Vaccines

Moderna confirmed it will begin a 30,000 patient trial of its Covid-19 vaccine in July 2020. [CNBC] The primary endpoint will be prevention of Covid-19 infection. The secondary endpoint is the prevention of severe disease.

This latter endpoint suggests that the company does not expect the vaccine to be anywhere near 100% effective because an effective vaccine completely prevents disease. Why, then, would they use the trial to find out if the vaccine reduces severity of Covid-19? This seems to suggest that many vaccinated persons will still become ill, and the company hopes the vaccine will lower the percentage of severe cases among those who become ill. What is a severe case of Covid-19? It’s a case that requires hospitalization, perhaps transfer to ICU, perhaps mechanical ventilation, and/or death.

What can we expect from this or any other Covid-19 vaccine? Reduction in risk of being infected, and if infected, reduction in severity of disease. The question is how many older persons (over 65 years represents 80% of Covid deaths) will still die of the disease. If the vaccine only works in healthy persons, with strong immune systems and therefore strong reactions to the vaccine, it wouldn’t have enough of an effect on the case fatality rate.

Research

Important new research came out this past week. Be advised that the conclusions of any individual study need to be confirmed by other studies and perhaps other types of research.

Pregnancy

A new study looked at the effects of SARS-CoV-2 infection on the fetus in first trimester pregnancies. [1]

Their conclusion is that Covid-19 does not harm the fetus when the mother becomes infected during her first trimester: “Conclusion Maternal SARS-CoV-2 infection did not seem harmful in first trimester pregnancies.” This good news should be tempered by another study which, as this news report explains, found that the SARS-CoV-2 does considerable harm to the placenta.

“Most of these babies were delivered full-term after otherwise normal pregnancies, so you wouldn’t expect to find anything wrong with the placentas, but this virus appears to be inducing some injury in the placenta,” said senior author Dr. Jeffrey Goldstein, assistant professor of pathology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine pathologist. “It doesn’t appear to be inducing negative outcomes in live-born infants, based on our limited data, but it does validate the idea that women with COVID should be monitored more closely.”

Hydroxychloroquine

More research indicating that perhaps hydroxychloroquine does not work as well as we had hoped. “A pooled analysis of recently published studies suggests no additional benefit for reducing mortality in COVID-19 patients when Hydroxychloroquine is given as add-on to the standard care.” [2] Other studies have shown modest benefits. One study showed that azithromycin by itself worked very well, and adding hydroxychloroquine only provided a small additional benefit: mean times to clinical recovery for symptomatic treatment, 25.8 days; azithromycin alone, 12.9 days; and azithromycin plus hydroxychloroquine, 9.2 days. [3].

Another study found that hydroxychloroquine did not work as a prophylaxis against Covid-19 [6]. At this point, especially given the dangers of QT elongation, it seems that azithromycin by itself is better than either hydroxychloroquine by itself or even hydroxychloroquine plus azithromycin.

Vitamin D

The evidence in favor of taking vitamin D supplements continues to pile up. A new study found that untreated vitamin D deficiency was associated with a 77% increase in likelihood of Covid-19 infection. Persons with sufficient vitamin D were 56% less likely to become infected with Covid-19. [4]

Ivermectin

As the evidence against hydroxychloroquine increases, the evidence in favor of ivermectin is also increasing. In a new study, the use of Ivermectin in hospitalized Covid-19 patients reduced mortality, “especially in patients who required higher inspired oxygen or ventilatory support”. Controls were not randomized. Patients treated with ivermectin were 48% less likely to die; patients with severe pulmonary disease were 85% less likely to die [5]. Compare this result to a recent trial in which “13.9% of the remdesivir patients had died compared to 12.8% of patients in the control arm.”

The dosing of ivermectin is 18 mg once. It’s safety profile is well-established. And when not used to treat parasites (its original purpose), there are even fewer side effects. Read about a Bangladeshi study using ivermectin and doxycycline.

Covid-19 vs. the Immune System

There are two proteases used by SARS-CoV-2 in order to convert two long non-functional viral proteins into many smaller functional proteins. The proteases cleave the protein at specific places along the amino acid chain. PLpro cleaves in three places, while 3CLpro (also called Mpro) cleaves in 11 places. We’ve known this for, what seems like a long time, several months now.

But just this past week a study was published with asserted that these two proteases have a secondary function. PLpro (NSP3) cleaves one, and 3CLpro (NSP5) cleaves two more proteins involved in the human immune system [7]. The SARS-CoV-2 virus uses two of its proteases to attack the immune system by cutting up proteins which have important functions in controlling immunity to viruses.

“Direct cleavage of IRF3 by NSP3 could explain the blunted Type- I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients.” [7]

The cleavage of immune system protein “IRF3” disrupts the response of the innate arm of the immune system to the viral infection. Then the cleavage of NLRP12 and TAB1 results in hyper-inflammation which can kill the patient in a so-called cytokine storm. The take-away is that treatment of Covid-19 should include medications that inhibit both viral proteases, so as to spare the immune system from this attack.

The ACEi/ARB drug debate

In a new study, discontinuing ACEi/ARB drugs more than doubled mortality for hospitalized Covid-19 patients [8]. It might seem that continuing ACE inhibitor or Angiotensin Receptor Blocker drugs during Covid-19 infection would be counterproductive. But a recent study found that discontinuing these drugs greatly increases risk of death in these patients.

“A total of 397 patients with COVID-19 were included; 14.1% continued ACEi/ARB therapy, 29.5% discontinued ACEis/ARBs at time of hospitalization, and 56.4% did not take these drugs at home. Mortality rates were 12.5% in the continuation group, 27.4% in the discontinuation group, and 17.4% in patients not taking ACEis/ARBs at home (P = 0.036).” [8]

The patients who continued taking ACEi or ARB drugs had a lower mortality rate than patients who either were not on these types of drugs, or who were on them and discontinued taking them. Discontinuation increased risk of death by 2.19 times over those who continued taking them. And, interestingly, those who remained on the drugs did better even than those patients never taking them. Taking these types of drugs indicates probable co-morbidity, which should generally increase mortality. Yet the drugs seem to confer some type of benefit, as patients continuing the drugs were 28% less likely to die that patients never on them.

Perhaps these drugs could be used as a type of treatment for Covid-19. In any case, there’s enough evidence now for physicians to keep their patients on ACE inhibitor or ARB drugs, rather than discontinuing them.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

Endnotes

1. la Cour Freiesleben, Nina, et al. “SARS-CoV-2 in first trimester pregnancy-does it affect the fetus?.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.06.08.20125195v1

2. Patel, Tejas K., et al. “Does Adding of Hydroxychloroquine to the Standard Care Provide any Benefit in Reducing the Mortality among COVID-19 Patients?: a Systematic Review.” Journal of Neuroimmune Pharmacology: 1.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280684/

3. Guérin, Violaine, et al. “Azithromycin and hydroxychloroquine accelerate recovery of outpatients with mild/moderate COVID-19.” (2020).
https://www.preprints.org/manuscript/202005.0486/v1

4. Meltzer, David O., et al. “Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.05.08.20095893v1

5. Rajter, Juliana Cepelowicz, et al. “ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.06.06.20124461v2

6. Boulware, David R., et al. “A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.” New England Journal of Medicine (2020). — Hydroxychloroquine did not work as a prophylaxis against Covid-19.
https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

7. Moustaqil, Mehdi, et al. “SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts.” bioRxiv (2020).
https://www.biorxiv.org/content/10.1101/2020.06.05.135699v1

8. Cannata, Francesco, et al. “Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality.” European Heart Journal-Cardiovascular Pharmacotherapy (2020).
https://academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvaa056/5851727