Correct my H5N1 research ($reward)

I love this detailed list. I've responded in-line to every one, but feel free to ask more questions, here or over email. 

1. Livestock vs. Wild Birds
   The distinction between livestock and wild birds is significant. Livestock are in much closer contact with humans and are biologically closer as well. How granular of an analysis are you interested in here?

I care about wild birds to the extent they're spreading disease to livestock or serve as reservoirs.

I've also heard a wide number of mammals have been infected. I care about this to the extent it affects humans and livestock. E.g. does this suggest it's airborne after all, or say something about the mutation rate?

1. US-specific H5N1 Trends
   It's peculiar that H5N1 seems so prevalent in the US. Could this be due to measurement bias, or does the US simply have more factory farming? How interested are you in exploring the reasons behind this trend?

I'm interested in quantifying the quality of US surveillance, but otherwise deprioritize this.  

1. Citations and Depth
   While most points aren’t cited (which is fine), it might be valuable to compile both a list of key aspects and resources for further reading. Are you looking for a more polished, thoroughly cited document?

Citations are important to the extent they let people check and build on your work. But if it's a widely known consensus such that it's easy to look up but complicated to cite, it's not important to add a citation. E.g. my fact about RNA segments is very easy to check but would have been annoying to find a citation for because I learned it 20 years ago. 

Overall citations for the current state of things (e.g. how many human infections of unknown providence) are more important than citations for basic science.

1. Biological Factors of Severity
   Binding to human receptors is just one factor controlling the severity and infectiousness of a virus. Would you like a deeper dive into the biology of respiratory infections and what makes them dangerous?

Low priority. Pass on resources if you find them but don't bother with synthesis. 

1. Tamiflu and Xofluza
   Wikipedia notes that Tamiflu has limited evidence of being worth the side effects. Are you interested in a detailed evaluation of its effectiveness? Similarly, how interested are you in assessing the likelihood of shortages and efficacy of Tamiflu/Xofluza during an H5N1 pandemic?

I'm very interested in tamiflu's efficacy. Some specific important questions: 

• is tamiflu more effective when taken very early? when did the people in the studies that found low efficacy take tamiflu? My understanding is it is effective for prophylactic use, which suggests earlier is better.
• how does the math change if the flu is more dangerous or virulent?

Not interested in assessing likelihood of shortages.

1. Over-the-counter Tests
   Is the issue a lack of over-the-counter tests specifically for H5N1, or for flu in general? General flu PCR testing is likely available—should we investigate this?

My assumption is the European OTC tests will catch H5N1, but if that's wrong I'd like to know. 

I don't care much about non-home tests, except I am interested in the national flu surveillance program and how much we can trust it. 

1. Trajectory of Illness
   For past H5N1 cases, is there a treatable "window of opportunity" before the infection becomes severe? How critical is it to determine whether mild cases might escalate and require aggressive intervention?

Very interested in this. 

1. Historical Epidemics
   I could pull together a list of relevant modern epidemics (human-to-human airborne transmission without an animal vector). Are there any specific criteria you'd like to prioritize?

The reference class is "things that got at least as far as H5N1 did this year"- widespread in livestock and with some humans infected.

1. Cross Immunity
   While cross immunity seems important, determining decision-relevant information may be challenging. Would you like a summary of existing knowledge or only actionable insights?

Medium priority for a summary of existing knowledge, bonus points for a quantitative model even if it's low confidence.

1. Respiratory Infection Dynamics
   Epidemiologists suggest that respiratory infections are deadlier lower in the lungs but more infectious higher in the system. Is this a fundamental tradeoff? Would a "both-and" virus be possible? What evolutionary advantages might viruses have in infecting the lower lungs?

If you happen to stumble on relevant information I'd like to hear it, but I don't want synthesis.

1. Government Stockpiles and Interventions
   What stockpiles of H5N1 vaccines exist? What options are available for increasing testing and vaccination of livestock? How are governments incentivizing medication, vaccine, and PPE production?

Yes to stockpiles, yes to shallow investigation of options for livestock.

1. Political Considerations
   Should we examine how a Trump presidency or similar political scenarios might influence the interaction between local and federal health agencies?

No.

1. Species-to-Species Spread
   The rapid spread of H5N1 to multiple bird and mammal species raises the question of whether humans will inevitably be affected. Is this worth exploring in-depth?

Yes.

1. Mortality and Long-term Effects
   What demographics do other flu strains tend to affect most? Are there long-term side effects comparable to "long COVID"?

We know who normally gets hit hardest by diseases, I'm only interested in deviation from that.

No to "long flu", because I am already convinced it exists but the data on it is bad.

1. Mutation and Vaccine Efficacy
   How quickly do flu strains, especially H5N1, tend to mutate? What implications does this have for vaccine efficacy and cross-reactivity? How much asymptomatic spread occurs with flu, and how long does it remain airborne?

Yes to mutation rate, especially if you can quantify what's needed to allow human-to-human transfer.

Yes to general flu knowledge like asymptomatic period and time airborne.

1. No Deaths Yet
   How should we update based on the fact that, contrary to past occurrences of H5N1 that had a ~50% CFR, none of the 58 confirmed cases have died?

 

This paper says there has been one death from the current clade. I'm very interested in knowing if that's correct. It also says tamiflu was found to reduce mortality in earlier, more deadly forms of H5N1.

That's a lot, so here are my top three priorities: vaccine efficacy (wide confidence intervals are fine), treatment efficacy, and likelihood of human-to-human transmission.

How sure are you that flu is generally spread through fluids? It seems like the medical system is ~prejudiced against the concept of airborne transmission. 

The use case is a lesswrong post people use to make decisions (which could be written by me, or you, but it's looking like @DirectedEvolution [LW · GW]).

"Is there something better than tamiflu?" - Thank you for posing this question, I enjoyed researching it. 

I'm going to propose two candidates that could be superior against H5N1: Aspirin (acetylsalicylic acid) and Methylene blue (methylthioninium chloride). 

Aspirin 

First, consider aspirin’s safety profile. For short-term use—relevant in acute infections—the risks are minimal for most individuals. GI upset, often cited as a concern, is only marginally higher than placebo (source: PMC3586117). The notable exception is its association with Reye's syndrome in children, but this is exceptionally rare. The risk-benefit calculus remains favorable for adults, particularly in acute scenarios.

Efficacy-wise, aspirin’s NF-κB-inhibiting activity shows promise as an antiviral. It has demonstrated robust effects against H5N1 in vitro and in vivo (source: Wiley). This pathway is a compelling mechanism of action that Tamiflu does not directly address, positioning aspirin as a strong candidate for consideration.

Methylene blue

Next, methylene blue is another plausible alternative. Its safety profile for short-term use is generally acceptable, barring contraindications such as risk of serotonin syndrome, hypersensitivity, or severe renal impairment (source: Medsafe). For those without contraindications, it represents a well-tolerated option.

Methylene blue's broad-spectrum antiviral properties are underappreciated. It has shown potent virucidal activity against H1N1 (source: PMC8275569), and while H5N1-specific data is lacking, the mechanism of action suggests potential efficacy. Notably, there’s already a patent application exploring its antiviral indications (source: WO2007086995A2). Given this, methylene blue is a viable contender worthy of further clinical study.

Comparing with Tamiflu 

Tamiflu has well-documented side effects—nausea, vomiting, diarrhea, and abdominal pain—that overlap with the profiles of both aspirin and methylene blue (source: Medsafe Tamiflu). While tolerable for most, its mild benefits against H5N1 are unlikely to significantly outperform the mechanistic potential of aspirin or methylene blue (source: JHEOR).

Conclusion 

In a pandemic preparedness scenario, Aspirin and Methylene blue deserve serious consideration alongside Tamiflu. They offer distinct mechanisms of action, robust preliminary data, and manageable safety profiles. If you're prioritizing interventions that maximize cost-effectiveness and theoretical efficacy, these "old drugs" might hold the key to new antiviral strategies. Rational prioritization of research and clinical trials could unlock their full potential.

Disclaimer: I am not your doctor, please see a medical professional for personalized advice. The information presented is only for the interests of research and should not be interpreted as clinical advice.