Current Clinical Definitions Research Articles

Applicability of Intentional Topographic Revascularization Following the Angiosome Model in Patients with Chronic Limb-Threatening Ischemia: From Theory, to Current Clinical Challenges

Since its first description almost four decades ago in the plastic surgery field, the angiosome theory has shown encouraging clinical success in Chronic Limb-Threatening Ischemia (CLTI) revascularization in recent years. Gradual scientific knowledge and evidence-based feedback are necessary to assess its usefulness and to overcome various challenges lingering in its practical application at the patient’s bedside. Despite the increasing number of publications in recent years indicating its acceptable suitability in clinical practice, only a few provide conspicuous information regarding the applicability of angiosome-guided Direct Revascularization (DR) compared with the analysis of hurdles in the vascular approach, regardless of its clinical results. The current review aimed to provide an updated interpretation of DR applicability rates in daily practice, delineated through tangible assessments of feasibility, clinical match, and technical success (as previously mentioned). This analysis considered the applicability of DR, Indirect Revascularization via collaterals, (IRc), and “Wound-Targeted Revascularization” (WTR) within the broader perspective of “Intentional Topographic Revascularization” (ITR) in patients with CLTI foot. ITR affords a novel conceptualization of regional foot reperfusion via deliberate anatomical and functional orientation of the foot arterial flow to the ischemic zones (owing specific pedal arteries and regional collaterals). The analysis of data revealed significant differences in the current clinical definitions, interpretation, and application methods of TR. Inconsistent views on DR were also observed in the context of “wound-dependent” localization and the identification of the most suitable target foot artery for treatment. Unfortunately, a standardized definition of angiosome-oriented DR, IR, IRc, and WTR has not been established. Owing to the lack of a universally accepted definition and unified anatomical and functional foot arterial occlusive disease stratification, evidence supporting the applicability of ITR (by all its variants) is still awaited.

Osteoporosis and vertebral trabecular bone health: an historico-anthropological perspective

This brief review article aims to recapitulate the history of osteoporosis from the most ancient observations to the current clinical definition, by offering a perspective on trabecular bone health and degeneration, which has become of paramount important both in clinical, radiological and biological anthropological studies.

Identifying unmet needs and challenges in the definition of a plaque in mycosis fungoides: An EORTC-CLTG/ISCL survey.

Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.

AGA-PancreasFest Joint Symposium on Exocrine Pancreatic Insufficiency.

Exocrine pancreatic insufficiency (EPI) is a clinically defined syndrome based on the physician's assessment of a patient's maldigestion. However, current clinical definitions are inadequate in determining (1) the threshold of reduced pancreatic digestive enzyme secretion that determines "pancreatic insufficiency" in an individual patient; (2) the role of pancreatic function tests; (3) effects of differing metabolic needs, nutrition intake, and intestinal function/adaptation (4) when pancreatic enzyme replacement therapy is needed; and (5) how to monitor and titrate multiple therapies. Experts and key opinion leaders were invited to PancreasFest 2021 to discuss and help clarify mechanistic issues critical to defining EPI and to address misconceptions and barriers limiting advancements in patient care. Clinically EPI is defined as inadequate delivery of pancreatic digestive enzymes to meals to meet nutritional needs and is reversed with appropriate treatment. A new mechanistic definition of EPI was proposed that includes the disorders essence and character: (1) EPI is a disorder caused by failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine in concert with ingested nutrients, followed by enzymatic digestion of a series of individual snacks and meals over time to meet nutritional and metabolic needs, given (a) the specific macronutritional and micronutritional needs; (b) nutrient intake; (c) exocrine pancreatic function; and (d) intestinal anatomy, function, diseases, and adaptative capacity. (2) EPI is characterized by variable deficiencies in micronutrients and macronutrients, especially essential fats and fat-soluble vitamins, by gastrointestinal symptoms of nutrient maldigestion and by improvement or correction of nutritional state with lifestyle changes, disease treatment, optimized diet, dietary supplements, and/or administration of adequate pancreatic enzyme replacement therapy. EPI is complex and individualized and multidisciplinary approaches are needed to optimize therapy. Better pancreas function tests and biomarkers are needed to diagnose EPI and guide treatment.

Genetic architecture of heart failure with preserved versus reduced ejection fraction

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.

Acute kidney injury biomarkers in the single-cell transcriptomic era.

Acute kidney injury (AKI) affects many hospitalized patients and is associated with increased morbidity and mortality even at milder and reversible stages. The current clinical definition relies on serum creatinine increases or decreased urinary output. However, both parameters are of limited use because of poor sensitivity, specificity, and timeliness. Furthermore, the complex pathophysiology and diverse etiologies underlying AKI confound these issues. Precise biomarkers for specific aspects of AKI are needed. Earlier AKI biomarkers were unsuccessful in addressing these needs because they either lacked sensitivity and specificity or failed to aid in guiding clinical management. The advent of single-cell transcriptomics technologies provides an unprecedented opportunity to analyze cells from urine, blood, or kidney biopsies to elucidate the detailed, cell-specific, molecular responses in AKI. These technologies uncover the cellular sources of traditional biomarkers, capture patient heterogeneity, define cell states associated with different AKI subtypes, and might eventually help to predict therapeutic response. We discuss how single-cell technologies might transform diagnostic approaches to AKI by moving from single biomarkers to cell-specific molecular signatures.

Machine Learning Analysis Reveals Biomarkers for the Detection of Neurological Diseases.

It is critical to identify biomarkers for neurological diseases (NLDs) to accelerate drug discovery for effective treatment of patients of diseases that currently lack such treatments. In this work, we retrieved genotyping and clinical data from 1,223 UK Biobank participants to identify genetic and clinical biomarkers for NLDs, including Alzheimer's disease (AD), Parkinson's disease (PD), motor neuron disease (MND), and myasthenia gravis (MG). Using a machine learning modeling approach with Monte Carlo randomization, we identified a panel of informative diagnostic biomarkers for predicting AD, PD, MND, and MG, including classical liver disease markers such as alanine aminotransferase, alkaline phosphatase, and bilirubin. A multinomial model trained on accessible clinical markers could correctly predict an NLD diagnosis with an accuracy of 88.3%. We also explored genetic biomarkers. In a genome-wide association study of AD, PD, MND, and MG patients, we identified single nucleotide polymorphisms (SNPs) implicated in several craniofacial disorders such as apnoea and branchiootic syndrome. We found evidence for shared genetic risk loci among NLDs, including SNPs in cancer-related genes and SNPs known to be associated with non-brain cancers such as Wilms tumor, leukemia, and colon cancer. This indicates overlapping genetic characterizations among NLDs which challenges current clinical definitions of the neurological disorders. Taken together, this work demonstrates the value of data-driven approaches to identify novel biomarkers in the absence of any known or promising biomarkers.

Defining Subtypes of Escitalopram Response Using Resting-State fMRI

A major challenge in identifying biomarkers of antidepressant response is that current clinical definitions of response may not fully represent symptom-specific improvements, particularly in clinically heterogeneous disorders like major depression (MDD). Resting-state functional connectivity (RSFC) and multivariate approaches like canonical correlation analysis (CCA) may help to explain the biological underpinnings of symptom-specific antidepressant response. Therefore, the purpose of this study was to characterize patterns of pre-treatment RSFC predictive of symptom-specific improvement in MDD.

Biomarkers of acute kidney injury after pediatric cardiac surgery: a meta-analysis of diagnostic test accuracy.

A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management. • Acute kidney injury (AKI) occurs in about 30-60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes.However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury. • Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy. • Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers. • A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.

Using Innovative Machine Learning Methods to Screen and Identify Predictors of Congenital Heart Diseases.

Objective: Congenital heart diseases (CHDs) are associated with an extremely heavy global disease burden as the most common category of birth defects. Genetic and environmental factors have been identified as risk factors of CHDs previously. However, high volume clinical indicators have never been considered when predicting CHDs. This study aimed to predict the occurrence of CHDs by considering thousands of variables from self-reported questionnaires and routinely collected clinical laboratory data using machine learning algorithms.Methods: We conducted a birth cohort study at one of the largest cardiac centers in China from 2011 to 2017. All fetuses were screened for CHDs using ultrasound and cases were confirmed by at least two pediatric cardiologists using echocardiogram. A total of 1,127 potential predictors were included to predict CHDs. We used the Explainable Boosting Machine (EBM) for prediction and evaluated the model performance using area under the Receive Operating Characteristics (ROC) curves (AUC). The top predictors were selected according to their contributions and predictive values. Thresholds were calculated for the most significant predictors.Results: Overall, 5,390 mother-child pairs were recruited. Our prediction model achieved an AUC of 76% (69-83%) from out-of-sample predictions. Among the top 35 predictors of CHDs we identified, 34 were from clinical laboratory tests and only one was from the questionnaire (abortion history). Total accuracy, sensitivity, and specificity were 0.65, 0.74, and 0.65, respectively. Maternal serum uric acid (UA), glucose, and coagulation levels were the most consistent and significant predictors of CHDs. According to the thresholds of the predictors identified in our study, which did not reach the current clinical diagnosis criteria, elevated UA (>4.38 mg/dl), shortened activated partial thromboplastin time (<33.33 s), and elevated glucose levels were the most important predictors and were associated with ranges of 1.17-1.54 relative risks of CHDs. We have developed an online predictive tool for CHDs based on our findings that may help screening and prevention of CHDs.Conclusions: Maternal UA, glucose, and coagulation levels were the most consistent and significant predictors of CHDs. Thresholds below the current clinical definition of “abnormal” for these predictors could be used to help develop CHD screening and prevention strategies.

Effect of Cigarette Smoking on Location of Infarction in Patients Presented with ST-Segment Elevation Myocardial Infarction

Background: In an acute ST-elevation myocardial infarction, transmural myocardial ischemia causes myocardial damage or necrosis (STEMI). In order to establish myocardial ischemia damage, the current clinical definition of myocardial infarction (MI) in 2018 includes abnormal cardiac biomarkers. STEMI is linked to a greater risk of mortality in the hospital compared to non-ST segment elevation acute coronary syndromes. The study's purpose was to investigate and assess the effect of cigarette smoking on the location of infarction in people who had ST-segment elevation myocardial infarction.&#x0D; Methods: The present case-control research investigated 100 individuals who had a first ST segment elevation acute myocardial infarction and got split into two groups based on the smoking status: group 1 (50 patients): Group 1 (50 patients) were smokers, whereas group 2 (50 patients) were nonsmokers.&#x0D; Results: Smokers were significantly younger than non-smokers (53.86±7.77) years vs. (58.20 ± 7.80), P = 0. 006. Gender distribution: Smokers were significantly more likely to be male (82.0% vs. 58.0%, P = 0.009). inferior STEMI was statistically significant difference among the two groups (P value =0.045*). Myocardial Infarction Localization by electrocardiogram was statistically significant different among the two groups (P value =0.045*). Ejection fraction (EF) was statistically significant different among the two groups (smoker and nonsmokers respectively 54.86 ± 8.58% vs. 49.04 ± 6.61%) (P value =0.001*).&#x0D; Conclusions: Smoking raises STEMI risk, and smokers are more likely than non-smokers to develop coronary artery disease at an earlier age.

Delineating the Molecular Events Underlying Development of Prostate Cancer Variants with Neuroendocrine/Small Cell Carcinoma Characteristics.

The treatment landscape of prostate cancer has changed dramatically following the advent of novel systemic therapies, most of which target the androgen receptor (AR). Agents such as abiraterone, enzalutamide, apalutamide, darolutamide were designed to further suppress androgen receptor signaling following gonadal suppression achieved by first-line androgen deprivation therapies. These potent AR targeting agents are increasingly used in the earlier stages of the disease spectrum with the goal of delaying disease progression and extending survival. Although these therapies are effective in controlling prostate tumors dependent on or addicted to AR signaling, prostate tumors surviving the onslaught of potent treatments may evolve and develop drug resistance. A substantial proportion of treatment failures can be explained by the development of treatment-induced aggressive prostate cancer variants such as neuroendocrine/small cell carcinoma. These emerging disease entities demand detailed characterization and precise definitions. We postulate that these treatment-induced prostate cancer entities should be defined molecularly to overcome the drawbacks associated with the current clinical and pathological definitions. A precise molecular definition conforms with current knowledge on the molecular evolution of this disease entity and will enable early detection and early intervention.

Screening and diagnosis of prediabetes and diabetes in US children and adolescents

BACKGROUND: The optimal approach to screening and diagnosis of prediabetes and diabetes in youth is uncertain. METHODS: We conducted a cross-sectional analysis of 14 119 youth aged 10 to 19 years in the 1999–2016 NHANES. First, we examined the performance of American Diabetes Association risk-based screening criteria. Second, we evaluated the performance of current clinical definitions of prediabetes and diabetes based on hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), either HbA1c or FPG, or both HbA1c and FPG (confirmatory definition) to identify youth at high cardiometabolic risk. RESULTS: Overall, 25.5% of US youth (10.6 million in 2016) were eligible for screening. Sensitivity and specificity of the screening criteria for detecting any hyperglycemia were low for both HbA1c ≥5.7% (sensitivity = 55.5%, specificity = 76.3%) and FPG ≥100 mg/dL (sensitivity = 35.8%, specificity = 77.1%). Confirmed undiagnosed diabetes (HbA1c ≥6.5% and FPG ≥126 mg/dL) was rare, 85%) cases of diabetes were diagnosed. Associations with cardiometabolic risk were consistently stronger and more specific for HbA1c-defined hyperglycemia (specificity = 98.6%; sensitivity = 4.0%) than FPG-defined hyperglycemia (specificity = 90.1%; sensitivity = 19.4%). CONCLUSIONS: One-quarter of US youth are eligible for screening for diabetes and prediabetes; however, few will test positive, especially for diabetes. Most cases of diabetes in US youth are diagnosed. Regardless of screening eligibility, we found that HbA1c is a specific and useful nonfasting test to identify high-risk youth who could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood.

Reliability and Agreement of 2D and 3D Measurements on MRAs for Growth Assessment of Unruptured Intracranial Aneurysms

Reliable and reproducible measurement of unruptured intracranial aneurysm growth is important for unruptured intracranial aneurysm rupture risk assessment. This study aimed to compare the reliability and reproducibility of 2D and 3D growth measurements of unruptured intracranial aneurysms. 2D height, width, and neck and 3D volume measurements of unruptured intracranial aneurysms on baseline and follow-up TOF-MRAs were performed by two observers. The reliability of individual 2D and 3D measurements and of change (growth) between paired scans was assessed (intraclass correlation coefficient) and stratified for aneurysm location. The smallest detectable change on 2D and 3D was determined. Proportions of growing aneurysms were compared, and Bland-Altman plots were created. Seventy-two patients with 84 unruptured intracranial aneurysms were included. The interobserver reliability was good-to-excellent for individual measurements (intraclass correlation coefficient > 0.70), poor for 2D change (intraclass correlation coefficient < 0.5), and good for 3D change (intraclass correlation coefficient = 0.76). For both 2D and 3D, the reliability was location-dependent and worse for irregularly shaped aneurysms. The smallest detectable changes for 2D height, width, and neck and 3D volume measurements were 1.5 , 2.0, and 1.9 mm and 0.06 mL, respectively. The proportion of growing unruptured intracranial aneurysms decreased from 10% to 2%, depending on the definition of growth (1 mm or the smallest detectable changes for 2D and 3D). The interobserver reliability of the size measurements of individual 2D and 3D unruptured intracranial aneurysms was good-to-excellent but lower for 2D and 3D growth measurements. For growth assessment, 3D measurements are more reliable than 2D measurements. The smallest detectable change for 2D measurements was larger than 1 mm, the current clinical definition of unruptured intracranial aneurysm growth.

Specificity of International Classification of Diseases codes for bronchopulmonary dysplasia: an investigation using electronic health record data and a large insurance database.

ObjectiveInternational Classification of Diseases (ICD) codes in electronic health records (EHRs) are increasingly used for health services research, in spite of unknown diagnostic accuracy. The accuracy of ICD codes to identify bronchopulmonary dysplasia (BPD) is unknown.Study designRetrospective cohort study in a single-center NICU (n = 166) to evaluate sensitivity and specificity of ICD-10 codes for the diagnosis of BPD. Analysis of large insurance claims database (n = 7887) to determine date of assignment of the code.ResultsThe sensitivity of any BPD-related ICD codes ranged from 0.82 to 0.95, while the specificity ranged from 0.25 to 0.36. In a large national insurance database, the most common date of ICD-9 or ICD-10 code assignment was the day of birth, which is inconsistent with the clinical definition.ConclusionsICD codes registered for BPD are unlikely to accurately reflect the current clinical definition and should be interpreted with caution.

Risk of Insulin Resistance and Metabolic Syndrome in Women with Hyperandrogenemia: A Comparison between PCOS Phenotypes and Beyond.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women, with a wide spectrum of possible phenotypes, symptoms and sequelae according to the current clinical definition. However, there are women who do not fulfill at least two out of the three commonly used “Rotterdam criteria” and their risk of developing type 2 diabetes or obesity later in life is not defined. Therefore, we addressed this important gap by conducting a retrospective analysis based on 750 women with and without PCOS. We compared four different PCOS phenotypes according to the Rotterdam criteria with women who exhibit only one Rotterdam criterion and with healthy controls. Hormone and metabolic differences were assessed by analysis of variance (ANOVA) as well as logistic regression analysis. We found that hyperandrogenic women have per se a higher risk of developing insulin resistance compared to phenotypes without hyperandrogenism and healthy controls. In addition, hyperandrogenemia is associated with developing insulin resistance also in women with no other Rotterdam criterion. Our study encourages further diagnostic and therapeutic approaches for PCOS phenotypes in order to account for varying risks of developing metabolic diseases. Finally, women with hyperandrogenism as the only symptom should also be screened for insulin resistance to avoid later metabolic risks.

Serological survey following SARS-COV-2 outbreaks at long-term care facilities in metro Vancouver, British Columbia: Implications for outbreak management and infection control policies

A cross-sectional serological survey was carried out in two long-term care facilities that experienced COVID-19 outbreaks in order to evaluate current clinical COVID-19 case definitions. Among individuals with a negative or no previous COVID-19 diagnostic test, myalgias, headache, and loss of appetite were associated with serological reactivity. The US CDC probable case definition was also associated with seropositivity. Public health and infection control practitioners should consider these findings for case exclusion in outbreak settings.

Screening and Diagnosis of Prediabetes and Diabetes in US Children and Adolescents.

The optimal approach to screening and diagnosis of prediabetes and diabetes in youth is uncertain. We conducted a cross-sectional analysis of 14 119 youth aged 10 to 19 years in the 1999-2016 NHANES. First, we examined the performance of American Diabetes Association risk-based screening criteria. Second, we evaluated the performance of current clinical definitions of prediabetes and diabetes based on hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), either HbA1c or FPG, or both HbA1c and FPG (confirmatory definition) to identify youth at high cardiometabolic risk. Overall, 25.5% of US youth (10.6 million in 2016) were eligible for screening. Sensitivity and specificity of the screening criteria for detecting any hyperglycemia were low for both HbA1c ≥5.7% (sensitivity = 55.5%, specificity = 76.3%) and FPG ≥100 mg/dL (sensitivity = 35.8%, specificity = 77.1%). Confirmed undiagnosed diabetes (HbA1c ≥6.5% and FPG ≥126 mg/dL) was rare, <0.5% of youth. Most (>85%) cases of diabetes were diagnosed. Associations with cardiometabolic risk were consistently stronger and more specific for HbA1c-defined hyperglycemia (specificity = 98.6%; sensitivity = 4.0%) than FPG-defined hyperglycemia (specificity = 90.1%; sensitivity = 19.4%). One-quarter of US youth are eligible for screening for diabetes and prediabetes; however, few will test positive, especially for diabetes. Most cases of diabetes in US youth are diagnosed. Regardless of screening eligibility, we found that HbA1c is a specific and useful nonfasting test to identify high-risk youth who could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood.

Diffuse Alveolar Damage Correlation with Clinical Diagnosis of Pediatric Acute Respiratory Distress Syndrome.

Diffuse alveolar damage (DAD) is one of the pathological hallmarks of acute respiratory distress syndrome (ARDS). We aimed to compare pathological findings of DAD with clinical ARDS criteria. We re-evaluated 20 patients whose clinical autopsy revealed DAD. Total 11/20 patients with DAD (55%) met the 1994 American-European Consensus Conference and 7/17 (41%) met the 2012 Berlin clinical criteria. DAD showed only moderate correlation with current clinical ARDS definition. Oxygenation index (OI), seems to be the most valuable tool in predicting pulmonary damage severity, though OI is not listed in either of the previous definitions. We support the recommended use of OI by 2015 consensus conference.

Systematic review on the definition and predictors of severe Clostridiodes difficile infection.

Clostridiodes difficile infection (CDI) is one of the most common hospital-acquired infections with high mortality rates. Optimal management of CDI depends on early recognition of severity. However, currently, there is no acceptable standard of prediction. We reviewed severe CDI predictors in published literature and its definition according to clinical guidelines. We systematically reviewed studies describing clinical predictors for severe CDI in medical databases (Cochrane, EMBASE, Global Health Library, and MEDLINE/PubMed). They were independently evaluated by two reviewers. Six hundred thirty-three titles and abstracts were screened, and 31 studies were included. We excluded studies that were restricted to a specific patient population. There were 16 articles that examined mortality in CDI, as compared with 15 articles investigating non-mortality outcomes of CDI. The commonest risk factors identified were comorbidities, white blood cell count, serum albumin level, age, serum creatinine level and intensive care unit admission. Generally, the studies had small patient populations, were retrospective in nature, and mostly from Western centers. The commonest severe CDI criteria in clinical guidelines were raised white blood cell count, followed by low serum albumin and raised serum creatinine levels. There was no commonly agreed upon definition of severe CDI severity in the literature. Current clinical guidelines' definitions for severe CDI are heterogeneous. Hence, there is a need for prospective multi-center studies using standardized protocol for biospecimen investigation collection and shared data on outcomes of patients in order to devise a universally accepted definition for severe CDI.