You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Introduction {#s1}
============

The fatal outcome from coronavirus disease 2019 (COVID-19) is attributed to terminal respiratory failure secondary to bilateral pneumonia from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection ([@B1]--[@B3]). However, a subset of younger patients with severe COVID-19 suffer from uncontrolled hyperinflammation and succumb to acute organ failure and cardiac arrest while still being adequately oxygenated ([@B4]--[@B7]). The "cytokine storm" or "cytokine release syndrome" (CRS) has been implicated in adverse patient outcomes, with interleukin-6 (IL-6) representing a key inflammatory mediator and surrogate marker of CRS ([@B8], [@B9]). The U.S. Food and Drug Administration (FDA) approved the expanded access to a recombinant monoclonal antibody against human IL-6 receptors (tocilizumab), and a randomized controlled phase 3 clinical trial on tocilizumab in adult patients suffering from severe COVID-19 is currently ongoing ([@B10]--[@B13]). The available empirical treatment modalities include a wide spectrum of off-label indications for antirheumatic agents, including cytokine inhibitors, corticosteroids, intravenous immunoglobulin, and other novel anti-inflammatory molecules ([@B13]--[@B15]). However, the exact mechanisms of hyperinflammation and hypercoagulation in COVID-19 patients remain enigmatic and poorly understood.

Role of Complement in COVID-19? {#s2}
===============================

The complement system serves as a "first line of defense" against invading viruses and as a bridge between innate and adaptive immune responses ([@B16], [@B17]). Interestingly, complement has received limited attention in the quest for effective anti-inflammatory treatment strategies in spite of multiple intuitive targets in COVID-19, and most of the prevalent anti-inflammatory agents currently under investigation do not include a consideration for complement inhibitors ([@B8], [@B13], [@B14]). Complement activation has been previously implicated in the pathophysiology of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) which are severe infectious diseases mediated by coronaviruses that are similar to the pathogen responsible for the current COVID-19 pandemic (SARS-CoV-2). Experimental studies revealed that complement activation occurs in response to SARS-CoV infection, and mice deficient in genes for the central complement component C3 were shown to be protected from pulmonary inflammation and respiratory failure ([@B18]). Furthermore, the complement activation fragment anaphylatoxin C5a is a potent mediator of acute lung injury in highly pathogenic viral infections, including MERS and SARS ([@B19]). The pharmacological blockade of the C5a receptor (C5aR, CD88) attenuated pulmonary inflammation in a mouse model of MERS-CoV infection, and C5aR blockade led to decreased viral replication in infected lungs ([@B20]). In addition, there is an established crosstalk between the coagulation cascade and the immune proteolytic system through thrombin- and plasmin-mediated complement activation, and complement activation was recently postulated to induce thrombotic microangiopathy in COVID-19 ([@B21], [@B22]). In light of these presumed "key" pathophysiological features mediated by complement activation in response to coronavirus infections, it appears intuitive to consider the pharmacological complement inhibition as part of the "expanded access" paradigm to off-label indications for anti-inflammatory treatment strategies in COVID-19.

Pharmacological Complement Inhibition {#s3}
=====================================

There are currently multiple pharmacological complement inhibitors available for the treatment of rare inflammatory and autoimmune disorders in humans ([@B17], [@B23], [@B24]). Preliminary case reports from "hot zones" in Italy outlined the anecdotal success by compassionate use of the complement C3 inhibitor AMY-101 (Amyndas Pharmaceuticals, Glyfada, Greece) and by administration of the anti-C5 monoclonal antibody eculizumab (Soliris; Alexion, Boston, MA) in the rescue of critically ill COVID-19 patients ([@B25], [@B26]). From a mechanistic perspective, AMY-101 inhibits cleavage of C3, the central component in the complement cascade, and thus prevents the formation of the C3 and C5 convertases and the subsequent release of the inflammatory mediators C3a and C5a and formation of the tissue-damaging membrane attack complex (MAC; C5b-9). Further downstream, eculizumab prevents cleavage of C5 and the formation of the inflammatory anaphylatoxin C5a and of the MAC/C5b-9 ([@B27]). Indeed, a recent study from Milan, Italy, reported elevated levels of the C5 activation fragment C5a and soluble MAC (sC5b-9) in plasma samples of patients with severe COVID-19, confirming the notion that C5 blockade represents a potentially relevant therapeutic consideration ([@B28]). A prospective randomized controlled trial evaluating the safety and efficacy of eculizumab in patients with COVID-19 infection is currently under way ("CORIMUNO-19" trial). Several additional complement inhibitors are under consideration for compassionate use in COVID-19 ([Figure 1](#F1){ref-type="fig"}). Of these, avdoralimab (Innate Pharma, Marseille, France) is an anti-C5aR monoclonal antibody that prevents binding of C5a to its receptor (C5aR, CD88), while IFX-1 (InflaRX; Martinsried, Germany) is a monoclonal antibody that targets C5a, preventing it from interacting with the C5aR. In addition, the recombinant human C1 esterase inhibitor conestat alfa (Ruconest; Pharming Group & Salix Pharmaceuticals, Bridgewater, NJ) is a specific inhibitor of the classical complement activation pathway which is currently approved for treatment of hereditary angioedema. This C1 inhibitor (C1-INH) is under consideration as an open-label, multicenter pilot trial in adult patients with SARS-CoV-2 pneumonia ("PROTECT-COVID-19" trial).

![Therapeutic targeting options of the complement cascade in COVID-19. The schematic depicts the complement activation pathways and the sites of inhibition by the various pharmacological compounds.](fimmu-11-01661-g0001){#F1}

In addition to the classical and alternative complement activation pathways, the lectin pathway provides another new promising avenue for pharmacological targeting in COVID-19. The complement lectin pathway is activated when a pattern recognition receptor, such as mannose binding lectin (MBL), binds to pathogen-associated molecular patterns expressed on the surface of invading microorganisms ([@B29]). The complement cascade is then initiated by MBL forming complexes with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2, respectively) in a similar fashion that C1 is activated through the classical pathway, leading to C4 and C2 cleavage and assembly of the C3 convertase ([@B30]). A historic case-control study on 569 SARS patients demonstrated a role of MBL gene polymorphisms in contributing to the susceptibility of viral invasion, and implied that the complement lectin pathway represents the "first line of defense" against SARS-CoV infection ([@B31], [@B32]). This notion is supported by recent histopathological findings in patients with severe COVID-19, demonstrating the deposition of complement lectin pathway components MBL and MASP-2, as well as complement activation fragments C4d and C5b-9, in the microvasculature of human lung tissue specimens with SARS-CoV-2 infection ([@B21]). Narsoplimab (OMS721; Omeros Corporation, Seattle, WA) is a novel human monoclonal antibody that targets MASP-2 and prevents lectin pathway-mediated inflammation and endothelial damage in a variety of autoimmune disorders ([@B33]). The safety and efficacy of narsoplimab is currently being investigated in a phase 2 dose-escalation cohort study in patients with complement-mediated hyperinflammatory conditions, including hematopoietic stem cell transplantation-associated thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome ([@B33]). Several other human complement inhibitors are currently in phase 2 or phase 3 clinical trials for different indications, raising the possibility that FDA-approved complement inhibitors will quickly join the developing arsenal of therapeutics for treatment of COVID-19 patients beyond compassionate use ([@B34]--[@B36]).

Summary {#s4}
=======

In summary, the complex immune dysregulation observed in patients with severe COVID-19 remains poorly understood. The pharmacological targeting of complement activation in severe COVID-19 may attenuate the increased mortality observed in a younger cohort of patients with persistent hyperinflammation, thromboembolic complications, and cardiac arrest beyond terminal respiratory failure associated with SARS-CoV-2 pneumonia. Moving forward, it will be important to carefully monitor for beneficial and adverse effects associated with therapeutic complement inhibition ([@B36]). In addition, well-designed clinical studies are needed to determine patient outcomes by inhibiting complement in isolation vs. a combination therapy by targeting other key mediators responsible for the "cytokine storm" ([@B37]). Finally, from a patient safety perspective, we will have to determine the extent of retained innate immunity required for viral clearance and prevention of secondary bacterial infections.

Author Contributions {#s5}
====================

Both authors conceived the concept of this article and wrote the manuscript together.

Conflict of Interest {#s6}
====================

PS has a United States Patent No. 11,441,828 entitled: "Inhibition of the alternative complement pathway for treatment of traumatic brain injury, spinal cord injury, and related conditions." PS is employed by HCA Healthcare as the chief medical officer at the Medical Center of Aurora. SB has a United States Patent \# 10,535,004 "Methods and compositions for diagnosis and treatment of meningitis." SB is employed by CNine Biosolutions LLC, a company involved in developing complement diagnostic assays. The authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest. Specifically, there is no conflict of interest whatsoever by either of the two authors related to the pharmacological agents and companies cited in this manuscript.

[^1]: Edited by: Yolande Richard, Institut National de la Santé et de la Recherche Médicale (INSERM), France

[^2]: Reviewed by: Cecilia Garlanda, Humanitas University, Italy; Ka Man Law, University of California, Los Angeles, United States

[^3]: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology