COVID: ??worse outcomes with other viral infections in asthmatics

A prepublication and pre-peer reviewed article found that rhinovirus infection in asthmatics increased ACE2 levels (see covid rhinovirus in asthmatics inc ACE2 amjrespcritcaremed2020 in dropbox, or https://www.atsjournals.org/doi/pdf/10.1164/rccm.202004-1343LE)

 

Details:

-- 22 asthmatic patients were evaluated in the initial cohort, with 8 more in a validation cohort. Each had nasal biopsies, subsequently used in tissue culture with interventions as below (ie, this was basically a lab study)

 

Results:

-- 2 common rhinovirus infections (RV-A16 and RV-C15) inoculated onto the tissue samples resulted in a >3-fold increase in ACE2 expression in both the initial and validation cohorts

-- rhinovirus was associated with increased ACE2 overexpression, which was associated with increased production of genes leading to high levels of many cytokines associated with severe  infection (IL-1, IL-2, IL-6, IL-8, IL-10, TNF, and interferon-gamma)

-- ACE2 levels were also increased after exposure to influenza A and RSV, 6-fold higher

 

Commentary:

-- patients with severe Covid-19 infection and poor outcomes seem to have very high cytokine levels (“cytokine storm”)

-- young asthmatic adults have higher rates of severe Covid-19 than nonasthmatics, with one study suggesting asthmatics represented 27% of hospitalized patients in the US aged 18-49. and genetic analysis does confirm this association (not all studies do, though studies mostly look at presence of asthma as comorbidity and not whether patients had symptomatic asthma or not; ie, do those with poorly controlled asthma who then get SARS-CoV-2 infection do worse??. for the genetic analysis, see https://www.sciencedirect.com/science/article/pii/S009167492030806X )

-- rhinovirus infections, the most common causes of the common cold, are also the most common causes for asthma exacerbations in children and adults [ie: ?? link here--rhinovirus increases asthma and puts people with asthma exacerbations at higher risk for morbidity/mortality??)

-- angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and promotes cellular entry by the virus

-- these 2 common rhinovirus infections in the study are potent inducers of interferon-stimulated genes (ie they enhance the effect of interferon), and ACE2 itself has recently been found in vitro to be an interferon-stimulated gene in human airway epithelial cells: see https://pubmed.ncbi.nlm.nih.gov/32413319/). 

-- this article provides some evidence, albeit laboratory-based, that rhinovirus infections might increase the expression of ACE-2 as well as interferon levels. And in conjunction with a SARS-CoV-2 infection, this might lead to much higher cytokine activation, associated with more severe Covid-19 cases (and, perhaps by increasing ACE2 expression, make it easier to get the SARS-CoV-2 infection in the first place)

-- one possibly brightish note in asthmatics is that inhaled or intranasal corticosteroids seem to lower ACE2 expression  (at least in some studies), raising a few possibilities that might be explored more rigorously:

    -- perhaps there are protective effects of inhaled steroids in asthmatics, and, if so, we should have a lower threshold to prescribe inhaled steroids

    -- perhaps there may be even more benefit to nasal steroids, since the most common entry of SARS-CoV-2 seems to be though attachment of the virus to the ACE2 receptors on the nasal epithelium. And maybe not just for asthmatics??? [there is some suggestion in the medical literature that the reason kids seem to get less Covid-19 is that they have less ACE2 gene expression, independent of age or asthma: see https://jamanetwork.com/journals/jama/fullarticle/2766524 ).

    -- But there is considerable controversy at this point on the benefit of steroids with Covid-19 (eg see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252138/ )

    -- The point here is that there may be important treatments that should be explored to see if there is a real clinical value in preventing or ameliorating SARS-CoV-2 disease. And the use of inhaled steroids in patients with asthma or allergic rhinitis might be a pretty easy study to do....

 

Limitations of the study:

-- this is laboratory-based analysis using tissue culture and is not necessarily reflective of what happens in the human body

    -- for example, they did not evaluate the surface protein expression of ACE2 after rhinovirus infection

-- there are incompletely understood links between ACE2 overexpression and the cytokine surge, though the above study does suggest that some of those cytokines found elevated in severe Covid-19 patients are the ones found with the rhinovirus infection

 

So, it is not clear how this article translates into clinical outcomes in real people. However:

-- there is significant concern that SARS-CoV-2 will return as a 2^nd or 3^rd wave at a time when there are many other viruses around, including rhinovirus and influenza. The CDC director Robert Redfield noted that  the second wave of Covid-19 will likely coincide with the flu season, putting an "unimaginable strain on the health-care system" and further limiting medical supplies/hospital beds that will be needed for each of these infections (see https://www.washingtonpost.com/health/2020/04/21/coronavirus-secondwave-cdcdirector/ )

-- But, this article suggests there may also be significant viral synergy in the cytokine response, above and beyond what Redfield warned against: ie, it is not just the co-occurrence of severe Covid-19 and severe influenza putting a strain on access to necessary hospital beds, ventilators, etc that might be needed for each of these infections. But that the interaction of Covid-19 with influenza or other respiratory infections could lead to more severe cases of and worse outcomes from SARS-CoV-2 infection (with the caveat that this laboratory study offers just a potential warning and not clear, solid clinical evidence)

--and, all of this really highlights and reinforces the imperative to prevent a reoccurence of Covid-19: the second or third wave MAY BE MUCH WORSE than the horror we have seen so far. We really need to have a strong and coherent message throughout the country that social distancing and masks are essential to decreasing SARS-CoV-2 transmission, and these are the mainstay for our public health initiatives so far, at least until an effective and safe vaccine becomes available. 

geoff

 

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