Complement and COVID-19: Three years on, what we know, what we don't know, and what we ought to know.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was identified in China in 2019 as the causative agent of COVID-19, and quickly spread throughout the world, causing over 7 million deaths, of which 2 million occurred prior to the introduction of the first vaccine. In the following discussion, while recognising that complement is just one of many players in COVID-19, we focus on the relationship between complement and COVID-19 disease, with limited digression into directly-related areas such as the relationship between complement, kinin release, and coagulation. Prior to the 2019 COVID-19 outbreak, an important role for complement in coronavirus diseases had been established. Subsequently, multiple investigations of patients with COVID-19 confirmed that complement dysregulation is likely to be a major driver of disease pathology, in some, if not all, patients. These data fuelled evaluation of many complement-directed therapeutic agents in small patient cohorts, with claims of significant beneficial effect. As yet, these early results have not been reflected in larger clinical trials, posing questions such as who to treat, appropriate time to treat, duration of treatment, and optimal target for treatment. While significant control of the pandemic has been achieved through a global scientific and medical effort to comprehend the etiology of the disease, through extensive SARS-CoV-2 testing and quarantine measures, through vaccine development, and through improved therapy, possibly aided by attenuation of the dominant strains, it is not yet over. In this review, we summarise complement-relevant literature, emphasise its main conclusions, and formulate a hypothesis for complement involvement in COVID-19. Based on this we make suggestions as to how any future outbreak might be better managed in order to minimise impact on patients.

The susceptibility of the kidney to alternative pathway activation-A hypothesis.

The glomerulus is often the prime target of dysregulated alternative pathway (AP) activation. In particular, AP activation is the key driver of two severe kidney diseases: atypical hemolytic uremic syndrome and C3 glomerulopathy. Both conditions are associated with a variety of predisposing molecular defects in AP regulation, such as genetic variants in complement regulators, autoantibodies targeting AP proteins, or autoantibodies that stabilize the AP convertases (C3- and C5-activating enzymes). It is noteworthy that these are systemic AP defects, yet in both diseases pathologic complement activation primarily affects the kidneys. In particular, AP activation is often limited to the glomerular capillaries. This tropism of AP-mediated inflammation for the glomerulus points to a unique interaction between AP proteins in plasma and this particular anatomic structure. In this review, we discuss the pre-clinical and clinical data linking the molecular causes of aberrant control of the AP with activation in the glomerulus, and the possible causes of this tropism. Based on these data, we propose a model for why the kidney is so uniquely and frequently targeted in patients with AP defects. Finally, we discuss possible strategies for preventing pathologic AP activation in the kidney.

Evaluation of CME Arrival Prediction Using Ensemble Modeling Based on Heliospheric Imaging Observations.

In this study, we evaluate a coronal mass ejection (CME) arrival prediction tool that utilizes the wide-angle observations made by STEREO's heliospheric imagers (HI). The unsurpassable advantage of these imagers is the possibility to observe the evolution and propagation of a CME from close to the Sun out to 1 AU and beyond. We believe that by exploiting this capability, instead of relying on coronagraph observations only, it is possible to improve today's CME arrival time predictions. The ELlipse Evolution model based on HI observations (ELEvoHI) assumes that the CME frontal shape within the ecliptic plane is an ellipse and allows the CME to adjust to the ambient solar wind speed; that is, it is drag based. ELEvoHI is used to perform ensemble simulations by varying the CME frontal shape within given boundary conditions that are consistent with the observations made by HI. In this work, we evaluate different setups of the model by performing hindcasts for 15 well-defined isolated CMEs that occurred when STEREO was near L4/5, between the end of 2008 and the beginning of 2011. In this way, we find a mean absolute error of between 6.2 ± 7.9 and 9.9 ± 13 hr depending on the model setup used. ELEvoHI is specified for using data from future space weather missions carrying HIs located at L5 or L1. It can also be used with near-real-time STEREO-A HI beacon data to provide CME arrival predictions during the next ∼7 years when STEREO-A is observing the Sun-Earth space.

Professor Sir Peter J. Lachmann, FRS, FMedSci (1931-2020).

As members of the International Complement Society (ICS) will be aware, Professor Sir Peter Lachmann sadly passed away, peacefully and at home, on 26th December 2020 [...].

Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases.

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

Complement and Bacterial Infections: From Molecular Mechanisms to Therapeutic Applications.

Complement is a complex protein network of plasma, and an integral part of the innate immune system. Complement activation results in the rapid clearance of bacteria by immune cells, and direct bacterial killing via large pore-forming complexes. Here we review important recent discoveries in the complement field, focusing on interactions relevant for the defense against bacteria. Understanding the molecular interplay between complement and bacteria is of great importance for future therapies for infectious and inflammatory diseases. Antibodies that support complement-dependent bacterial killing are of interest for the development of alternative therapies to treat infections with antibiotic-resistant bacteria. Furthermore, a variety of novel therapeutic complement inhibitors have been developed to prevent unwanted complement activation in autoimmune inflammatory diseases. A better understanding of how such inhibitors may increase the risk of bacterial infections is essential if such therapies are to be successful.

The properdin pathway: an "alternative activation pathway" or a "critical amplification loop" for C3 and C5 activation?

This review is not intended to cover in detail all aspects of the discovery and evolution of our understanding of the "alternative pathway" of complement activation, there are many excellent reviews that do this (see Fearon (CRC Crit Rev Immunol 1:1-32, 1979), Pangburn and Müller-Eberhard (Springer Semin Immunopathol 7:163-192, 1984)), but instead to give sufficient background for current concepts to be put in context. The prevailing textbook view, of components having a primary role as an alternative "pathway" for C3 activation, is challenged, with an argument developed for the primary role of the system being that of providing a surface-dependent amplification loop for both C3 and C5 activation. Whatever the mechanism by which the initial C3b molecule is generated, deposition onto a surface has the potential to target that surface for elimination. Elimination or escape from initial targeting is determined by a sophisticated and highly regulated amplification loop for C3 activation. This viewpoint of the system is then briefly developed to provide a context for therapeutic treatment of disease caused, at least in part, by dysregulated amplification of C3 activation, and to highlight some of the challenges that such therapies will face and need to address.

Utility of the Surgical Apgar Score in a district general hospital.

BACKGROUND: The Surgical Apgar Score (SAS) is a simple tool for intraoperative risk stratification. The aim of this prospective observational study was to assess its performance in predicting outcome after general/vascular and orthopedic surgery and its utility in a U.K. district general hospital. METHOD: A prospective cohort of 223 consecutive general, vascular, and orthopedic surgical cases was studied. The SAS was calculated for all patients, and its relationship to 30 day mortality and major complication assessed with reference to the mode of surgery (elective or emergent). Statistical analysis of categorical data was performed with Fisher's exact test and the AUC (area under the curve) on receiver operating characteristic (ROC) analysis. Selected cases were reviewed to assess the potential of the SAS to modify postoperative management. RESULTS: The proportion of patients who died or experienced major complications increased monotonically with Surgical Apgar Score category in general and vascular but not orthopedic cases. The relative risks of mortality or major complication between SAS categories were less marked than in previous publications. The SAS performed variably on ROC curve analysis, with an AUC of 0.62-0.73. Discrimination achieved significance in general and vascular cases (p = 0.0002) but not in orthopedic cases (p = 0.15). Subgroup analysis of high (SAS < 7) and low risk (SAS ≥ 7) groups demonstrated utility of the score in general surgery and vascular cases overall (p < 0.0001), and in the emergency (p = 0.004) but not elective (p = 0.12) subgroups. Case note review of those patients who died indicated that despite their identification by the SAS, there would have been limited scope to modify outcome. CONCLUSION: This study provides further evidence that the SAS is a simple and effective predictive tool in the emergency general and vascular surgical setting. It appears to have a limited role in the management of individual patients after orthopedic surgery and elective general/vascular surgery. The SAS has been proven to reliably stratify risk in larger populations and might be applied most usefully as a marker of quality. Further studies are required to determine whether its application can influence outcome.

Medical response planning for pandemic flu.

This quantitative research study evaluates the health care infrastructure necessary to provide medical care in US hospitals during a flu pandemic. These hospitals are identified within the US health care system because they operate airborne infectious isolation rooms. Data were obtained from the 2006 American Hospital Association annual survey. This data file provides essential information on individual US hospitals and identifies the health care capabilities in US communities. Descriptive statistics were evaluated to examine hospitals with the appropriate infrastructure to treat a flu pandemic. In addition, geographic information system software was used to identify geographic areas where essential infrastructure is lacking. The study found 3,341 US hospitals operate airborne infectious isolation rooms, representing 69% of reporting hospitals. The results also indicate that those hospitals with airborne infectious isolation rooms are larger and are located in metropolitan areas. The study has managerial implications associated with local medical disaster response and policy implications on the allocation of disaster resources.

Role of information technology in disaster medical response.

This article addresses the importance of information technology (IT) in support of disaster medical response and provides a framework for the use of IT in response to natural disasters or terrorist activities. The appropriate use of IT enhances the effectiveness of the disaster response system, thereby safeguarding the population and the community infrastructure. This study found that most US hospitals have wireless local area networks (LANs) with disaster medical response capabilities. The data indicate that combined with the wireless LAN, many hospitals have acquired personal digital assistants, tablets, and handheld personal computers, which are important disaster medical response resources. This research shows that the wireless LAN networks and remote input devices are in place to ensure a timely medical response to disasters within many US communities.

The magnetic Sun.

The nature of our star, the Sun, is dominated by its complex and variable magnetic fields. It is the purpose of this paper to review the fundamental nature of our magnetic Sun by outlining the most basic principles behind the way the Sun works and how its fields are generated, and to examine not only the historical observations of our magnetic star, but, in particular, to study the wonderful observations of the Sun being made from space today. However, lying behind all of this are the most basic equations derived by James Clerk Maxwell, describing how the magnetic fields and plasmas of our Sun's atmosphere, and indeed of all stellar atmospheres, work and how they influence the Earth.

Plain abdominal radiographs: can we interpret them?

INTRODUCTION: Plain abdominal radiographs commonly form a part of medical assessments. Most of these films are interpreted by the clinicians who order them. Interpretation of these films plays an important diagnostic role and, therefore, influences the decision for admission and subsequent management of these patients. The aim of this study was to find out how well doctors in different specialties and grades interpreted plain abdominal radiographs. MATERIALS AND METHODS: A total of 76 doctors from the Departments of Accident & Emergency, Medicine, Surgery and Radiology (17, 32, 23 and 4, respectively) participated in the study which involved giving a diagnosis for each of 14 plain abdominal radiographs (5 'normal' and 9 'abnormal'). They were also asked the upper limit of normal dimensions of small bowel and large bowel. One point was awarded for correctly identifying whether a radiograph was normal/abnormal, 1 point for the correct diagnosis and 1 point for the correct bowel dimensions, giving a total score of 30. RESULTS: Mean scores out of 30 for specialties were as follows: Accident & Emergency 13.1 (range, 2-22), Medicine 11.2 (range, 2-23), Surgery 15.0 (range, 8-24) and Radiology 17.0 (range, 14-20; P = 0.241). Mean scores out of 30 for different grades of doctors were as follows: pre-registration house officers 10.8 (range, 4-20), senior house officers 13.0 (range, 2-22), registrars/staff grades 13.8 (range, 2-23) and consultants 17.3 (range, 12-24; P = 0.028). Fifteen out of 76 (19.7%) doctors correctly identified the upper limit of normal dimension of small bowel; 24 out of 76 (31.6%) correctly identified the upper limit of normal dimension of large bowel. DISCUSSION: The level of seniority positively correlated with skills of plain abdominal radiograph interpretation. A large number of doctors were unable to give the correct upper limit of normal dimensions for small and large bowel. CONCLUSIONS: All doctors could benefit from further training in the interpretation of plain abdominal radiographs. This could perhaps take place as formal teaching sessions and be included in induction programmes. Until then, plain abdominal films should ideally be reported by radiologists where there are clinical uncertainties; important management decisions made by junior doctors based on these films should at least be confirmed with a registrar, if not a consultant.

Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival?

PURPOSE: This study set out to determine the impact of a positive circumferential resection margin (CRM) (R1-R2) and pathologic downstaging on local recurrence and survival in patients with borderline resectable or unresectable rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy (CRT). METHODS AND MATERIALS: A total of 150 patients with locally advanced rectal cancer were treated with long-course neoadjuvant CRT using low-dose folinic acid and 5-fluorouracil. CRT was followed 6-12 weeks later by surgical excision. The CRM rate and incidence, site, and pattern of local and systemic recurrences were recorded. The median follow-up was 25 months. RESULTS: The overall median survival was 37 months, with a 5-year overall survival rate of 34%. Of the 150 patients, 122 underwent curative resection; 12% had a complete pathologic response, and downstaging to pT1-T2 occurred in an additional 16%. A negative CRM (R0) was achieved in 65% overall (98 of 150). Local recurrence occurred in 10% of those with R0 resection and 62% of those with R1-R2 resections. Distant metastases occurred in 29% of those with R0 resections and 75% of those with R1-R2 resections. The 3-year disease-free and 3-year overall survival rate was 9% and 25% and 52% and 64%, respectively, for patients with and without a histologically positive CRM. CONCLUSION: After 5-fluorouracil-based CRT, a positive CRM predicted for a high risk of subsequent local recurrence and a 3-year disease-free survival rate of only 9%. For this reason, the CRM should be considered a major prognostic factor and should be validated in future trials as an early alternative clinical endpoint.

Effect of complement fragment 1 esterase inhibition on survival of human decay-accelerating factor pig lungs perfused with human blood.

BACKGROUND: The role of complement in hyperacute lung xenograft rejection has not been fully elucidated. The present study evaluates the effect of complement (C) 1 esterase inhibition on hyperacute rejection of human decay-accelerating factor (hDAF)-positive pig lung by human blood. METHODS: Using a modification of an established ex vivo model, right and left lungs from individual animals were surgically isolated and separately perfused. Pigs homozygous for hDAF were perfused with fresh human blood that was either untreated or treated with complement 1 esterase inhibitor (C1-Inh) at doses of 1 U/ml (n = 5), 5 U/ml (n = 3) or 10 U/ml plasma (n = 5). RESULTS: Only C1-Inh at 10 U/ml prolonged survival time (230 +/- 48.3 minutes) as compared with controls (65.6 +/- 26.5 minutes, p < 0.05) and diminished complement activation (C3a and C5a, p < 0.05). Interestingly, a low concentration of C1-Inh increased the pulmonary vascular resistance (PVR; 1 U/ml: 0.54 +/- 0.3; 10 U/ml: 0.19 +/- 0.08). Sequestration of neutrophils (92 +/- 3%) and platelets (64 +/- 13%) was not prevented by any concentration of C1-Inh. Tissue deposition of C3b and C5b-9 were diminished by hDAF expression, and further blunted by treatment, with 10 U/ml C1-Inh. CONCLUSIONS: Complement plays a critical role in early events of lung hyperacute rejection (HAR). However, even potent inhibition of C1 esterase and C3/C5 convertase, using serum C1-Inh in pig lungs homozygous for hDAF expression, does not prevent rapid lung injury. Our findings implicate innate immune pathways resistant to efficient complement regulation, and suggest a role for neutrophils and platelets in the lung's particular vulnerability.