CharonY

Most tests require isolation of RNA. It is a bit difficult and requires a lab (not to mention the subsequent RT-PCR). Antibody based assays are coming but are not optimized yet, and most (that I know of) require lab conditions to yield accurate results. To make it possible for accurate (diagnostic) self testing, they need to be highly optimized and error proof. That takes time and is not a priority, considering that other tests are running low in many areas. I should add that there are lateral flow immunoassays, but they alone are not good for diagnosis of ongoing infections as the immunoresponse is not fully characterized yet. I.e. they may be good if there was a strong response, but a negative test will have uncertainties associated with it. Fundamentally self-tests are also prone to user errors, even with simple tests, which is why even well-established tests (e.g. pregnancy tests) usually require additional confirmation. Here, the uncertainty is higher.

It is unclear as a) we do not know whether or in which patients influenza may result in different clinical manifestations b) studies are local with small sample sets which makes it difficult to build representative cohorts c) we do not know whether there is a relationship in infection process regardless of clinical outcome. That all being said, there is a paper (but I cannot quite recall the authors) which indicated that the influenza cases went down as COVID-19 went up in Wuhan. I do not recall the precise dates of the patients, so not sure whether it coincided with the shutdown. Edit: And did not come across any studies in the US yet.

As mentioned there are only few reports, mostly on cases with positive outcomes. One by Ding et al. (2020) J Med Vir has not found any more severe clinical indicators. The numbers of co-infection are based on small sample sizes and depending on how the cohorts are built (e.g. severity of symptoms) the outcome may be biased.

Took a look at the first posts and they look very good. Certainly more effort were put into them than I would realistically do. Don't think I would have anything to contribute (unless there are specific questions that went unanswered and I happen to have read something about it or have general molecular biological knowledge that applies). I don't think that there there is a database that would try to deconvolute that information. Given the current situation folks are probably more likely to be tested for COVID-19 than for influenza, meaning that after a positive I suspect that this would take precedence. There are case reports with co-infections reported in small studies (e.g. individual clinics) but I am not aware of large-scale surveys. Within hospitals the cases detected with co-infections were fairly low (but rarely quantified in detail).

There is some data out there, but typical molecular information are derived from animal models, rather than autopsies. It takes time to develop good animal or in vitro models and conduct the experiments. On top of that, creating targeted treatments based on biological information is really, really tricky, and takes even longer. Which is why medical research often skips the deeper biological parts at the beginning and focuses on outcomes instead. The ultimate reason is that biology is one of the most complex subjects out there and there is simply a ton we do not fully understand. Moreover, similar to the overall thrust of the post, more folks are interested in the applied bits. I.e. "treatment for the disease" is going to get more funds than "understanding the fundamentals of host-pathogen interactions", for example. While I may lament that from scientific and research interest point of view, I do see that the long-term research needs to take a seat on the back on this one. That being said, much of the pathophysiology is centered around the mechanisms related to adult respiratory stress syndromes (ARDS). The pattern is very similar to secondary haemophagocytic lymphohistocytosis and related hyperinflammation (or cytokine storm). One strategy is there to use cytokine-inhibition therapies, though they still remain to be tested.

Nope but considering that there are not really large scale reports of relapses, the signs are positive as a whole I'd say.

Why not both?

I do not think it is. Or rather there is no evidence that it might be the case. Rather the issue many countries is still undertesting and prioritizing tests on folks with symptoms. If you look at more fully tested populations there does not seem to be a vast discrepancy compared to China at comparable time points. On this point, the hygiene hypothesis is mostly used in the context of autoimmune diseases and allergies. I.e. low exposure to foreign substances might result in inbalances that cause the immune system to overreact (I think atrophy is not a good analogy, the responses are strong, but confused). Also when it comes to the adaptive part of the immune system, actual exposure is needed. At least in theory exposure to another related virus might raise imperfect antibodies which may attenuate the infection. But there is no data that suggests that at this point. Finally, especially when comparing to strongly urbanized countries like Taiwan and South Korea, I doubt that there are many differences in terms of hygiene. I think you will find larger differences within each country between, say rural and urban centres. Especially in areas with a lot of of livestock.

I am not sure whether it was the same one that I have seen, but if I understood it correctly these are total positive for virus but asymptomatic cases, rather than exclusively new ones (but I may be mis-remembering and can't find the report now). In their official reports China only listed symptomatic cases (originally via RNA test, later also those with confirmed symptoms via CT but without additional test). While it may have made clinical sense at that time to focus on symptomatic cases, especially since all positive cases were isolated anyway, it is now a liability. Exactly that.

No, I get that. I was just hoping naively that such essential agencies would be left to do their work, especially during emergencies. But similar to FEMA, it does not seem to be the case. Yes and some countries (Swededen, I think for example) have stopped as in addition to low or lack of efficacy, there are also more reports on side effects.

SJ, thanks for the link. I was not aware of that and it is very worrying. I generally hold the CDC in high regard, but that has dampened quite a bit.

There is also the other explanation that he is not able to deal with complex situations. When offered a potential solution, he seized it as in his world things become truth if repeated often enough.

There is actually also the issue that some practitioners have taken to prescribe it as a prophylaxis agent, without any proven benefit. The broader issue here is probably that especially in times of crisis folks would normally (and perhaps rightfully) assume that the information provided by the government is based on the current best available information and is part of the (inter)national strategy to address the issue. But the current US administration is not stepping back and let the health professionals provide the info (contrast that with the briefings in Canada for a start difference) but rather provides contradicting information. As such it is no unsurprising that folks take it to themselves to do things, unfortunately.

There are also concerns that pitching hydrocholorquine as an unproven drug can (and starts) to cause shortages for their intended use.

Folks, can I ask everyone to stay on topic and/or open a new thread elsewhere to discuss this?

Partially, a lot is also because of the imbalance between public dissemination and the strength of the data. Scientists are usually very critical to overhyping results (and specific endorsement from POTUS could amplify it). There a couple of letters you might find interesting: https://annals.org/aim/fullarticle/2764199/use-hydroxychloroquine-chloroquine-during-covid-19-pandemic-what-every-clinician https://annals.org/aim/fullarticle/2764065/rush-judgment-rapid-reporting-dissemination-results-its-consequences-regarding-use

Well, there are no strong evidence. While numerous treatment options have been and are being tested, so far the reports are at best weak. As perhaps discussed earlier hydroxychloroquine (either alone or in combination) has shown some faster recovery in cohorts with weak symptoms (based on a French and Chinese study). Most recent studies that included patients with more severe symptoms did not see any benefit over placebos. Molina et al (2020) Med et Mal Inf.. It still in pre-proof (i.e. peer reviewed but not typeset yet) so here is also the title, which is pretty clear: "No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection". All were pilot studies, so more studies would be needed to establish effects (or lack thereof) fully. Some researchers find the strong focus on it a bit worrying as the evidence for efficacy is still rather lacking. For vitamin C as well as for plasma treatment I have not seen any trial results yet, so I am not sure how solid the data can be.

Well, to be precise it leads to lung damages. While that can make the patient more susceptible to secondary infections, it is not necessarily connected. It ultimately depends on what the patients dies from first (if they die). I also do not think that folks have actually a consensus on whether the 1918 influenza epidemic actually caused things like cytokine storms. There are papers out there that have argued that the vastly different outcomes in various subgroups of patients indicates that host immune intensity actually plays a role (and would also be in agreement with the dominant role of secondary infections. I know that folks like to pick up the Spanish flu due to the large number of deaths, but for a variety of reasons it is not a good reference point (not least because we only have limited pathobiological information from that time). A cytokine storm in itself can be deadly. In the case where we have good data (as obviously the assumption on the 2019 pandemic are based on forensic reconstruction and indirect evidence), such as the 2009 swine flu pandemic, severe alveolar damage and signs of capillary damages were observed, these then can to lead to organ failure. In addition, the cytokines can also spill into circulation which can cause multi-organ dysfunctions. Either way the patient is gets in a really bad shape, which also makes the vulnerable to secondary infections. However, even if isolated in a sterile room, there is a risk of organ failure. The latter usually happens fairly fast, those that survive beyond that point are usually those that are at risk of getting infected.

Ah, no. Cytokines are signalling molecules produced by your body. Some of them are proinflammatory and are produced as response to infections. If they get too high while reacting to an infection the inflammation response of your body can start to cause damage. These responses tend to be stronger in younger folks (or conversely, in older folks immune responses are often muted). In very bad cases theses pro-inflammatory responses can lead to death, which has happened during the Spanish flu as well as Swine flu, which caused many of the deaths among younger folks.

I do not have any real expertise on that, but the connection is complex and different pathways are activated (I'd have to ask my wife for more insights). But on the outcome levels there is evidence that if you are already suffering from inflammation, virus infection can have worse outcomes. Conversely respiratory diseases seem to make folks more susceptible to things like asthma (or at least worsen symptoms). But the immune system is notoriously complex. It is perhaps not surprising that we do not fully understand allergies yet, for example (with quite a few uncertainties regarding regarding the hygiene hypothesis, for example). It should also be acknowledged that immune responses need to be modulated properly. It is not a system that works better the stronger its responses are. In fact, certain aspects can result in damages themselves (cytokine storms have made the press a while connected with the swine flu pandemic, for example).

Yes there are some conflicting results. A few studies from Italy and China indicate no difference in the load between asymptomatic and severe patients, for example. Another one suggests that the load is only different in swabs. Also animal studies with other coronaviruses suggest worse outcome with higher loads. As with anything, the knowledge is very much in flux.

AFAIK the minimal infectious dose for SARS-Cov2 has not been established yet. I.e. no one knows yet.

It is a common observation that pathogens with long evolutionary history tend to become less virulent. Our genomes are quite full with dormant viral sequences, indicating that at some point they just became part of us. There is an assumption that there is an optimum on what level is the optimum, depending on a variety of host-pathogen factors (e.g. resistance). There has also been experimental evidence in simple systems. However, due to the nature of interact there can be cases where virulence can increase (but again, the current outbreak does show how effective tempering virulence can be). It also means that pathogens jumping hosts are often maladapted and may have suboptimal virulence (e.g. too high).

Another random thought regarding SARS-Cov vs SARS-cov2 is that the latter is much less virulent. But in this case it does show how reduced virulence actually leads to far wider spread.

There are easier explanations. The first is that in some states there was earlier spread from folks that returned from holidays and there were carnival festivities resulting in major infections in NRW. In Baden-Wuertemberg folks travelling from Italy were diagnosed with COVID-19 in February for example. Another element is that aside from major cities the population density in East Germany is fairly low (unless it has changed in recent years) and I would think that together with spread pattern it could account for most of the differences. There are also differences in the length and time of winter holidays in the different states, so depending on when they are, there might also be different timing in when folks returned from holidays. Those coming back earlier might have evaded infection in Italy, for example, in addition to the point MigL made..