The closest animal version of the virus remains a bat sample collected by scientists in 2013 a thousand miles away in Yunnan. Details of where and how that sample was collected have been sketchy, but a new paper by two scientists from the Agharkar Research Institute in Pune, India, show that it is the same as a published sample with a different name that was collected from an abandoned mineshaft in southern Yunnan in 2013, following an outbreak of pneumonia-like illness that killed three miners there the year before. But that virus cannot be the immediate source of Covid-19. Part of one of its key genes, coding for the “spike” protein that allows the virus to lock onto human cells, is distinct from the version that is causing the pandemic. In the human virus, this part of the gene, called the “receptor binding motif,” more closely resembles the virus found in smuggled pangolins, though the rest of the pangolin virus is less similar. Compared with the bat and pangolin viruses, the one now infecting human beings also has an extra 12-letter nucleotide sequence, called a “furin cleavage site,” in the spike protein gene; this greatly enhances the virus’s ability to get into and out of different types of human cells. Kristian Andersen of the Scripps Institute in La Jolla, Calif., and colleagues argue that this might have arisen by mutation during “a period of unrecognized transmission in humans” after the original transmission from an animal.
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So what did happen? At present, the evidence is pointing tentatively to a chain of person-to-person infections occurring somewhere outside a city before somebody brought the virus to Wuhan, where the market acted as an amplifier. The first case could have been a rural farmer or possibly a bat researcher collecting samples for virologists. Or it is possible that another animal was involved in some way, with the virus bouncing between a farmer and his animals, or a wildlife smuggler and his poor pangolins.

Results: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed.

As this new work details, an initial hypothesis was that the compound had some effect on one of the viral proteases, and you can still find that rationale if you start looking around for comments on the drug’s MOA. That hasn’t held up, though – the compound does not seem to be an inhibitor of these enzymes. Moreover, it is not effective in a cell-based infection model with the virus, either – basically, it’s not an antiviral in any sense of the term.

What does that leave you with? The downstream effects of being infected – all the cytokine storm stuff, the inappropriate immune response that gets so many patients into trouble. And that brings the histamine receptor mechanism back around again. The paper confirms that famotidine is a much more potent H2 ligand than is cimetidine (technically, it’s more of an inverse agonist than a classic antagonist), and moreover it seems to have different consequences on receptor binding. It seems to stimulate beta-arrestin binding to the receptor and subsequent internalization (a mechanism that complicates all sorts of G-protein coupled receptor signaling), and it appears that cimetidine doesn’t do this, either. There is also a possibility that the compound acts on the CCR2L and CXCR3 chemokine receptors, which would certainly be of interest, but this needs to be firmed up.

But one of the biggest differences between famotidine and cimetidine is in their pharmacokinetics. As the preprint illustrates, the higher potency and better blood levels of famotidine mean that it has much stronger coverage of the H2 mechanism in general, especially at the dosages that seem to have an effect in coronavirus infections. So here’s the paper’s mechanistic summary:

That’s an interesting and plausible idea – mast cells are what are involved in sudden histamine release – they’re sitting there loaded up with granules of the stuff, which can be dumped out on short notice. That’s an important part of a sudden anaphylaxis reaction, and mast cells are also involved in other immune response pathways, tissue permeability, and other processes. It’s certainly possible that they could be part of the inappropriate response to coronavirus infection and that inhibiting histamine release could be beneficial. The paper goes into details about lung physiology that tie the receptor’s action to some of the pathology seen in patients – for example, one thing that’s been noted is a lack of neutrophils and eosinophils in lung tissue samples, and both of these cell types have their activities inhibited by histamine release. In addition, the edema seen in coronavirus-affected lung tissue is unusual by the standards of viral infection, but makes more sense in light of a histamine-driven response. Mast cell degranulation also matches up with some of the other well-known symptoms (effects on smell and taste sensation, etc.)

The authors advance the idea, then, that many of the unusual features of the current virus in the clinic can be tied to histaminergic effects, and finish up this way:

Use of famotidine in this patient was recommended due to meeting FDA criteria for severe COVID-19 and his COVID-19 risk factors: male, 47yo, hypertension, obesity and diabetes mellitus Type 2. Although this is an anecdotal example, the patient experienced relief of symptoms overnight upon initiating use of famotidine. While not sufficient to demonstrate proof of cause and effect, this case does provide context for typical COVID-19 presentation and symptoms, as well as support for additional well-controlled famotidine therapeutic clinical trials in an outpatient setting.

other histamine antagonists (for example H1 and H4 types), leukotriene antagonists and leukotriene receptor antagonists 98, anti-inflammatory agents such as those developed for inflammatory bowel diseases, and mast cell activation inhibitors 99.

Nafamostat and camostat are serine protease inhibitors both approved in Japan for use against pancreatitis in humans. Camostat was previously found in vitro to block the entry of SARS-CoV by acting as an antagonist to the serine protease TMPRSS2, and researchers believe both nafamostat and camostat could have a similar effect in inhibiting SARS-CoV-2. In vitro, both have been found to block the entry of SARS-CoV-2 into cells, although one preprint study reported that nafamostat inhibited viral cell entry with an efficiency roughly 15-fold higher than that of camostat.

These drugs are undergoing phase 2 and phase 2/3 clinical trials in the USA and Japan for their effectiveness against COVID-19, the primary outcome of which will be time to clinical improvement for nafamostat and reduced viral load after treatment for camostat.

“These drugs are quite old, they’re well studied, they have known targets that are exactly the same protease that the virus uses,” says Anton Yuryev, professional services director at Elsevier, who has done screenings for possible COVID-19 drug treatments.