The Use of Automated Electronic Alerts in Studying Short-Term Outcomes Associated with Community-Acquired Acute Kidney Injury.

BACKGROUND/AIMS: The use of electronic alerts (e-alerts) may increase the detection rate of acute kidney injury (AKI) since they are sensitive to small changes in serum creatinine. Our aim was to follow-up a cohort of patients presenting to hospital from the community with AKI (community-acquired AKI [c-AKI]), detected through the use of e-alerts, and describe their short-term outcomes regardless of whether they were subsequently admitted to hospital. METHODS: Blood samples for all hospital attenders from the community either to the Accidents and Emergency department or one of the acute care areas of the hospital during a 6-month period (November 1, 2013-April 30, 2014) were screened for presence of c-AKI using a locally developed e-alerts system based on Kidney Disease: Improving Global Outcomes criteria. Follow-up data were obtained for a period of 3 months. RESULTS: A total of 1,277 c-AKI episodes were identified in 1,185 patients (incidence 579 per 100,000 persons). Episodes that lead to hospitalization (n = 1,096 [86%]) were associated with a median length of hospital stay of 6.6 days; a graded increase in duration of stay was noted with increasing severity of AKI. Acute dialysis was needed during 21 (1.6%) episodes. For mortality rates, only the first AKI episode was considered. There were 298 deaths within 30 days of diagnosis irrespective of admissions status (30-day mortality rate: 25%). CONCLUSIONS: Using e-alerts in acute care settings to detect c-AKI is novel and may be used to stage and follow-up AKI using existing diagnostic criteria. c-AKI is relatively common and leads to significant mortality.

Do anti-smooth muscle antibodies predict development of autoimmune hepatitis in patients with normal liver function? - A retrospective cohort review.

BACKGROUND: The presence of anti-smooth muscle autoantibody (SMA) in Autoimmune Hepatitis (AIH) is well established. However, there are no data demonstrating the clinical significance in patients with normal liver function and few showing positive predictive value for AIH when alanine aminotransferase (ALT) is raised. METHODS: We retrospectively established outcomes in a cohort of 251 consecutive patients with positive tubular or glomerular SMA. Patient records were checked for 12years after the positive SMA result to identify development of AIH. RESULTS: Of 202 patients with SMA and ALT <55IU/L, one (0.5%) had a subsequent diagnosis of AIH and this patient probably had abnormal ALT at the time of SMA detection. 22% of 45 patients with raised ALT (>55IU/L) and 23% of 43 patients with persistently raised ALT (>3months duration), had a diagnosis of AIH on follow up. Of 10 patients with AIH, 80% were diagnosed within three months of the positive SMA. CONCLUSIONS: Progression to AIH in patients with normal liver function and positive SMA-T/G is rare but patients with positive SMA and raised ALT (>55IU/L) should be referred to secondary care for investigation. Positive predictive value of SMA with raised ALT for AIH was 22%.

Current screening approaches for antibody deficiency.

PURPOSE OF REVIEW: Diagnostic delay is a major problem for rare diseases including primary antibody deficiency (PAD). The aim of this review is to discuss the opportunities and challenges of current and future screening approaches for antibody deficiency, to reduce the delay and its impact on patients. (Figure is included in full-text article.) RECENT FINDINGS: Diagnostic delay in PAD is known to result in increased morbidity, mortality, and permanent functional impairment. Approaches to prevent this have been only partially successful and the delay may still be many years as the clinical presentation of PAD is highly variable and may be at any age, making screening difficult. Patients often have numerous healthcare encounters generating repeated cycles of laboratory and clinical data before the diagnosis is made. Low immunoglobulin levels result in alterations in laboratory tests not directly aimed at measuring immunoglobulins. We describe these and highlight the growing evidence in support of using calculated globulin which is part of the liver function test profile as a screening tool for antibody deficiency. Additional approaches include using embedded algorithms to analyse data generated by repeated clinical encounters (e.g. infections, antibiotics, cytopenias), potentially in combination with laboratory results such as calculated globulin, to help bring forward the diagnosis of PAD in patients in whom this has not yet been considered. SUMMARY: There is a strong case for the use of calculated globulin in screening for antibody deficiency. Further work is required to integrate laboratory results with clinical data to reduce diagnostic delay in patients with hitherto unsuspected antibody deficiency.

Incidence of PR3- and MPO-ANCA autoantibody specificity changes in ANCA-associated vasculitis.

BACKGROUND: Monitoring of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in remission usually includes indirect immunofluorescence (IIF), proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA. Typically, PR3 and MPO-ANCA are both performed because patients sometimes switch specificity during follow up. Published data are limited to case reports and incidence of change is not reported. The aim of this study was to quantify the incidence of antibody switching. METHODS: Hull and East Yorkshire Hospitals National Health Service Trust serves a population of 720,000 for ANCA testing. We reviewed all ANCA results from January 2000 to August 2012 to quantify incidence of antibody switching. A total of 22,002 IIF screens (14,518 patients) were performed. A total of 9838 (45%) also had PR3- and MPO-ANCA (6439, 44% of patients). Patients that changed specificity from PR3- to MPO-ANCA and vice versa were identified and case notes reviewed. RESULTS: A total of 218 patients with confirmed AAV positive for PR3/MPO-ANCA were followed for a mean of 2.6 years (range <0.1 to 12.4 years; with 113 (52%) patients followed for >1 year). Five patients (2%) changed specificity during follow up (3 GPA, 1 MPA & 1 EGPA). In two patients this was associated with relapse. Incidence of specificity change was 1 per 82 years (including two reversions to presenting specificity) and one per 286 years for changes associated with relapse. Monitoring using only the initial antibody specificity would have resulted in missed relapse in one patient. CONCLUSION: Antibody specificity changes in AAV are rare. Monitoring only the initial antibody specificity would have missed clinical events but rising C-reactive protein presaged relapse in these cases.

Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project.

BACKGROUND: Median diagnostic delay of five to six years seen in primary hypogammaglobulinaemia results in morbidity including bronchiectasis. Patients typically have multiple health care encounters and blood tests before the diagnosis is considered. We report outcomes from using the difference between total protein and albumin (globulin fraction) to reduce diagnostic delay in unsuspected hypogammaglobulinaemia. METHODS: A prospective >5 year programme in the setting of a National Health Services Hospital Blood Sciences pathology service processing serum samples from primary and secondary care. Patients with globulin fraction below the first percentile were reviewed in the context of supplied clinical details. Immunoglobulin measurements were performed in selected patients. RESULTS: Of 2,910,850 globulin fractions 27,304 (0.9%) were below the 1st percentile globulin fraction (<18 g/L). After exclusions, 933 (3% of these) had immunoglobulins measured. Of these, 292 had IgG < 5 g/L, 186 < 4 g/L and 80 < 3 g/L, giving respective positive predictive values of 31%, 20% and 8.6%. Positive predictive value for common variable immunodeficiency was 1.3%. We identified 12 new cases of common variable immunodeficiency, 10 new haematological disorders and 20 hypogammaglobulinaemias secondary to medication. Locally derived cut-offs are required as small differences between analysers have a significant effect on screen-positive rates. CONCLUSIONS: Use of a 1st percentile globulin fraction improved early detection of hypogammaglobulinaemia. This is a useful adjunct to alert clinicians to unsuspected hypogammaglobulinaemia but should not replace immunoglobulin measurement. Patients with globulin fraction below the first percentile should be reviewed for possible hypogammaglobulinaemia.

Clinical evaluation of the BioPlex 2200 Celiac IgA and IgG Kits - a novel multiplex screen incorporating an integral check for IgA deficiency.

INTRODUCTION: Celiac disease screening is commonly based on detection of IgA anti-tissue transglutaminase (TTGA). IgA deficiency (IgAD) is associated with celiac disease and must be identified to enable use of IgG based assays in these patients. The BioPlex® 2200 Celiac IgA and IgG kits use Luminex methodology to provide a method of simultaneously measuring TTG and deamidated gliadin peptide (DGP) antibody levels using a fully automated random access analyzer based on Luminex® technology. Separate kits are available for IgA (TTGA and DGPA) and IgG (TTGG and DGPG) isotypes. The IgA based kit includes a novel "IgA Verification Bead" (AVB) to check for IgAD (at <0.07g/L) to ensure that these patients are identified and tested using the IgG based kit. AIM: To perform a clinical and technical evaluation of the BioPlex® 2200 Celiac IgA and IgG kits. METHODS: 116 sera from 116 biopsy proven celiac disease patients were tested (58 new presentations on a gluten containing diet and 58 known TTGA positive patients on a gluten free diet but with suspected poor compliance). IgAD was present in 5 patients. Ability to flag IgAD sera was assessed by analysis of 29 IgAD and 200 non-IgAD sera. Specificity was calculated from 124 unselected consecutive disease control sera. RESULTS: Sensitivity and specificity for IgAD were 100%. Screening with TTGA and adding TTGG when IgAD was identified, gave clinical sensitivity of 100% for celiac disease. Specificity was 100% for TTGA and TTGG, and 98% and 97% for DGPA and DGPG respectively. CONCLUSION: Use of the BioPlex® 2200 Celiac IgA and Celiac IgG kits in a standard protocol gave excellent sensitivity and specificity with highly effective detection of IgAD, no false positive IgAD flags and little evidence of interference from high IgA levels. The ability to detect IgAD without pre-screening with a separate IgA assay should have a significant beneficial impact on laboratory workflow by identifying those patients requiring IgG based testing and IgA measurement to confirm IgAD.

Direct access midwifery booking for prenatal care and its role in Down syndrome screening.

OBJECTIVE: To compare the uptake of Down syndrome screening by women following referral by direct access and general practitioner (GP) modes. METHODS: The method of referral by either GP or direct access, for women who booked into prenatal care in Hull and East Yorkshire in 2010, was analysed using data collected from the Protos database at the Women and Children's Hospital, Hull. Subsequently, the uptake of first and second trimester screening for Down syndrome was reviewed by combining the Protos database to the screening data collected by the Clinical Biochemistry Laboratory at Hull Royal Infirmary, Hull. RESULTS: Women booked into prenatal care significantly earlier when referred by GP in comparison to direct access with a significant difference in screening uptake of 49.5 and 42.7%, respectively. The ratio of uptake between first and second trimester screening was not significantly different. CONCLUSIONS: Further research on the new direct access method of referral is required, as it may have a role in the uptake of prenatal screening for Down syndrome. More time is needed to show a definitive effect.

Introduction of first trimester combined test increases uptake of Down's syndrome screening.

OBJECTIVE: To describe any trends in the uptake of antenatal screening for Down's syndrome since the addition of the earlier first trimester combined test. STUDY DESIGN: All antenatal screening tests for Down's syndrome were carried out and their results were recorded by the Clinical Biochemistry Department at the Hull Royal Infirmary (HRI) and reviewed against the antenatal booking data held at the Women and Children's Hospital at HRI. The uptake of antenatal Down's syndrome screening for 5 different age groups of women across a four-year-period from 2007 to 2010 was analysed. RESULTS: There was a significant increase in uptake of antenatal screening for Down's syndrome from 43.9% to 56.5% after the introduction of the combined test in 2010. This increase was apparent in all age groups. There was no change in the proportion of women opting for an invasive test following a positive screening test. CONCLUSION: Addition of the earlier first trimester combined test has increased uptake of antenatal screening for Down's syndrome in women of all ages. This is most likely due to the advantages this test gives women such as earlier decision making, earlier further invasive diagnostic testing and earlier termination, if necessary.

Use of serum free light chain analysis and urine protein electrophoresis for detection of monoclonal gammopathies.

BACKGROUND: Serum free light chain (FLC) analysis is used in the prognostic assessment and monitoring of patients with monoclonal gammopathies (MG). Its use in detection of MG is less widespread despite good sensitivity for diseases poorly detected by serum protein electrophoresis (SPE), e.g., FLC disease and AL amyloidosis. FLC analysis may facilitate earlier diagnosis in these diseases. However, if replacing urine protein electrophoresis (UPE) in an initial screening algorithm, this must be balanced against any loss of detection of Bence Jones proteinuria (BJP). METHODS: We assessed the effect of replacing UPE with FLC. Sensitivity of FLC for BJP was assessed in 126 clinical cases where UPE and FLC analyses were performed. Impact on disease detection was assessed from 753 patient sera tested by SPE and FLC and 128 patients matched associated urine samples. RESULTS: Sensitivity of FLC for BJP was 98%. Use of FLC in routine testing increased the number of MG detected by 7%. CONCLUSIONS: Using FLC alongside or in place of UPE can give clinical benefit through earlier diagnosis and hence treatment earlier in the patients' disease.

Reduction in Down's syndrome screening acceptance is predominantly observed in women aged 25-35 years.

BACKGROUND: The risk of having a child with Down's syndrome increases with maternal age. However, uptake of screening has never been analyzed according to age. Different studies have shown different screening uptake rates, some low and some high, but it is not clear which age categories are responsible for these trends. AIMS: To demonstrate if any age cohorts are responsible for the noted decline in uptake of serum screening. SETTING: A large teaching hospital in Hull and East Yorkshire, which has offered second trimester serum screening for Down's syndrome for over 16 years using the same test (triple test). MAIN OUTCOME MEASURES: Uptake of serum screening for Down's syndrome in each 5-year age cohort per year, over 4 years. A secondary outcome measure was the uptake according to parity. METHODS: We accessed our hospital records covering a 5-year period for all women booking and delivering in a large North of England teaching hospital. The women were categorized into 5-year age cohorts for analysis of the data. RESULTS: Down's syndrome screening uptake rates indicate a decline from 63.2 and 65.1% in 2003 to 38.6 and 39% in 2006, respectively, in the age groups 25-29.9 and 30-34.9 years who constitute at least 50% of all pregnant women. There was no evidence of the effect of parity on serum screening. CONCLUSION: It is apparent that the noted overall decline in the trends of serum screening uptake are due to the reduced uptake by the 25-35 years age group.

The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome.

BACKGROUND: The luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio is often requested to help diagnose polycystic ovarian syndrome (PCOS) despite a recent consensus recommending against its use. This study aimed to compare the variability of the LH/FSH ratio in PCOS with that of normal menstruating women over a full cycle in order to establish the diagnostic utility, or otherwise, of the test. METHODS: Twelve women with PCOS and 11 matched controls had blood collected at four-day intervals on 10 consecutive occasions over a complete menstrual cycle. RESULTS: The median LH/FSH ratio for individual subjects did not differ significantly between the PCOS and the non-affected group (1.6 versus 1.2, P = 0.14). Only 7.6% of samples from PCOS patients had an LH/FSH ratio above three, compared with 15.6% of samples from normal subjects. CONCLUSION: This study confirms that measurement of the LH/FSH ratio is of limited use in the diagnosis of PCOS.

Current state of screening for Down's syndrome.

Down's syndrome has an incidence of about 1.3 per 1000 births. Antenatal testing for this disorder on the basis of maternal age has been common practice (increasing age is associated with increasing risk of having an affected pregnancy). Since the late 1980s it has been possible to calculate a pregnancy-specific risk using maternal age and serum marker levels, but the absence of a national screening policy in the UK has resulted in a diversity of screening practice. Screening may take place in the first or second trimester of pregnancy, using maternal age in combination with up to six serum markers, with or without ultrasound markers. Additionally, some units offer the screen only to women in specific age groups. Risk and marker levels are affected by a number of factors for which adjustments in the calculation may be made. Laboratories offering screening must also establish robust monitoring and quality management systems to ensure continued confidence in the reported result. Current diagnostic techniques require the use of invasive procedures which pose a risk to the fetus and the mother. Future screening may combine new technologies with the identification of fetal cells in maternal blood to reduce or abolish the need for these procedures.