The role of in vitro testing in pharmacovigilance for ß-lactam-induced serum sickness-like reaction: A pilot study.

Background: Current pharmacovigilance (PV) methods for detection of adverse drug reactions (ADRs) fail to capture rare immune-mediated drug hypersensitivity reactions (DHRs) due to their scarcity and the lack of clear diagnostic criteria. Drug-induced serum sickness-like reactions (SSLRs) are rare type of DHRs that occur in susceptible patients 1-3 weeks after exposure to the culprit drug with ß-lactam antibiotics being the most associated drugs. The diagnosis of drug induced SSLR is difficult due to the lack of safe and reliable diagnostic tests for identifying the culprit drug. The lymphocyte toxicity assay (LTA) is an in vitro test used as a diagnostic tool for drug hypersensitivity reactions (DHRs). Objective: To evaluate the role of the LTA test for diagnosing and capturing SSLR due to ß-lactam antibiotics in a cohort of patients. Methods: Patients were recruited from patients referred to the Drug Hypersensitivity Clinic at Clinic at London Health Science Centre with suspicion of drug allergy. Twenty patients (10 males and 10 females) were selected to be tested to confirm diagnosis. Demographic data was collected form the patents and blood samples were withdrawn from all patients and from 20 healthy controls. The LTA test was performed on all subjects and data is expressed as percentage increase in cell death compared to control (vehicle without the drug). Results: In the result of LTA tests performed on samples from the selected 20 patients. There was a significant (p < 0.05) concentration-dependent increase in cell death in cells isolated from patients as compared to cells from healthy controls when incubated with the drug in the presence of phenobarbitone-induced rat liver microsomes. Conclusion: Giving its safety and good predictive value the LTA test has very strong potential to be a useful diagnostic tool for ß-lactam-induced SSLR. The test procedure is relatively simple and not overly costly. Further studies including other drug classes are needed to evaluate the utility of the LTA test for SSLR due to other drugs.

Drugs and the skin: A concise review of cutaneous adverse drug reactions.

Drug-induced skin disease or cutaneous adverse drug reactions (CADRs) are terms that encompass the clinical manifestations of the skin, mucosae and adnexa induced by a drug or its metabolites. The skin is the organ most frequently affected by drug reactions, which may affect up to 10% of hospitalized patients and occur in 1-3% of multimedicated patients. Most CADRs are mild or self-resolving conditions; however, 2-6.7% of could develop into potentially life-threatening conditions. CADRs represent a heterogeneous field and can be diagnostically challenging as they may potentially mimic any dermatosis. Currently, there are between 29-35 different cutaneous drug-reaction patterns reported ranging from mild dermatitis to an extensively burnt patient. The most frequently reported are maculopapular rash, urticaria/angioedema, fixed drug eruption and erythema multiforme. Less common but more severe patterns include erythroderma, drug reaction with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Almost any drug can induce a CADR, but antibiotics, nonsteroidal anti-inflammatory drugs and antiepileptics are the most frequently involved. Different mechanisms are involved in the pathogenesis of CADRs, although in some cases, these remain still unknown. CADRs could be classified in different ways: (i) type A (augmented) or type B (bizarre); (ii) immediate or delayed; (iii) immune-mediated or nonimmune-mediated; (iv) nonsevere or life-threatening; and (v) by their phenotype, including exanthematous, urticarial, pustular and blistering morphology. Recognizing a specific CADR will mostly depend on the ability of the physician to perform a detailed clinical examination, the proper description of the morphology of the skin lesions and supporting laboratory and/or skin biopsy findings.

Drug reaction with eosinophilia and systemic symptoms (DRESS): A tertiary care centre retrospective study.

AIMS: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced severe adverse reaction that usually occurs 3-6 weeks after initial exposure to certain drugs. It affects mainly adults and children to a lesser extent. Clinical features include fever, facial oedema, generalized skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement. The objective was to investigate the clinical and laboratory features of patients with DRESS in our centre. METHODS: We retrospectively describe and analyse 19 cases of DRESS whose diagnosis was based on the RegiSCAR criteria (≥6 points) that occurred from January 2009 to December 2019. RESULTS: Patient age ranged from 4 to 76 years (4 children/15 adults); 10 were female (52.3%). The most common culprit drugs were antibiotics (74%) and anticonvulsants (21%). The most common comorbidities were epilepsy (26%) and hypertension (26%). All patients developed cutaneous manifestations and of those, 58% presented facial oedema. Liver function tests, urea/creatinine and troponin elevation were present in 74, 32 and 42%, respectively. The median time to develop the skin rash after the drug exposure was 3.7 weeks (interquartile range 2.4-4.2 wk). Eosinophilia (≥0.7 × 109 /L) was present in 95% of the patients and peaked around 10 days after the skin manifestations. Leucocytosis and reactive lymphocytes were reported in 84% and 26% of all patients respectively. Treatment with systemic steroids was reported in 16 patients. The mean recovery time was 2 weeks (interquartile range 2-3.5 wk) and mortality was 5%. CONCLUSION: DRESS is a serious condition with significant morbidity and mortality, which requires more research for a better understanding.

Paediatric serum sickness-like reaction: A 10-year retrospective cohort study.

BACKGROUND: Serum sickness-like reaction (SSLR) is an acute inflammatory condition affecting predominantly children. The pathophysiology remains unclear, but drugs are considered the main trigger. OBJECTIVE: The aim of this study was to describe the clinical and laboratory features, triggers, and treatment modalities in children diagnosed with SSLR. METHODS: We conducted a 10-year retrospective cohort study including all paediatric patients (0 to 18 years old) with query SSLR referred to the Adverse Drug Reactions Clinic at the Children's Hospital of Western Ontario. Diagnostic criteria included acute skin rash plus joint inflammation with or without fever. RESULTS: We included 83 patients (47 females). Age ranged from 11 months to 12 years (mean 3.2 years). Amoxicillin was the trigger in 82.7% of patients. The mean time between the exposure to the triggering drug and the development of the symptoms was 8.5 days. Urticaria-like and Erythema multiforme-like lesions were present in 35% and 38.5% of the cases, respectively. Joint inflammation affecting hands/feet was present in 60%. Pruritus, lip/eye swelling, and fever were reported in 33, 31, and 45% of patients, respectively. The lymphocyte toxicity assay (LTA) showed incremental T-cell toxicity in 32 of 34 patients. Children that received treatment with antihistamines/nonsteroidal anti-inflammatory drugs (NSAIDs) plus oral steroids had a mean recovery time shorter than those treated only with antihistamines/NSAIDs (6 versus 8 days; P=0.09). CONCLUSIONS: In our study, SSLR was mostly triggered by amoxicillin and had a mean time presentation of 8.5 days. Further prospective and well-conducted studies are needed.

Health-related quality of life in children with cutaneous adverse drug reactions.

Adverse drug reactions (ADRs) are a common problem in children. Health-related quality of life in patients with such conditions has not been well studied. In this study we found that health-related quality of life is adversely affected in children who developed ADRs with cutaneous manifestations.

Subcutaneous Fat Necrosis of the Newborn: A 20-Year Retrospective Study.

Subcutaneous fat necrosis of the newborn (SFN) is a rare form of panniculitis that can be complicated by hypercalcemia and nephrocalcinosis. We conducted a 20-year retrospective cohort study of 30 patients to describe the clinical characteristics of SFN and the prevalence of hypercalcemia and other complications. Hypoxia and therapeutic hypothermia (TH) seem to play an important role in the development of SFN. Hypercalcemia developed in 63% of patients, three of whom developed nephrocalcinosis. There is a need for well-controlled prospective studies to determine the natural history, prevalence, and incidence of complications of SFN.

Quality of life in children with adverse drug reactions: a narrative and systematic review.

AIMS: Adverse drug reactions are a common problem affecting adults and children. The economic impact of the adverse drug reactions has been widely evaluated; however, studies of the impact on the quality of life of children with adverse drug reactions are scarce. The aim was to evaluate studies assessing the health-related quality of life of children with adverse drug reactions. METHODS: We conducted a systematic review that included the following electronic databases: MEDLINE, EMBASE and the Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Controlled Trials Register and the Health Technology Assessment Databases). RESULTS: Nine studies were included. Four of the studies were conducted in children with epilepsy; the rest of them involved children with chronic viral hepatitis, Crohn's disease, paediatric cancer and multiple adverse drug reactions compared with healthy children. Based on their findings, authors of all studies concluded that adverse drug reactions had a negative impact on the quality of life of children. No meta-analysis was conducted given the heterogeneous nature of the studies. CONCLUSIONS: To date, there is no specific instrument that measures quality of life of children with adverse drug reactions, and the information available is poor and variable. In general, adverse drug reactions have a negative impact on the quality of life of affected children. For those interested in this area, more work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of children with adverse drug reactions and chronic diseases.

A systematic review of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children.

Stevens-Johnson (SJS) and Toxic Epidermal Necrolysis (TEN) are two uncommon mucocutaneous diseases usually considered as severe drug reactions and are characterized by different grades of epidermal necrosis. Several treatment modalities have been proposed with variable results but the lack of controlled studies makes difficult to analyze them objectively especially in children. All publications describing management for SJS and TEN in children were searched in MEDLINE, EMBASE, and the Cochrane Library. Reports included were divided in two categories: A, studies with 5 or more patients and observational studies; and B, reports with less than 5 patients. A formal meta-analysis was not feasible. Description was made using central tendency measures. From 1389 references only 31 references with a total of 128 cases were included, 88 category A and 40 category B. The 4 main treatment modalities were: intravenous immunoglobulin (IVIG), steroids (prednisolone, methylprednisolone, dexamethasone), dressings with or without surgical debridement, and support treatment alone. Miscellaneous treatments: Of 12 patients, 3 received ulinastatin, 4 patients plasmapheresis, 2 patients IV pentoxifylline and the last three patients received different treatment each (cyclosporine, methylprednisone/G-CSF and methylprednisolone/IVIG). Patients receiving IVIG and steroids showed similar findings while patients treated with dressing and support treatment alone, reported both longer time to achieve remission and hospitalization stays and appear to be associated with more complications and deaths. There is scant quality literature about management of SJS and TEN in children. Steroids and IVIG seem to improve the outcome of SJS and TEN patients but results from different reports are variable. Patients treated only with care support seem to have higher morbidity and mortality. Further studies are necessary to define optimal management.

Predictive value of the lymphocyte toxicity assay in the diagnosis of drug hypersensitivity syndrome.

BACKGROUND: Drug hypersensitivity syndrome (DHS) is a rare but potentially fatal adverse drug reaction that develops in susceptible patients following exposure to certain drugs. Because of the variable clinical picture of DHS and its resemblance to other diseases, the diagnosis of DHS is challenging. The lymphocyte toxicity assay (LTA) is an in vitro test that has been used in the diagnosis of DHS. However, its predictive values are still controversial because of the lack of a 'gold standard' test to measure it against. OBJECTIVES: To determine the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the LTA in the diagnosis of DHS due to different classes of drugs, based on systemic re-exposure as a gold standard, and to evaluate the current clinical utility of the LTA in clinical practice. METHODS: Potential participants were identified from their medical records and contacted to obtain their consent to participate in the study. One hundred forty-seven patients were recruited and interviewed by telephone to identify events of re-exposure and their consequences. These data were used to determine true positive, false positive, true negative, and false negative results of the test, which were then used to estimate the predictive value of the test. RESULTS: We identified 26 re-exposure events in 22 patients: 4 were true positives, 17 were true negatives, 1 was a false positive, and 4 were false negatives, as determined by systemic re-exposure. Although the number of identified re-exposures limited the ability to calculate the predictive values, our data provide an estimate of the clinical value of the test for the diagnosis of DHS. The data also highlight the effect of the type of drug involved in the reaction on the predictive value of the test. CONCLUSION: The LTA is potentially a valuable diagnostic tool for DHS; however, its sensitivity, specificity, NPV, and PPV seem to vary according to the drug involved in the reaction.