The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts.

BACKGROUND: In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts. METHODS: The aim of the present study was to compare the 4C mortality score, other measures of the systemic inflammatory response and clinicopathological characteristics in two consecutive cohorts of patients on admission with COVID-19. Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17/3/2020-1/5/2020) and (cohort 2: 18/5/2020-6/7/2020) were examined for routine clinical, laboratory and clinical outcome data. RESULTS: Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). In cohort 2, age >70 (p<0.05), male gender (p<0.05), COPD (p<0.05), cognitive impairment (p<0.05), frailty (p<0.001), delirium (p = 0.001), CRP>150mg/L (p<0.05), albumin <30 g/L (p<0.01), elevated perioperative Glasgow Prognostic Score (p<0.05), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated PT (p<0.05), sodium <133 mmol/L (p<0.01) elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.001) and the 4C score (p<0.001) were associated with 30-day mortality. In multivariate analysis, greater frailty (CFS>3) (OR 11.3, 95% C.I. 2.3-96.7, p<0.05), low albumin (<30g/L) (OR 2.5, 95% C.I. 1.0-6.2, p<0.05), high NLR (≥3) (OR 2.2, 95% C.I. 1.5-4.5, p<0.05) and the 4C score (OR 2.4, 95% C.I. 1.0-5.6, p<0.05) remained independently associated with 30-day mortality. CONCLUSION: In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19. TRIAL REGISTRATION: clinicaltrials.gov: NCT04484545.

Setting up a service for a faecal immunochemical test for haemoglobin (FIT): a review of considerations, challenges and constraints.

Quantitative faecal immunochemical tests for haemoglobin (FIT) have now been advocated by the National Institute for Care and Health Excellence (NICE: DG30) to assist in the triage of patients presenting with symptoms that suggest a low risk of colorectal (bowel) cancer. The evidence is that FIT provides a good rule out test for significant bowel disease. However, a small number of cases will be missed, and robust safety-netting procedures are required to follow up some FIT-negative patients. A range of diagnostic pathways are possible, and there is no best approach at present. Introduction of FIT requires careful consideration of the logistics of supply of devices and information to requesting sites and of transport to the laboratory. A number of FIT analytical systems are available. Three are documented as appropriate for use in assessment of patients with symptoms. However, preanalytical, analytical and postanalytical challenges remain. The methods have different specimen collection devices. The methods use polyclonal antibodies and there is no primary reference material or method to which FIT methods are standardised. Third-party internal quality control is lacking, and external quality assessment schemes have many difficulties in providing appropriate materials. Reporting of results should be done using µg Hb/g faeces units and with knowledge of the limit of detection and limit of quantitation of the analytical system used. FIT can be used successfully in an agreed diagnostic pathway, along with other clinical and laboratory information: this requires a multidisciplinary approach, providing opportunities for professionals in laboratory medicine involvement.

Application of NICE guideline NG12 to the initial assessment of patients with lower gastrointestinal symptoms: not FIT for purpose?

Background The National Institute for Health and Care Excellence (NICE) published NG12 in 2015. The referral criteria for suspected colorectal cancer (CRC) caused controversy, because tests for occult blood in faeces were recommended. Faecal immunochemical tests for haemoglobin (FIT), which estimate faecal haemoglobin concentrations (f-Hb), might more than fulfil the intentions. Our aim was to compare the utility of f-Hb as the initial investigation with the NICE NG12 symptom-based guidelines. Methods Data from three studies were included. Patients had sex, age, symptoms, f-Hb and colonoscopy and histology data recorded. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of f-Hb and NG12 were calculated for all significant colorectal disease (SCD: CRC, higher risk adenoma and inflammatory bowel disease). Overall diagnostic accuracy was also estimated by the area under the receiver operating characteristic curve (AUC). Results A total of 1514 patients were included. At a cut-off of ≥10 µg Hb/g faeces, the sensitivity of f-Hb for CRC was 93.3% (95% confidence interval (CI): 80.7-98.3) with NPV of 99.7% (95%CI: 99.2-99.9). The sensitivity and NPV for SCD were 63.2% (95%CI: 56.6-69.4) and 96.0% (95%CI: 91.4-94.4), respectively. The NG12 sensitivity and NPV for SCD were 58.4% (95%CI: 51.8-64.8) and 87.6% (95%CI: 85.0-89.8), respectively. The AUC for CRC was 0.85 (95% CI: 0.87-0.90) for f-Hb versus 0.65 (95%CI: 0.58-0.73) for NG12 ( P < 0.005). For SCD, the AUC was 0.73 (95%CI: 0.69-0.77) for f-Hb versus 0.56 (95%CI: 0.52-0.60) for NG12 ( P < 0.0005). Conclusion f-Hb provides a good rule-out test for SCD and has significantly higher overall diagnostic accuracy than NG12.

The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients.

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02-1.05), male sex: 1.6 (95% CI: 1.1-2.3) and f-Hb (0-<20 µg Hb/g feces): 2.0 (95% CI: 0.7-5.5), (20-<200 µg Hb/g): 16.8 (95% CI: 6.6-42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3-164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85-0.90) in the derivation and 0.91 (95% CI: 0.90-093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value-PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.

Use of a faecal immunochemical test for haemoglobin can aid in the investigation of patients with lower abdominal symptoms.

BACKGROUND: This study aimed to determine whether patients with lower abdominal symptoms can be investigated quickly using results of faecal haemoglobin concentration (f-Hb) measurements, and whether this test could form part of a diagnostic pathway for significant colorectal disease. METHODS: Nine hundred and nine consecutive patients referred from primary care for colonoscopy were invited: 507 submitted samples for f-Hb measurement with a quantitative faecal immunochemical test for haemoglobin (FIT) (HM-JACKarc, Kyowa-Medex, Japan) and a diagnostic colonoscopy was completed in 484 patients. RESULTS: Colorectal cancer (CRC), higher risk adenoma (HRA), inflammatory bowel disease (IBD) and/or colitis was found in 45 patients (9.3%); these had significantly higher (p<0.0001) f-Hb than the group of 243 with normal colonoscopy plus the 196 patients with less significant clinical findings. The 11 (2.2%) patients with CRC all had f-Hb >190 µg Hb/g faeces. Using a f-Hb cut-off of 10 µg Hb/g faeces, for the group with CRC or HRA or IBD or colitis, sensitivity was 68.9%, specificity 80.2%, positive predictive value (PPV) 26.3% and negative predictive value (NPV) 96.2%. Sensitivity and NPV were 100% for CRC suggesting f-Hb is a good rule-in test for CRC. Of the 243 patients with normal colonoscopy, 81.2% had f-Hb<10 µg Hb/g faeces. CONCLUSIONS: The high NPV for significant colorectal diseases suggests that f-Hb could be used as a rule-out test in this context. Potential exists for using f-Hb measurements to investigate symptomatic patients and guide the use of colonoscopy resources: detailed algorithms for the introduction of f-Hb measurements requires further exploration.

Defending a traditional practice in the modern era: The use of lumbar puncture in the investigation of subarachnoid haemorrhage.

INTRODUCTION: Acute severe headache is a common medical presentation, and a common area of diagnostic uncertainty. Subarachnoid haemorrhage (SAH) is the cause in a minority of patients and has a high rate of morbidity and mortality. Therefore, its conclusive diagnosis with computed tomography (CT) or lumbar puncture (LP) is paramount. With advancement in imaging technology, emerging evidence now suggests that LP is no longer required for a subset of patients as CT has 100% sensitivity in detecting SAH, when performed under specific conditions. OBJECTIVES: To assess the proportion of patients with conclusive CSF xanthochromia results following a negative CT scan in suspected SAH to determine the diagnostic efficacy of LP. METHODS: CSF bilirubin and oxyhaemoglobin spectrophotometric absorbance data from all centres in a regional health board were identified for consecutive patients over a 6-month period. Results were stratified as conclusive (positive or negative), or inconclusive according to national guidelines. RESULTS: 239 of 255 (93.7%) results were conclusive: 89.0% were negative (227 of 255). 4.7% of results were positive (12 of 255), revealing 4 cerebral aneurysms requiring treatment. 16 out of 255 (6.3%) samples were inconclusive, yielding 1 aneurysm requiring treatment. In the same period, there were 27 CT-positive cases of SAH. CONCLUSIONS: LP has a high diagnostic yield, eliminating the need for neurosurgical opinion or investigation in almost 90% of cases. The test is both cost and time efficient and subjects only a small number of patients to the radiation and contrast risks of angiography.

Hypokalaemia following paracetamol overdose in two teenage girls.

We report on two teenage girls presenting following significant paracetamol overdoses (>28 g paracetamol). Both presented within 4 h of the overdose and both were treated with N-acetylcysteine, in accordance with the National Poisons Information Service protocol. Within 8 h of presentation both had developed significant hypokalaemia with serum potassium concentrations <3.0 mmol/L and were treated with intravenous potassium chloride. Potassium concentrations returned to within reference limits (>3.5 mmol/L) after commencing potassium chloride supplementation. An audit of potassium concentrations in 254 patients presenting with significant paracetamol overdose (paracetamol >0.5 mmol/L) admitted through four A&E departments in the West of Scotland showed a significant decline in mean serum potassium from 3.9 mmol/L on admission to 3.6 mmol/L (P = <0.001) over the next 36 h. The mechanism for this hypokalaemia in these two individuals is unclear, however regular monitoring of potassium is advocated in such patients during their initial treatment.

The influence of a cooked-meat meal on estimated glomerular filtration rate.

BACKGROUND: Chronic kidney disease (CKD) is an important but under-recognized condition. Recent national guidelines have recommended that biochemistry laboratories report estimated GFR (eGFR) to improve diagnosis of CKD and facilitate disease staging and management. Previous reports have suggested that intake of large amounts of cooked meat can lead to a significant increase in serum creatinine concentration. METHODS: Participants (n = 32), consisting of 17 healthy volunteers and 15 outpatients, were recruited. Measurement of serum creatinine (kinetic Jaffe method, enzymatic, isotope-dilution mass spectrometry [IDMS]) and cystatin C, and calculation of eGFR were carried out before (i) and after a meal containing cooked meat (ii) and a meat-free meal (iii). RESULTS: Following intake of cooked meat, median serum creatinine concentration (kinetic Jaffe) increased from 80.5 micromol/L preprandially to 101.0 micromol/L 1-2 h postprandially (P<0.0001), and 99.0 micromol/L 3-4 h postprandially (P<0.0001). Median eGFR decreased from 84.0 mL/min/1.73 m2 preprandially to 59.5 mL/min/1.73 m2 1-2 h postprandially (P<0.0001), and 64.0 mL/min/1.73 m2 3-4 h postprandially (P<0.0001). Consumption of non-meat-containing meals had little impact on serum creatinine (kinetic Jaffe) and eGFR. Changes in serum creatinine were similar using all three methods, and cystatin C concentration was generally uninfluenced by food intake. CONCLUSIONS: Intake of cooked meat has a significant effect on serum creatinine concentration and eGFR. Misclassification of CKD is possible if measurements are made after meals containing cooked meat. Clinicians should ensure that CKD classification is based on samples taken in the appropriate conditions: either fasting or after avoidance of cooked meat on the day of sampling. National guidelines which overlook this factor should be revisited.

Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism.

BACKGROUND: Osteoporosis is increasingly recognized as a major source of morbidity following renal transplantation. The aim of this cross-sectional study was to determine the prevalence of osteoporosis in a cohort of male transplant recipients and examine factors that may influence their bone loss. METHODS: Bone mineral density (BMD) and biochemical markers of bone metabolism were measured in 134 out of 154 male renal allograft recipients in our center. RESULTS: The mean age of the patients was 49.7 years (range 26-76) with a median of 6 years post-transplant. Only 17% had normal BMD, 30% were osteoporotic at either hip or spine, and this proportion rose to 41% if the ultradistal radius was included. Parathyroid hormone (PTH) was negatively correlated with BMD at all skeletal sites. In a multiple regression model, independent predictors of femoral neck BMD included body mass index (p=0.004), diabetes (p=0.025), and PTH (p=0.049). The only independent predictor of BMD at the ultradistal radius was PTH (p<0.001). Nineteen men sustained a total of 25 appendicular fractures after transplantation (median time to fracture was 3 years). Prevalent vertebral fractures were only identified in five men. PTH was elevated in 72.4% of patients (mean PTH 142 +/- 118 pg/ml). Bone resorption markers were increased in 48% of patients. PTH was positively correlated with serum carboxyterminal telopeptide of type 1 collagen (r=0.473, p<0.001) and procollagen type 1 amino terminal propeptide (r=0.419, p<0.001). CONCLUSIONS: Osteopenia and osteoporosis are common in male transplant recipients, and the hip and radius are the most severely affected sites. Elevated rates of bone resorption driven by hyperparathyroidism appear to be the most important contributing factor.

Iatrogenic copper deficiency causing anaemia and neutropenia.

A 79-year-old woman presented with an obstructed femoral hernia and had a wedge resection of the small intestine. Post-operatively she developed wound dehiscence and spent 3 days in the adult critical care unit. Good recovery followed and she was allowed home after 2 months in hospital. Six months later she presented with anaemia, neutropenia and a very low serum copper concentration. Review of her notes revealed that she had been given oral zinc therapy while in the critical care unit and this treatment had been continued on discharge from hospital. Serum copper, haemoglobin and white cell count recovered after oral zinc was discontinued. Oral zinc treatment can lead to symptomatic copper deficiency in susceptible patients.

Longitudinal changes of insulin-like growth factors and their binding proteins throughout normal pregnancy.

BACKGROUND: Insulin-like growth factors (IGFs) are anabolic proteins that are essential regulators of cell division, differentiation and growth. We describe the longitudinal changes in IGF-I, IGF-II and the binding proteins IGFBP-1, -2 and -3 before and during normal pregnancy. METHOD: Serum samples were taken before conception and then at 12, 24 and 36 weeks of gestation in 41 healthy women with uncomplicated pregnancies. We measured IGF-I using an automated chemiluminescent method, IGF-II and IGFBP-2 using in-house radioimmunoassays (RIAs), and IGFBP-1 and IGFBP-3 using commercial enzyme-linked immunosorbent assay (ELISA) and RIA kits, respectively. Because of the potential haemodilution effects during pregnancy, albumin was also measured in all samples. RESULTS: There was a significant fall in IGF-I during the first (36%) and second trimesters (21%) followed by an increase of 25% at 36 weeks. During pregnancy, the mean IGF-II concentrations fell by 12% at 12 weeks, 8% at 24 and 8% at 36 weeks compared with pre-conception values. When IGF-II results were adjusted for the haemodilution of pregnancy, its concentrations increased. During pregnancy, there was a rapid increase in mean IGFBP-1 levels by 17-fold (12 weeks), 24-fold (24 weeks) and 25-fold (36 weeks). IGFBP-2 concentrations fell after conception but started to increase towards term. This increase was more significant when adjusted for haemodilution. In contrast, IGFBP-3 concentrations increased significantly throughout pregnancy. CONCLUSION: Our data on the physiological changes of IGFs and their binding proteins add further evidence of the vital roles of these hormones throughout normal pregnancy.

Changes in serum markers of bone turnover during normal pregnancy.

BACKGROUND: Maternal calcium homeostasis adapts during pregnancy to provide for the needs of the growing fetal skeleton. Wide selections of bone turnover markers are currently available to assess the changes taking place; here, data are presented on two serum-based markers. METHODS: The use of serum-based biochemical bone turnover markers during pregnancy was assessed in a cohort of 41 women recruited prior to conception. Serum N-terminal extension peptide of procollagen (P1NP) was used to monitor bone formation and serum beta-crosslaps (S-CTX) used to assess resorption. Blood samples were measured at five time points from a pre-conceptual baseline, through pregnancy, to the final sample, which was taken within 1 week of delivery. RESULTS: An initial decrease from the baseline in both P1NP and S-CTX was observed at 12 weeks; however, it is suggested that this may be due to the haemodilutional effect of pregnancy rather than a true change in bone turnover. Significant increases from the baseline of both analytes were observed by 36 weeks (P1NP, P = 0.013; S-CTX, P = 0.002), when the calcium demands of the fetus are greatest. CONCLUSIONS: This study illustrates the use of serum-based bone turnover markers to assess turnover during normal pregnancy, a time when ionizing radiation cannot be used to assess bone turnover.

Comparison of intact and 'whole molecule' parathyroid hormone assays in patients with histologically confirmed post-renal transplant osteodystrophy.

BACKGROUND: Fragments of parathyroid hormone (PTH) have been identified (amino acids 7-84) which may interfere with commercially available 'intact molecule' PTH assays. Novel assays which employ an antibody directed to the first seven amino acids of the N-terminus of PTH are thought to be free from cross-reactivity with the 7-84 fragments, and therefore measure true 'whole molecule' PTH. Transplant recipients (as well as those in end-stage renal failure) have been reported to have elevated levels of 'intact' in comparison with 'whole molecule' PTH. METHODS: PTH concentrations were assessed in serum samples obtained from female renal transplant recipients previously classified as either having hyperparathyroid (n = 14) or adynamic bone disease (n = 14) by transiliac crest bone biopsy. PTH was measured as 'whole molecule' (Scantibodies 'whole molecule' PTH) and 'intact' (DPC Immulite 2000 intact PTH and Scantibodies total PTH). RESULTS: Scantibodies 'whole molecule' PTH (all-subject mean 48.7 ng/L, +/- 53.0) were significantly lower than DPC intact (83.5 ng/L, +/- 88.1; P < or = 0.0001) and Scantibodies total PTH (80.5 ng/L, +/- 92.4; P < or = 0.0001). However, the differences between the 'whole molecule' and 'intact' measurements were similar across the two patient groups, and reflected the lower reference range employed by the 'whole molecule' assay. CONCLUSION: The 'whole molecule' PTH assay was unable to discriminate between the two patient populations and provided very little additional clinical information to that obtained from the intact PTH assays.