method by pharmacovigilance centers. Its "voluntary nature" represents the main cause of adverse drug reaction (ADR) under-reporting phenomena. The aim of this study was to point out the issue of ADR under-reporting from doctors, particularly serious ADRs and adverse reactions caused by medicinal products subject to additional monitoring, such as novel oral anticoagulants (NOACs). Only serious ADRs were analyzed, defined as death, life-threatening ADR, hospitalization (initial or prolonged), disability (significant or permanent), congenital anomaly. Firstly, we analyzed suspected adverse reaction alerts to NOACs submitted to the Area Vasta 2 (ASUR Marche) pharmacovigilance center, from June 16, 2013 to January 14, 2017. Then, we examined alerts coming from all over Italy and from the Marche Region in the same time period. Secondly, the analysis was focused on the Senigallia hospital (where we had an easy access to the medical records archive); patients who experienced an ADR in that time period were identified retrospectively and an alert was submitted. Thirdly, from January 15, 2017 to March 15, 2017, suspected ADR alerts were submitted prospectively. Phase 1: in 43 months, 1625 alerts were submitted from all over Italy, 18 from the Marche Region (one of them from the Senigallia hospital). Phase 2: 8 suspected serious ADRs were collected retrospectively (2 fatal and 3 life-threatening). Phase 3: in only 2 months, 7 serious ADRs were observed prospectively (2 fatal and 1 life-threatening). Our study shows that among doctors the under-reporting phenomenon is remarkable and it also involves medicinal products subject to additional monitoring and serious ADRs, including deaths.

How to prevent allopurinol hypersensitivity reactions?

Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life-threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures. Most cases occur within 8-9 weeks of commencing allopurinol, and good patient education at initiation may lead to rapid drug cessation at onset of symptoms. Pretreatment testing for HLA-B*5801 and avoidance of allopurinol when positive reduces the risk of AHS and is cost-effective in some ethnic groups. A low starting allopurinol dose may reduce AHS risk, but the relationship between maintenance dose and AHS is more controversial. Chronic kidney disease increases AHS risk, but slowly increasing the allopurinol dose in chronic kidney disease has not been associated with AHS. Alternative newer treatments are available for patients at risk of AHS, but similar adverse reactions can also occur with these.

Antibiotic Drug Use and the Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Population-Based Case-Control Study

Abstract Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening mucocutaneous adverse drug reactions. Sulphonamide antibiotics are commonly accepted as one of the primary causes of SJS/TEN. This notion is based on results from two hospital-based case-control studies that identified the combined antibiotic cotrimoxazole (sulfamethoxazole and trimethoprim) as the cause of several SJS/TEN cases. Associations were also reported for penicillins, quinolones, cephalosporins, macrolides, tetracyclines, and metronidazole. Using data from the UK-based Clinical Practice Research Datalink, we conducted a 1:4-matched case-control study including 480 previously validated SJS/TEN cases (1995-2013) to quantify the association between SJS/TEN and antibiotics. We further quantified absolute risks of SJS/TEN within separate cohorts of antibiotic users and assessed causality in each exposed case using an adapted version of the algorithm of drug causality in epidermal necrolysis (ALDEN). We observed a strong association between SJS/TEN and trimethoprim alone (odds ratio=9.44, 95% CI 3.83-23.25; absolute risk: 0.98 cases/100’000 users), which suggests that the previously reported association between cotrimoxazole and SJS/TEN is at least partly attributable to the non-sulphonamide antibiotic trimethoprim, which is frequently prescribed as a single agent in the UK. Our study further corroborates previously reported associations between SJS/TEN and use of penicillins, quinolones, cephalosporins, and macrolides.

Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype.

Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2–33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96–23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90–75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83–40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.

487 Phosphorylated MLKL and cleaved caspase8 are useful for early diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous adverse drug reactions. It is difficult to distinguish erythema multiforme (EM) and SJS/TEN in early stage. Although keratinocytes have been suggested to die as apoptosis, our recent study revealed that necroptosis, programmed necrosis, also contribute to keratinocyte death in SJS/TEN. We hypothesized that analyzing the form of keratinocyte death is useful for early diagnosis of SJS/TEN. The skin samples were obtained from non-bullous erythematus lesion of the patient who suspected drug eruption in the acute phase. We included 4 patients diagnosed as SJS/TEN and 10 patients diagnosed as EM. Anti-phosphorylated MLKL (pMLKL) antibody was used to detect necroptosis, and anti-cleaved caspase8 (cCas8) antibody was used to detect apoptosis. Both of pMLKL(+) cell (3.78±2.70%) and cCas8(+) cell (17.8±4.94%) were shown in the 4 SJS/TEN patients. In EM patients, pMLKL(+) cell was shown in 4 patients (1.47±2.56%) and cCas8(+) cell was shown in 2 patients (1.09±2.15%). In 4 all cases diagnosed as SJS/TEN, both of pMLKL and cCas8 cell were positive. In contrast, it was only 1 case that both pMLKL and cCas8 were positive and either pMLKL or cCas8 was positive in 4 cases in EM. The number of pMLKL(+) plus cCas8(+) cell were statistically higher than the number of death keratinocyte detected by HE staining (SJS/TEN: 13.42±5.39%)(EM: 1.02±1.38%). The results revealed that both of necroptosis and apoptosis are occurred in keratinocyte death in SJS/TEN. Although, in EM, both of necroptosis and apoptosis are shown, the amount of cell death is lower than SJS/TEN. It is suggested that the frequency of cell death is important for differentiation between SJS and EM. pMLKL and cCas8 may be able to detect earlier stages of cell death than HE staining, and it is expected that pMLKL and cCas8 can be the marker of SJS/TEN.

Implementation of a rapid HIT immunoassay at a university hospital – Retrospective analysis of HIT laboratory orders in patients with thrombocytopenia

BackgroundHeparin-induced thrombocytopenia (HIT) is a rare cause of thrombocytopenia and a potentially life-threatening adverse drug reaction. Clinical overdiagnosis of HIT results in costly laboratory tests and anticoagulation. Criteria and algorithms for diagnosis are established, but their translation into clinical practice is still challenging. Study design and methodsIn a retrospective approach we studied all HIT related laboratory test requests within four years and evaluated data before (1st period, 24month) and after (2nd period, 24month) replacing particle gel immunoassay (PaGIA) and enzyme-linked immunosorbent assay (ELISA) by a chemiluminescent immunoassay (CLIA). HIT was confirmed by heparin-induced platelet activation (HIPA) test. Clinical pretest probability for HIT using an implemented simplified 4Ts score and platelet count were evaluated. Costs for laboratory tests and alternative anticoagulation were calculated. ResultsIn 1850 patients with suspected HIT, 2327 laboratory orders were performed. In 87.2% of these orders an intermediate/high simplified 4Ts score was found. Thrombocytopenia was present in 87.1%. After replacing PaGIA and ELISA by CLIA the number of immunological and functional laboratory tests was reduced by 38.2%. The number of positive HIT immunoassays declined from 22.6% to 6.0%, while the number of positive HIPA tests among positive immunological tests increased by 19%. Altogether, acute HIT was confirmed in 59 patients. A decline in the use of alternative anticoagulants was observed in the 2nd period. ConclusionOur study shows that in a university hospital setting HIT is well-known, but diagnosis requires a precise laboratory confirmation. Replacing PaGIA and ELISA by CLIA did not influence laboratory order behavior but results in reduced overall costs for laboratory diagnostics and alternative anticoagulation.

Incidence, causative drugs, and economic consequences of drug-induced SJS, TEN, and SJS-TEN overlap and potential drug-drug interactions during treatment: a retrospective analysis at an Indonesian referral hospital.

BackgroundStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute life-threatening adverse drug reactions (ADRs) that are commonly caused by medications. Apart from their contribution to morbidity and mortality, these diseases may also present substantial consequences on health care resources. In this study, we aimed to identify the incidence, causative drugs, and economic consequences of these serious ADRs and potential drug–drug interactions (DDIs) during treatment.MethodsA retrospective study that included 150 patients diagnosed with drug-induced SJS, SJS–TEN overlap, and TEN, from 2009 to 2013 in a referral hospital in West Java Province, Indonesia, was conducted to analyze the causative drugs, cost of illness (COI) as a representation of economic consequences, and potential DDIs during treatment.ResultsThe results showed that analgesic–antipyretic drugs were the most frequently implicated drugs. The COIs for SJS, SJS–TEN overlap, and TEN patients were 119.49, 139.21, and 162.08 US dollars per day, respectively. Furthermore, potential DDIs with several therapeutic medications and corticosteroids used to treat SJS, SJS–TEN overlap, and TEN were also identified.ConclusionThis study showed that analgesic–antipyretic was the major causative drug which contributed to SJS, SJS–TEN overlap, and TEN. Furthermore, our results also showed that SJS, SJS–TEN overlap, and TEN may cause considerable financial consequences to patients.

Clinical Case of Toxic Epidermal Necrolysis

Abstract Toxic epidermal necrolysis or Lyell’s syndrome is a severe life-threatening adverse drug reaction with a high mortality rate. The drugs most commonly involved are: antibiotics; anticonvulsants; antiretroviral drugs; nonsteroidal anti-inflammatory drugs, allopurinol. Case report: A 68-year-old female, presented with complaints of fever and extensive rashes on the skin of the face, the neck and the trunk, severe itching of the skin, ulcerations and erythema of the conjunctiva and the oral cavity and difficulty in swallowing. She has a period of two or three days of general discomfort and fatigue, rash, fever up to 38°C, sore throat, arthralgia, myalgia, loss of appetite and have been treated with antipyretics, antibiotic – ampicillin, antihistamines, vitamins. Her state worsened during the next 3 days, therefore she was hospitalized in the Toxicology clinic of University Hospital “N. I. Pirogov”. Multiple maculopapular and bullous eruptions, plaques were present all over the body, blisters that cover a substantial portion of the body. The entire skin covering the body surface was denuded and peeled off with minor manipulation – the Nikolsky’s sign. Intraorally, multiple oral ulcers of the buccal mucosa, tongue, palate, labial mucosa, and soft palate were seen. Hemorrhagic erosions were also seen on both the upper and lower lips. Conjunctivitis and ulceration of genitalia were also noted. The lesions got slowly better with serum therapy, fluid and electrolyte replacement, systemic corticosteroids, antihistamines, antibiotic, vitamins, H2 blockers, topical care of mucosal changes. Evolution was satisfactory with epidermization and the patient was discharged from the hospital after 1 month.

Cost-effectiveness Analysis for Genotyping before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug Reactions.

Patients with an HLA-B*58:01 allele have an increased risk of developing severe cutaneous adverse drug reactions (SCAR) when treated with allopurinol. Although one-off pharmacogenetic testing may prevent life-threatening adverse drug reactions, testing prior to allopurinol initiation incurs additional costs. The study objective was to evaluate the cost-effectiveness of HLA-B*58:01 screening compared with using other available urate-lowering agents (ULA). A decision-analytical model was used to compare direct medical costs and effectiveness [including lifetime saved, quality-adjusted life-yrs (QALY) gained] in treating new patients with the following options: (1) genetic screening followed by allopurinol prescribing for noncarriers of HLA-B*58:01, (2) prescribing benzbromarone without screening, (3) prescribing febuxostat without screening, and (4) prescribing allopurinol without screening. A 1-year time frame and third-party payer perspective were modeled for both the entire cohort (base-case) and for the subgroup of patients with chronic kidney disease (CKD). The incremental cost-effectiveness ratio of genetic screening prior to ULA therapy was estimated as New Taiwan (NT) $234,610 (US$7508) per QALY gained in the base-case cohort. For patients with CKD, it was estimated as NT$230,925 (US$7390) per QALY. The study results were sensitive to the probability of benzbromarone/febuxostat-related hypersensitivity, and a negative predicted value of genotyping. HLA-B*58:01 screening gave good value for money in preventing allopurinol-induced SCAR in patients indicated for ULA therapy. In addition to the costs of genotyping, it is important to monitor ULA safety closely in adopting HLA-B*58:01 screening in practice.

The clinical efficacy of a clarithromycin-based regimen for Mycobacterium avium complex disease: A nationwide post-marketing study.

The revised 2007 American Thoracic Society/Infectious Diseases Society of America statement recommend clarithromycin-based combination therapy for treatment of Mycobacterium avium complex lung disease and stipulates approximately 1 year of continuous treatment after bacilli negative conversion. However, supporting data are insufficient. Our objective was to obtain data on the clinical outcome of clarithromycin-based daily regimens by conducting a nationwide retrospective post-marketing study of M. avium complex lung disease. In accordance with the Japanese guidelines, patients were enrolled in this survey according to their chest radiographic findings and microbiologic test results. They were treated with a multidrug regimen including clarithromycin, rifampicin, and ethambutol (clarithromycin-based regimen) until bacilli negative conversion, and the treatment was continued for approximately 1 year after the initial conversion. Data were collected before administration, at the time of bacilli negative conversion, at the end of treatment, and at 6 months after the end of treatment. Of the 466 subjects enrolled in the study, 271 patients who received clarithromycin at 800mg/day underwent evaluation for M. avium complex disease. The final bacilli negative conversion rate in those patients was 94.7%. The bacteriological relapse rate was 5.0% (5/100 patients). Bacteriological relapse was noted in patients treated for less than 15 months after conversion. No life-threatening or serious adverse drug reactions were observed. This study demonstrated that a clarithromycin-based daily regimen can yield a high bacteriological conversion rate in M. avium complex disease. After conversion, treatment for less than 15 months might be insufficient to prevent bacteriological relapse.

Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center.

Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening adverse drug reaction that occurs in patients during the treatment of Graves' disease. We aimed to comprehensively examine data for patients with this rare complication and to improve the clinical safety of ATDs. We retrospectively reviewed the medical records of 64 hospitalized patients diagnosed with ATD-induced agranulocytosis between 2000 and 2015. Agranulocytosis occurred in 52 (81.3%) patients within the first 3months after initiation of ATD therapy. Fever (84.4%) and sore throat (82.8%) were the most common symptoms. Although they experienced symptoms, 30 (46.9%) patients did not seek treatment immediately and delayed their diagnosis of agranulocytosis. The minimum granulocyte count was lower in the patients diagnosed after the appearance of symptoms than in those diagnosed before the appearance of symptoms (0.01 × 109/L (0 × 109/L - 0.06 × 109/L) versus 0.26 × 109/L (0.05 × 109/L - 0.40 × 109/L), P < 0.001). The interval days from the appearance of symptoms to the diagnosis of agranulocytosis were negatively correlated with the minimum granulocyte count (r = -0.348, P = 0.005). In addition, a lower minimum granulocyte count was associated with a longer recovery time (β = -11.899, 95% CI -15.304 to -8.496). Our findings have demonstrated that delayed diagnosis of ATD-induced agranulocytosis is common in our population. Delayed diagnosis is associated with severe agranulocytosis and may prolong the recovery time from agranulocytosis. Monitoring of the white blood cell and granulocyte counts may be an effective way to establish an early diagnosis and prevent progression to severe agranulocytosis.