Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

BACKGROUND: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. MATERIALS AND METHODS: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. RESULTS: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. CONCLUSION: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.

Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia.

BACKGROUND: Disease severity and outcome in community-acquired pneumonia (CAP) depend on the host and on the challenge of the causal microorganism(s). We measured levels of immunoglobulins (Igs) and complement in 257 hospitalized adults with CAP and examined the association of low levels of Igs or complement to microbial etiology, disease severity, and short-term and long-term outcome. METHODS: Serum Igs were analyzed in blood samples obtained at admission and at 6 weeks postdischarge if admission levels were low. Serum complement deficiencies were screened with a total complement activity enzyme-linked immunosorbent assay (ELISA), with further analyzes performed if justified. Disease severity was assessed by the CURB-65 severity score. Short-term outcome was defined as a composite end point of intensive care unit (ICU) admission and 30-day mortality, and long-term outcome as 5-year all-cause mortality. RESULTS: At admission, 87 (34%) patients had low levels of at least 1 Ig, with low IgG2 as the most prevalent finding (55/21%). IgG levels were lower in bacterial than viral CAP (8.48 vs 9.97 g/L, P = .023), but low Igs were not associated with microbial etiology. Fifty-five (21%) patients had low lectin pathway activity, of which 33 (13%) were mannose-binding lectin (MBL) deficient. Low admission levels of any Ig or MBL were not associated with disease severity, short-term outcome, or long-term outcome. Excluding patients defined as immunocompromised from analysis did not substantially affect these results. CONCLUSION: In hospitalized adults with CAP, low admission levels of Igs or complement were in general not associated with microbial etiology, disease severity, short-term outcome, or long-term outcome.

Clinical and Complement Long-Term Follow-Up of a Pediatric Patient with C3 Mutation-Related Atypical Hemolytic Uremic Syndrome.

We report a pediatric patient with atypical hemolytic uremic syndrome due to a C3 gain-of-function mutation diagnosed in infancy. She was treated from the start with a constant dose of 300 mg eculizumab every second week from the onset and followed by routine complement analyses for six years. Her complement system was completely inhibited and the dose interval was prolonged from 2 to 3 weeks without alteration of the dose and the complement activity continued to be completely inhibited. Blood samples taken immediately before, immediately after, and between eculizumab doses were analyzed for eculizumab-C5 complexes and percentage of total complement activity, using the Wieslab® test, and compared to a pool of sera from 20 healthy controls. The patient exhibited complete complement inhibition at all three time-points and had no free circulating C5 suggesting there was complete binding to eculizumab. She has now been treated for six years with full complement blockade. We suggest therefore that analysis of complement activity using the Wieslab® test is useful for evaluating the effect of eculizumab when dose intervals are prolonged.

Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives.

Early diagnosis and immediately started appropriate treatment are mandatory for the prevention of radiographic progression, functional disability and unfavourable disease outcome in rheumatoid arthritis (RA). The current classification criteria for RA include two different types of biomarkers representing inflammatory processes, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) or immune processes including autoantibodies, such as rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA). After the discovery of RF, the recent recognition of various autoantibodies against post-translationally modified proteins opened new avenues to diagnosing RA and predicting the course of the disease. Citrullination and carbamylation of amino acids generate new epitopes that can potentially promote the production of novel autoantibodies. In spite of growing knowledge, the pathogenic role of these autoantibodies is still not fully elucidated in RA. In this paper, we review the currently available and novel promising immune biomarkers, which may help in early diagnosis and estimating prognosis in RA.

Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome: A case report.

RATIONALE: Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. PATIENT CONCERNS, DIAGNOSIS AND INTERVENTIONS: We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications. The complement inhibitory effects of the treatment were examined both in the patient and the premature infant. OUTCOMES: Complement activity in the mother recovered considerably faster than anticipated; however, no new thrombosis or CAPS developed during the last week of pregnancy or postpartum. Blood sampling from the umbilical vein and artery, and from the infant after delivery showed low complement activity; however, only 0.3% of the eculizumab concentration detected in the mother, consistent with low placental passage of eculizumab. LESSONS: The data underscore the importance of close monitoring of complement inhibition and individualizing dosage regimens in pregnant patients receiving eculizumab. We document how traditional functional complement activity tests cannot assess the effect of eculizumab in premature infants due to the very low levels of complement factors detected in this infant born in gestational week 33. Only trace amounts of eculizumab passed the placenta. In conclusion, complement C5 inhibition might be a safe candidate treatment option for APS during pregnancy and delivery, and additionally, enables prolongation of pregnancy with important weeks.

Predicting blood donor arrival.

BACKGROUND: Keeping waiting time at blood donation short is important for making donation a good experience for the donors and hence to motivate for repeat donations. At the Blood Bank of Oslo, fixed appointments are used, and few donors arrive without appointments. On average, 59 percent of scheduled donors arrive, but day-to-day variations are large. Methods for predicting the number of donors that will arrive on a given day would be valuable in reducing waiting times. STUDY DESIGN AND METHODS: Information about candidate explanatory variables was collected for all appointments made in a 971-day period (179,121 appointments). A logistic regression model for the prediction of blood donor arrival was fitted. RESULTS: Among 18 explanatory variables, the most important were the time from appointment making to appointment date; the contact medium used; the donor age and total number of donations; and the number of no-shows, arrivals, and deferrals during the preceding 2 years. Compared to taking only the average arrival rate into account, prediction intervals were reduced by 43 percent. CONCLUSION: Statistical modeling can provide useful estimates of blood donor arrival, allowing for better planning of donation sessions.

Guidelines for transfusion in Norway.

The Norwegian guidelines for transfusion are harmonised in terms of standards with the European directives, but we have two areas where there are substantial differences. First, in Norway a blood donor is defined as a patient in legal terms. Secondly, we have stricter criteria for geographical origin of the people who are allowed to donate blood than most other countries. It is a challenge to provide information stating that these guidelines are related to the risk of transmitting infectious disease rather than discrimination. Increased focus on hemovigilance and closer contact between the blood banks and the national health authorities will be major issues in future work to improve the quality of Transfusion Medicine in Norway.