Since my last newsletter, none of the new preprints* look interesting enough for deep dives, but a number deserve a mention. Here they are.
One showed that immune system cells known as neutrophils respond to SARS-CoV-2, the coronavirus that causes COVID-19, with “neutrophil extracellular traps” (NETs), which play a role in damaging lung tissue. I first learned about NETs at the Experimental Biology conference in 2011. The neutrophils rearrange their DNA to form a net-like structure and then spit it out into their environment to trap invaders. It's very reminiscent of Spiderman.
Another found that there is very little difference in viral load between COVID-19 patients of different ages, across decades from 0-9 to 90-99. They used two different tests, one finding a very slight and probably meaningless increase in viral load with age, and another finding a slight decrease with age when analyzed as a continuous variable, and a randomly zigzagging pattern that was not statistically significant when analyzed by decade. This makes it unlikely that children are less often symptomatic because of viral load, and suggests that differences in their immune response are more likely at play.
While no one has shown exactly what makes a live human able to infect another live human, the authors of this study had previously shown that there is a certain threshold of viral load required to be able to infect cells in a lab dish using human samples. Presumably this correlates with the ability of a human to infect another human. About 30% of children under six had viral loads exceeding this threshold, 37% of all people 19 and younger, and 51% of those aged 20 and above. This offers support to the idea that children without symptoms can transmit the virus, but doesn't support it clearly enough to quell the controversy around asymptomatic transmission.
A third found that women mount a much more robust T cell response to COVID-19 than men. It is well established that low T cell counts correlate with poor outcomes, so this might help explain why men are more likely to have worse outcomes than women.
A fourth paper out of Cuba suggested that treatment with interferon alpha-2b, a genetically engineered form of type 1 interferon, increases the rate of full recovery 3.6-fold from 26.1% to 95.4%, and cuts the fatality rate down almost 70% from 2.95% to 0.92%. However, this study was not randomized, and the reason that less than 7% of the patient population did not receive the interferon was simply that they had contraindications. Here's a long list of such contraindications. 56.6% of those not getting interferon had co-morbidities, but only 3.2% of those getting interferon did. This strikes me as terrible evidence. I've covered why interferon may be harmful in the context of COVID-19. I'm ready to reverse my position in the face of high-quality human evidence, especially a randomized controlled trial, but this Cuban paper doesn't make the cut. I remain bearish on interferon.
A fifth paper out of Florida suggested the anti-parasitic drug ivermectin might be useful in COVID-19. Like the Cuban paper, this study was observational and was not randomized. Unlike the Cuban paper, however, only 61% of the 280 patients were given the treatment of interest, and most confounding variables were evenly distributed between the two groups. In fact, hypertension was somewhat more common in those treated with ivermectin and eight out of the nine HIV patients were in the ivermectin group. Mortality was 40% lower in the ivermectin group (15% vs. 25.2%).
I previously covered why the in vitro data suggested concentrations of ivermectin required to be antiviral toward SARS-CoV-2 are well into the unsafe range. I am now somewhat agnostic about the utility of ivermectin and would like to see a randomized controlled trial. My suspicion is that it might have effects completely independent of the antiviral properties that prevent the disease from becoming severe and fatal, and that the antiviral properties shown in vitro might be irrelevant. This framework of understanding ivermectin could reconcile the unsafe high concentrations needed for antiviral activity in vitro with the apparent utility of the drug in humans.
Three new papers (here, here, and here) on the interleukin-6 (IL-6) blocker tocilizumab were released. None of these were randomized; all were observational.
One found that giving the drug early rather than late was associated with an 80% lower risk of mortality (13.5% vs. 68.2%) and a 3.3-fold greater likelihood of being released from the hospital. What constituted “early” and “late” was not clearly defined, but co-morbidities were evenly distributed between the two groups.
The second compared patients who were or were not treated with the drug. Some of the confounding variables were different between the groups, but they statistically adjusted for the differences. In the unadjusted analysis, those receiving the drug were 71% less likely to die in a 28-day followup; in the adjusted analysis, those receiving it were 59% less likely to die. Similar results were found when invasive mechanical ventilation was grouped with 28-day mortality.
The third paper found that the drug was associated with a more than 60% lower risk of ICU admission and mortality only in those with CRP over 150 mg/L, indicating a very strong inflammatory response. In those with lower CRP, the drug was associated with a very slight increased risk that was not statistically significant.
Overall, these studies suggest that early treatment with tocilizumab in those with strong inflammatory responses indicated by very high CRP levels is beneficial. Nevertheless, when the randomized controlled trials are finished we will have much stronger evidence to confirm or refute this. The preliminary evidence favoring tocilizumab strengthens the case that efforts to restrain massive elevations in IL-6 should be helpful. I have suggested lactoferrin and vitamin D on this basis.
A new meta-analysis (a study that pools the results of other studies) found that ACE inhibitors and angiotensin-receptor blockers (ARBs) were associated with a 44% lower risk of a severe disease and were not associated with mortality at all. At the beginning of the COVID-19 pandemic, concerns were raised that these could increase ACE2 levels, which is the protein that allows the virus to enter our cells. As studies came out suggesting they don't worsen the risk of disease, many took this to imply that raising ACE2 isn't harmful. However, I previously pointed out that these drugs are not associated with increased ACE2 in human lungs. A tenth new paper found that, in male mice, these drugs do not impact ACE2 in lung, intestine, kidney, or heart. The same was true of TMPRSS2, a protein needed to allow the virus to fuse with the cell membrane after it binds to ACE2.
An eleventh new paper found that, in localities within England and Wales, for every 1% increase in the proportion of the population who are ethnic minorities, COVID-19 deaths increase by 5.1 per million. The authors concluded, “We suggest that this is a consequence of social and economic inequalities, including among key workers, driven by entrenched structural and institutional racism and racial discrimination. We argue that these factors should be central to any investigation of ethnic inequalities in COVID-19 outcomes.”
This is very difficult to square with the data from the UK Biobank, where adjusting for socioeconomic inequality only reduced the increased risk among blacks from 5.5-fold to 4.3-fold, and only reduced the increased risk among South Asians from 2.8-fold to 2.4-fold. Socioeconomic inequalities might contribute to roughly 20% of the racial disparities in this disease. While important, that leaves the lion's share of the disparity unexplained, suggesting it lies in interactions between the pathogenesis of the virus and key genetic variations that vary across ethnic populations in prevalence. As proof of principle, I previously covered how the C deletion in the human gene MX1 varies dramatically between North Americans and Europeans, on one hand, and East Asians on the other, and how this explains 91% of the variation in the spread of the viral G mutation. We need to study the biology of the racial disparities intensively in order to understand them and remedy them.
The twelfth and final paper I'm covering showed that a saliva-based at-home collection test for COVID-19 agrees with existing testing methods 97-98%, and maintains consistency with up to 56 hours of simulating shipping conditions. The test is made by Phosphorus, and is the second saliva test approved by the FDA after one made by Rutgers approved in May. Hopefully this will improve the accessibility of at-home testing.
That's all for today!
Stay safe and healthy,
Chris
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.