Severe Cutaneous Adverse Drug Reactions: Presentation,Risk Factors,and Management

Purpose of Study

Immune-mediated adverse drug reactions occur commonly in clinical practice and include mild, self-limited cutaneous eruptions, IgE-mediated hypersensitivity, and severe cutaneous adverse drug reactions (SCAR). SCARs represent an uncommon but potentially life-threatening form of delayed T cell-mediated reaction. The spectrum of illness ranges from acute generalized exanthematous pustulosis (AGEP) to drug reaction with eosinophilia with systemic symptoms (DRESS), to the most severe form of illness, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Recent Findings

There is emerging literature on the efficacy of cyclosporine in decreasing mortality in SJS/TEN.

Summary

The purpose of our review is to discuss the typical presentations of these conditions, with a special focus on identifying the culprit medication. We review risk factors for developing SCAR, including HLA alleles strongly associated with drug hypersensitivity. We conclude by discussing current strategies for the management of these conditions.

     

Dapsone induced cholangitis as a part of dapsone syndrome: a case report

Background

Dapsone can rarely cause a hypersensitivity reaction called dapsone syndrome, consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. Dapsone syndrome is a manifestation of the DRESS (drug rash with eosinophilia and systemic symptoms) syndrome which is a serious condition that has been reported in association with various drugs. Cholangitis in dapsone syndrome has not been reported so far in the world literature.

Case presentation

We report a patient who presented with fever, exfoliative dermatitis, jaundice and anemia within three weeks of starting of dapsone therapy. These features are typical of dapsone syndrome, which is due to dapsone hypersensitivity and is potentially fatal. Unlike previous reports of hepatitic or cholestatic injury in dapsone syndrome we report here a case that had cholangitic liver injury. It responded to corticosteroids.

Conclusion

We conclude that cholangitis, though unusual, can also form a part of dapsone syndrome. Physicians should be aware of this unusual picture of potentially fatal dapsone syndrome.

     

Uncommon Presentations of Idiosyncratic Drug-Induced Liver Injury

Purpose of Review

Idiosyncratic drug-induced liver injury (DILI) typically presents acutely with liver test abnormalities, sometimes with associated symptoms of abdominal pain, nausea, vomiting, jaundice, fevers, and rash. Histologic abnormalities in such cases of DILI typically range from lobular or portal hepatitis to hepatocyte necrosis. However, sometimes the drug-related liver injuries present with clinical and/or histological features atypical of garden variety DILI and they may be related to uncommon mechanisms of injury, histologic features, or clinical presentation.

Recent Findings

Multiple agents or classes of agents can result in uncommon forms of liver injury that are phenotypically unique and differ from commonly recognized acute DILI. These include unusual presentations of drugs commonly associated with typical acute DILI, such as drug-induced autoimmune hepatitis. Atypical DILI also includes histologically atypical manifestations of DILI, such as nodular regenerative hyperplasia, sinusoidal obstruction syndrome, granulomatous hepatitis, and steatosis/steatohepatitis.

Summary

Atypical DILI encompasses recognized patterns of injury associated with specific agents or drug classes. These can manifest by atypical biochemical, clinical, and histopathological signatures. An understanding of these types of liver injury is important for the timely recognition of such atypical DILI.

     

Reduced Effectiveness of Interruptive Drug-Drug Interaction Alerts after Conversion to a Commercial Electronic Health Record

Background

Drug-drug interaction (DDI) alerts in electronic health records (EHRs) can help prevent adverse drug events, but such alerts are frequently overridden, raising concerns about their clinical usefulness and contribution to alert fatigue.

Objective

To study the effect of conversion to a commercial EHR on DDI alert and acceptance rates.

Design

Two before-and-after studies.

Participants

3277 clinicians who received a DDI alert in the outpatient setting.

Intervention

Introduction of a new, commercial EHR and subsequent adjustment of DDI alerting criteria.

Main Measures

Alert burden and proportion of alerts accepted.

Key Results

Overall interruptive DDI alert burden increased by a factor of 6 from the legacy EHR to the commercial EHR. The acceptance rate for the most severe alerts fell from 100 to 8.4%, and from 29.3 to 7.5% for medium severity alerts (P?<?0.001). After disabling the least severe alerts, total DDI alert burden fell by 50.5%, and acceptance of Tier 1 alerts rose from 9.1 to 12.7% (P?<?0.01).

Conclusions

Changing from a highly tailored DDI alerting system to a more general one as part of an EHR conversion decreased acceptance of DDI alerts and increased alert burden on users. The decrease in acceptance rates cannot be fully explained by differences in the clinical knowledge base, nor can it be fully explained by alert fatigue associated with increased alert burden. Instead, workflow factors probably predominate, including timing of alerts in the prescribing process, lack of differentiation of more and less severe alerts, and features of how users interact with alerts.

     

Fettleberdiagnostik bei Diabetes mellitus Typ 2

Definition of terms

Under the term non-alcoholic fatty liver disease (NAFLD) both simple hepatic fat accumulation and non-alcoholic steatohepatitis (NASH) are combined. NASH is associated with liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

Epidemiological importance

In 2020, NAFLD will be the leading cause for liver transplantation in the USA, with rising financial costs for the healthcare system.

Comorbidities, diagnosis, and treatment

Type 2 diabetes (T2D) and metabolic syndrome (MetS) are important risk factors for the development of NAFLD, whereby these three diseases share similar pathophysiologic conditions, e.g., insulin resistance, obesity, and metabolic inflammation. Due to the rising number of patients with T2D and MetS, clinicians should aim to diagnose NAFLD early in this patient population and if necessary start treatment.

Goal

The aim of this work is to give an overview over the topic of NAFLD and diagnostic approaches in patients with T2D.

     

Low anterior resection syndrome: a survey of the members of the American Society of Colon and Rectal Surgeons (ASCRS), the Spanish Association of Surgeons (AEC), and the Spanish Society of Coloproctology (AECP)

Background

Low anterior resection syndrome (LARS) is frequent following sphincter-sparing procedures for rectal cancer.

Objective

This study aims to assess surgeons’ awareness of LARS.

Design

This was a survey study.

Settings

Members of the American Society of Colon and Rectal Surgeons (ASCRS), the Spanish Association of Surgeons (AEC), and the Spanish Society of Coloproctology (AECP).

Participants

Three hundred thirty-four surgeons from the ASCRS and 150 from the Spanish Societies completed a 23-item electronic questionnaire.

Main outcome measures

Surgeons’ opinions regarding different aspects of LARS.

Results

The proportion of rectal cancer patients undergoing sphincter-sparing operations ranged between 71 and 90 %. Low anterior resection with end-to-end anastomosis was the most frequently cited procedure after mesorectal excision. More than 80 % of participants were recognized to be moderately or extremely aware of the condition, but regarding the method used to assess LARS, the majority relied on clinical manifestations. Around 35 % of surgeons considered that severe LARS developed in less than 40 % of patients. The most important factor related to defecatory function impairment in the surgeons’ opinion was the distance from the anal margin to anastomosis. Other factors thought to be involved were anastomotic leakage, preoperative radiation therapy, age, and postoperative radiotherapy, with similar percentages in the two groups of surgeons. Lifestyle changes and dietary measures associated with or without drug treatment was the modality of choice. The experience with transanal irrigation or sacral nerve stimulation was limited. It was considered that <30 % of patients chronically suffer from severe LARS with significant quality of life impairment.

Limitations

The limitations of this study are the international mix and expert status of the specialists.

Conclusions

The probability of patients suffering from LARS was underestimated despite reporting good knowledge of the syndrome. Validated methods for the assessment of LARS were rarely used. Deficient awareness regarding risk factors for LARS was documented. Knowledge of therapeutic options was also limited.

     

Adenoma Detection Rate Falls at the End of the Day in a Large Multi-site Sample

Background

There is concern that mental and physical fatigue among endoscopists over the course of the day will lead to lower adenoma detection rate (ADR). There are mixed findings in the prior literature on whether such an association exists.

Aims

The aim of this study was to measure the association between the number of colonoscopies performed in a day and ADR and withdrawal time.

Methods

We analyzed 86,624 colonoscopy and associated pathology reports between October 2013 and September 2015 from 131 physicians at two medical centers. A previously validated natural language processing program was used to abstract relevant data. We identified the order of colonoscopies performed in the physicians’ schedule and calculated the ADR and withdrawal time for each colonoscopy position.

Results

The ADR for our overall sample was 29.9 (CI 29.6–30.2). The ADR for colonoscopies performed at the 9th + position was significantly lower than those at the 1st–4th or 5th–8th position, 27.2 (CI 25.8–28.6) versus 29.9 (CI 29.5–30.3), 30.2 (CI 29.6–30.9), respectively. Withdrawal time steadily decreased by colonoscopy position going from 11.6 (CI 11.4–11.9) min for the 1st colonoscopy to 9.6 (8.9–10.3) min for the 9th colonoscopy.

Conclusion

In our study population, ADR and withdrawal time decrease by roughly 7 and 20%, respectively, by the end of the day. Our results imply that rather than mental or physical fatigue, lower ADR at the end of the day might be driven by endoscopists rushing.

     

Nutritional status using subjective global assessment independently predicts outcome of patients waiting for living donor liver transplant

Background

Malnutrition is an important risk factor for adverse outcomes in patients awaiting liver transplant. Living donor liver transplant, being an elective procedure, allows nutritional rehabilitation and optimization of these patients before transplant.

Aim

This paper aimed to evaluate the outcome of end-stage liver disease (ESLD) patients with various degrees of malnutrition waiting for living donor liver transplant.

Methods

Nutritional status was assessed using subjective global assessment (SGA) in patients who were evaluated for a liver transplant at our center from January 2015 to September 2015. All the data were collected prospectively. Predictive factors for mortality were analyzed using logistic regression and survival was obtained using Kaplan-Meier curves.

Results

One hundred and seventeen patients were grouped based on their nutrition status into normal, mild-moderate, and severe malnutrition. The groups were comparable in terms of age, sex, etiology of liver disease except alcoholic liver disease. Graft recipient weight ratio was comparable among groups. There was no significant difference in hospital stay. However, severe malnourished patients had higher incidence of sepsis (p=0.005) and death due to sepsis (p=0.01). Nutritional status was the only independent predictor of mortality on multivariate analysis.

Conclusion

Nutritional status measured with SGA independently predicts short-term outcome of ESLD patients waiting and after living donor liver transplant.

     

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC,cblD, cblE,cblF, cblG,cblJ and MTHFR deficiency

Background

Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.

Objective

To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.

Data sources

Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.

Key recommendations

We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.

     

Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease

Introduction

Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity.

Case presentation

We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft-versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies.

Conclusion

High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis.

     

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Background

Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism.

Methods

Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated.

Results

The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients.

Conclusion

Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option.

     

Transjugular liver biopsy in severe alcoholic hepatitis

Background

Alcoholic hepatitis and cirrhosis although part of spectrum of alcoholic liver disease can have overlapping features, and differentiating them using clinical, biochemical, and imaging features is not always possible. Standard therapy for each differs, and steroid therapy while beneficial in alcoholic hepatitis may be detrimental in cirrhosis due to high infectious complications. We analyzed our experience with liver biopsy in patients with severe alcoholic hepatitis.

Methods

Male patients in the age group of 25–65 years who were clinically diagnosed with severe alcoholic hepatitis (DF > 32) were retrospectively analyzed and included in this study. All of them had undergone transjugular liver biopsy within the first 7 days of hospitalization.

Results

Thirty patients were included. Most were in the 35–55 age group. Jaundice was present in all patients with fever and tender hepatomegaly also being common. On histopathological evaluation, 33.3% (n = 10) suspected clinically to have alcoholic hepatitis had underlying cirrhosis.

Conclusion

Cirrhosis is found in one third of patients with severe alcoholic hepatitis. This may alter our approach to management of this condition.

     

A Mixed Method Study of the Merits of E-Prescribing Drug Alerts in Primary Care

Objectives

The objective of this paper was to describe primary care prescribers’ perspectives on electronic prescribing drug alerts at the point of prescribing.

Design

We used a mixed-method study which included clinician surveys (web-based and paper) and focus groups with prescribers and staff.

Participants

Prescribers (n?=?157) working in one of 64 practices using 1 of 6 e-prescribing technologies in 6 US states completed the quantitative survey and 276 prescribers and staff participated in focus groups.

Measurements

The study measures self-reported frequency of overriding of drug alerts; open-ended responses to: “What do you think of the drug alerts your software generates for you?”

Results

More than 40% of prescribers indicated they override drug–drug interactions most of the time or always (range by e-prescribing system, 25% to 50%). Participants indicated that the software and the interaction alerts were beneficial to patient safety and valued seeing drug–drug interactions for medications prescribed by others. However, they noted that alerts are too sensitive and often unnecessary. Participant suggestions included: (1) run drug alerts on an active medication list and (2) allow prescribers to set the threshold for severity of alerts.

Conclusions

Primary care prescribers recognize the patient safety value of drug prescribing alerts embedded within electronic prescribing software. Improvements to increase specificity and reduce alert overload are needed.

     

Sulfonamide Drug Allergy

Purpose of Review

We sought to review past and current literature on sulfonamide drug allergy and distill it in a practical manner to assist the clinician, specifically focusing on cross-reactivity and desensitization.

Recent Findings

There do not appear to be consistent genetic markers to reliably predict features of or the presence hypersensitivity reactions. Recent evidence continues to alleviate early concerns cross-reactivity between sulfonamide antibiotics and non-antibiotics.

Summary

Sulfonamide drug allergy is frequently encountered by the practicing clinician. For sulfonamide antibiotics, delayed rash is the most common clinical manifestation. There is no current evidence to support avoidance of all non-antibiotic sulfonamides in those with a reported allergy to sulfonamide antibiotics, although certain scenarios require caution. Available evidence supports the cautious reintroduction of sulfonamide antibiotics via desensitization, which is usually well tolerated and should be considered in those with strong indications for trimethoprim-sulfamethoxazole and a reported sulfonamide allergy.

     

An analysis of 8 cases of factor X deficiency

Background

Factor X deficiency is a rare coagulation defect. There are occasional reports of factor X deficiency from India. Difficulty in accurate diagnosis and non-availability of ideal treatment is discussed.

Methods

Eight cases of factor X deficiency, diagnosed from 1992 to 2007 are reported here

Results

Seven were male while one was female. Seven patients were symptomatic from early childhood. One patient became symptomatic from 18 years of age. Factor X assay was done in 4 patients, 3 had severe deficiency and one had mild deficiency. One patient had associated factor IX deficiency. Three patients had repeated bleeding episodes requiring multiple transfusions. Two patients had intracranial bleed and one had umbilical cord bleeding at birth. There was no mortality. No patient received prophylactic transfusion.

Conclusions

Factor X deficiency is a rare coagulation defect. Hereditary deficiency should be distinguished from acquired deficiency. CNS, joints and skin are the common sites of bleeding.

     

Clinical outcomes,histopathological patterns,and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury—A single-center experience from southern India

Introduction

Ayurvedic and herbal medicines (AHM) are known to cause varying degrees of drug-induced liver injury (DILI). Clinical, biochemical, histological spectrum and outcomes of AHM linked to severe DILI are not well studied.

Methods

Out of 1440 liver disease patients, 94 were found to have a severe liver injury and associated AHM intake. Thirty-three patients were suspected to have AHM-DILI on Roussel Uclaf Causality Assessment Scoring Method. Forty-seven and 30 of retrieved AHM samples were analyzed for heavy metals and hepatotoxic volatile organic compounds (hVOCs), respectively. Eleven patients ingested AHM from unregistered traditional healers (UTH). Clinicopathological outcomes were analyzed in 27 patients (who underwent liver biopsy) and outcomes with respect to chemical analyses were studied in 33 patients.

Results

Males predominated (70.4%) with mean age 46.9±15.8 years. Mean follow up was 119.2±81.4 days. The median duration of drug intake was 28 days (10 – 84). Five patients died (18.5%). Hepatic encephalopathy, hypoalbuminemia, and hepatic necrosis were significantly associated with mortality (p?<?0.005). Arsenic and mercury ingestion was significantly associated with death (p?<?0.005). hVOCs were detected in more than 70% of samples. AHM intake from UTH was associated with higher mortality.

Conclusion

Adequate regulation and scrutiny regarding AHM use among the general population is an unmet need. Early liver biopsy after clinical identification of at-risk patients can expedite definitive treatment with a liver transplant.

     

Diabetes und Hypertonie

Background

Diabetes mellitus is a disease which leads to vascular damage resulting in subsequent severe cardiovascular complications, such as myocardial infarction and stroke. This process is aggravated by coexisting hypertension.

Objective

This analysis gives a review of the latest study results on prognosis, blood pressure targets, drug therapy and interventional therapy in patients with diabetes and hypertension. Selected studies published in recent years with practical relevance for patients with diabetes and hypertension are presented.

Summary

Patients with simultaneous diabetes and hypertension have a poorer prognosis and a higher cardiovascular risk compared to patients with diabetes but without hypertension. Patients with diabetes and hypertension benefit from interventional blood pressure therapy

     

Genetic and Structural Analysis of a <Emphasis Type="Italic">SKIV2L</Emphasis> Mutation Causing Tricho-hepato-enteric Syndrome

Background

Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.

Aim

To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis.

Methods

Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function.

Results

We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein’s packing, or changes at the protein’s interface.

Conclusions

THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.