May 23, 2020

COVID-19 vs H1N1: Similar but Different

Disclaimer: This post explores some of the pathophysiologic findings in severe SARS-CoV-2 infection. It explores possible mechanisms-based and posits theories BUT, this is not a clinical post. The hypothesis and findings here are not confirmed and extrapolation to management is unclear.

Understanding of the mechanisms of COVID-19 is badly needed if we are to find treatments that may be beneficial. The leading cause of mortality in patients with COVID-19 is hypoxemic respiratory failure most frequently resulting in ARDS.  However, the mechanisms that bring patients from infection to ARDS are unknown:  is it diffuse alveolar damage (DAD), endothelial damage, or some combination of both? Although it may seem ridiculous to consider these two entities as separate, as the alveolar-capillary interface is submicrons in size, we want to know if one of these two entities is driving the injury more than the other? There have been some interesting pathological reports that have been published looking at the histopathology of COVID-19, and many more discussions about the similarities to other viral pneumonias (i.e. H1N1). A recent publication in NEJM compares the pathology of COVID-19 vs H1N1.

Below is an image from Teuwen LA et al [2] depicting a normal and abnormal interface between the alveolus and endothelial cells

The image above sets the stage to discuss several potential mechanisms of injury. In the rest of the post we will review a pathological study comparing the morphologic characteristics of COVID-19, H1N1, and case matched lungs. Although the Teuwen LA et al model is a proposed model of vascular leakage, coagulation, inflammation, and angiogenesis, the Ackermann M et al publication [1] shows us how H1N1 and COVID-19 are similar, yet different.

Article: Ackermann M et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in COVID-19. NEJM 2020. [Epub Ahead of Print]

What They Did:

  • Autopsy study of:
    • Patients who died of COVID-19: 7 lungs
    • Patients who died from ARDS secondary to A(H1N1): 7 lungs (Archived lung tissue from the 2009 pandemic)
    • Age-matched, uninfected control lungs: 10 lungs
  • All lungs were studied with various manners of analysis

Histology of Acute Respiratory Distress Syndrome (ARDS)

  • Diffuse alveolar damage (DAD) with edema, hemorrhage, and intraalveolar fibrin deposition
  • DAD is a nonspecific finding and can occur from many possible causes, both infectious and non-infectious
  • The SARS-CoV and SARS-CoV-2 versions of DAD also include reports of fibrin thrombi

Mean Weight of Lungs:

  • H1N1 > COVID-19 > Matched Controls
  • The increased weight of the lungs in COVID-19 and H1N1 is most likely from vascular leakage and pulmonary edema. Some of the possible mechanisms for this are described by Teuwen LA et al [2]:
    • Virus can directly affect endothelial cells resulting in endothelitis, lysis and death
    • SARS-CoV-2 binds to ACE2 receptors which impair its activity by downregulation or shedding. Reduced ACE2 activity indirectly activates kallikrein-bradykinin pathways which increase vascular permeability
    • Activated neutrophils produce histotoxic mediators (i.e. reactive oxygen species)
    • Immune cells, inflammatory cytokines, and vasoactive molecules lead to enhanced endothelial contractility and loosen the inter-endothelial junctions leading to gaps
    • IL-1B and TNF activate glucuronidases that degrade the glycocalyx and upregulate hyaluronic acid synthase 2, leading to increased hyaluronic acid deposition in the extracellular matrix and promote fluid retention
    • The net effect of all of these mechanisms is increased vascular permeability and vascular leakage

Proposed Mechanism of Vascular Leakage (Image from [2]

Angiocentric Inflammation

  • Both COVID-19 and H1N1 had DAD with necrosis of alveolar lining cells and intraalveolar fibrin deposition
    • COVID-19: The changes were more focal in most cases and only had mild interstitial edema
    • H1N1: The changes were more diffuse with massive interstitial edema and extensive fibrin deposition in all cases
    • This helps explain the higher weight of the lungs with H1N1 compared to COVID-19
  • Mean Angiotensin-Converting Enzyme 2 (ACE2) Expression (ACE2 positive cells per field of view):
    • There are significantly more ACE2 positive cells in the capillary endothelial cells than the alveolar epithelial cells in both COVID-19 and H1N1
    • Additionally, there were ACE2-positive lymphocytes seen in the perivascular tissue as well as the alveoli in both COVID-19 and H1N1
  • Increased vascular inflammation is present in both COVID-19 and H1N1, however appears to be more predominant in capillary endothelial cells (This explains the increase in MI, stroke, PE etc…seen in both diseases)

Thrombosis and Microangiopathy

  • Fibrin microthrombi could be seen in the alveolar capillaries in all the lungs from both COVID-19 and H1N1
    • Alveolar capillary microthrombi were 9x more prevalent in patients with COVID-19 vs H1N1
  • The authors also performed three-dimensional microCT of the pulmonary specimens which confirmed the histologic findings that both COVID-19 and H1N1 showed occlusions of precapillary and postcapillary vessels

COVID-19 Associated Thrombosis (Image from [1])

Microthrombi in Interalveolar Septa from COVID-19 (Image from [1]

  • Teuwen LA et al [2] propose a set of mechanisms as to why we see so much thrombosis in COVID-19
    • Disruption in vascular integrity and endothelial cell death leads to exposure of the thrombogenic basement membrane. This then activates the clotting cascade
    • IL-1B and TNF increase the expression of P-selecting, von Willebrand factor and fibrinogen (These are what platelets bind to)
    • Endothelial cells release trophic cytokines which can augment platelet production. Platelets release VEGF, which triggers endothelial cells to upregulate tissue factor (prime activator of the coagulation cascade)

Proposed Mechanisms of Coagulation Initiation (Image from [2])

  • Both COVID-19 and H1N1 lungs had microthrombi present, in the pre-capillary, alveolar capillary, and post capillary venules of varying degrees, but with a significantly higher prevalence seen in COVID-19 in the alveolar capillaries (This could explain why standard prophylactic anticoagulation may not work in some patients)

Angiogenesis

  • COVID-19: Distorted vascularity with structurally deformed capillaries. Elongated capillaries with sudden changes in caliber and intussusceptive pillars within the capillaries. Ultrastructural damage to endothelium with both intra- and extra-cellular SARS-CoV-2
  • Mean density of intussusceptive and sprouting angiogenic features were higher in COVID-19 vs H1N1

Intussusceptive and Sprouting Angiogenesis seen in COVID-19 (Image from [1])

Electron Micrographs Showing Microvascular Alterations in COVID-19 Lungs (Image from [1])

  • Teuwen LA et al [2] propose that due to increased microthrombosis seen with COVID-19, lung tissue ischemia begins to develop which triggers angiogenesis and endothelial cell hyperplasia
  • Pulmonary Angiogenic Counts vs Length of Hospital Stay
    • Intussusceptive angiogenesis and sprouting angiogenesis were significantly more profound compared to H1N1 and matched controls (See image below)

Density of Intussusceptive and Sprouting Angiographic Features of COVID-19, H1N1, and Matched Controls (Panels A & B) and vs Hospitalization Time (Panels C & D) (Image from [1])

  • Increased intussusceptive and sprouting angiographic features are seen in both COVID-19 and H1N1, however the density of these features is significantly more in COVID-19 (This is typically due to hypoxia and growth factors)

Important Limitations:

  • A major limitation of this study is that none of the COVID-19 patients were mechanically ventilated whereas 5 out of 7 patients in the H1N1 group were.
  • The differences in angiogenesis could also be due to the different time courses of COVID-19 and influenza which cannot be controlled for in this type of trial

Summary of Findings:

  • The lungs of patients with COVID-19 and H1N1 have some overlapping similarities and some major differences:
  • Both diseases have DAD and infiltrating perivascular lymphocytes and a greater number of ACE-2 positive cells in the lungs (Predominantly in the capillary endothelial cells)
  • However, COVID-19 differs from H1N1 in several distinct ways:
  1. Severe endothelial injury with disrupted endothelial cell membranes
  2. Widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries (9x more prevalent compared to H1N1)
  3. More new vessel growth (Intussusceptive and sprouting angiogenesis)

Additional Thoughts:

  • We know that patients who are older, obese, have hypertension and diabetes mellitus are at higher risk of more severe disease. Why might this be?  What do they all have in common?…They are all characterized by pre-existing vascular dysfunction and altered endothelial cell metabolism.

Bottom Line:

  • Both groups of patients have signs of tissue hypoxia, however, there appears to be a greater degree of endothelialitis and thrombosis in the lungs of patients with COVID-19 vs H1N1 (This could be why prophylactic anticoagulation may not be enough in COVID-19, but still remains to be proven)
  • There is overlap between the two diseases, but it seems COVID-19 appears to be more of an endothelial rather than an alveolar disease process as the primary driver (Future studies and discussion should look at treatments focused on this aspect of disease)

References:

  1. Ackermann M et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in COVID-19. NEJM 2020. [Epub Ahead of Print]
  2. Teuwen LA et al. COVID-19: The Vasculature Unleashed. Nature Reviews Immunology 2020. [Epub Ahead of Print]

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "COVID-19 vs H1N1: Similar but Different", REBEL EM blog, May 23, 2020. Available at: https://rebelem.com/covid-19-vs-h1n1-similar-but-different/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM
9 Comments
  • Karl Lai Lam
    Posted at 19:03h, 23 May Reply

    I have a background in software development and no medical training whatsoever, but I hope some doctors will have time to provide feedback on thoughts and questions of mine relating to COVID-19 pathophysiology.

    Thanks to doctors like Cameron Kyle-Sidell, Farid Jalali, and many others, us laymen can get a glimpse of what’s happening under the hood. As more information is made available on Twitter the more I ask myself if we should be looking at COVID-19 through the lens of rhabdomyolysis.

    Unfortunately, I haven’t come across any details relating to maintenance of vascular smooth muscle tone in this context so please bear with my lack of knowledge:
    What exactly are the metabolic consequences (in vascular smooth muscle) of the dysfunctional vasoconstriction associated with COVID-19? Is it accurate enough to say that it is similar, in terms of exercise, to asking someone to maintain an abnormally long and abnormally intense isometric hold? If this is the case then wouldn’t ground zero be, in many instances, the vascular smooth muscle?

    My hypothesis is that the extreme build-up of metabolites/waste due to the vasoconstriction energy expenditure in vascular smooth muscle causes widespread oxidative stress which would then be one of the first causes of damage to blood vessels. Naturally, inflammation follows the oxidative stress and the body then tries to mend the microwounds via clotting.

    I hope you can see why I’m asking if COVID-19 should be viewed through the lens of rhabdomyolysis brought on by physical exertion, in addition to any other dysfunction SARS-CoV-2 might cause. I suppose you could also look at it in terms of atherosclerosis.
    If my thoughts are headed in the right direction, I can see why COVID-19 would have a broad range of presentations, because this type of damage has the potential to start in so many different places if I’m not mistaken.

    At a minimum, I think this perspective reflects the significance of risk factors such as insulin resistance, mitochondrial disease, and declining muscle/cardiovascular function often associated with old age.

    Good luck to all the medical professionals trying to solve these problems. I hope this point of view is of use to someone.

    • Salim Rezaie
      Posted at 19:42h, 23 May Reply

      Hello Karl,
      Appreciate your comments. With rhabo we typically see elevations in CK levels, which is not the case here. I understand what you are getting at with the “lens” you are speaking of. The lung is very complicated, but the initial insult is low oxygen, which leads to vasoconstriction, but it seems the virus directly disrupts the endothelial cells in addition to that mechanism. What is being debated on social media amongst health care professionals is how much of the injury is from lung injury itself, vasoconstriction, or endothelial damage. We don’t know the answer to this at this time. I am in the camp that it seems to come more from endothelial disruption than the other mechanisms. More research is badly needed on this, and hopefully this will get worked out sooner than later. We have come a long way in 6 months, but have much more to go.

      Salim

      • Karl Lai Lam
        Posted at 19:47h, 23 May Reply

        Thank you, appreciate the feedback.

      • Karl Lai Lam
        Posted at 20:02h, 23 May Reply

        I think I was probably confused about something, but wouldn’t it be possible for vasoconstriction to come about through induced ACE2 deficiency with or without low oxygen at the start? Is my thinking correct that SARS-CoV-2 effectively consumes the receptor as it gains entry into the cell?

        I don’t understand everything discussed in this link below but I thought it might be interesting for anyone else reading these posts.
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167588/

        • Salim Rezaie
          Posted at 21:50h, 23 May Reply

          Yup…again…that is one of the insults, but it is multifactorial…the bigger question is which one of those things is the biggest driver…ACE2 deficiency, hypoxemia, endothelial injury. They could all be equally important, additional, or there is one that is the primary driver. Still unclear…

          • Karl Lai Lam
            Posted at 04:50h, 24 May

            I see. Thanks for your insights.

  • Dirk Woods
    Posted at 13:54h, 24 May Reply

    Great post. I await further clinical studies to see if aggressive anti-coagulation improves outcomes. Steroids and IL-6 inhibitors don’t seem to hold a lot of promise regarding the inflammatory aspects of this disease. It certainly is enticing to hope that the angiogenesis that is so disruptive to the alveolar function could be prevented by helping prevent micro-emboli . We need something beyond injecting disinfectants and hoping that Remdesivir is better than it looks.

    • Salim Rezaie
      Posted at 14:04h, 24 May Reply

      Hey Dirk,
      Appreciate it…crazy how quickly things are changing…I realize the post is super nerdy looking at pathology, but I found it useful to put things into perspective. So many potential options to be studied from this as you have stated: therapeutic anticoagulation, angiogenesis inhibitors, IL6 inhibitors, etc. I suspect it one be any one magic cure, but some combination of meds that makes the biggest impact from several different additive effects. We shall see.

  • Robin Whittle
    Posted at 01:29h, 29 May Reply

    The Teuwen article is appropriately titled like a horror movie.

    I think the material in these articles is broardly compatible with the work of Farid Jalali ( https://rebelem.com/covid-19-acute-lung-injury-a-proposed-model-v1-0-via-farid-jalali-md/
    & https://emcrit.org/emcrit/pathophysiology-of-covid19/ ) with this article:

    The trinity of COVID-19: immunity, inflammation and intervention
    Matthew Zirui Tay et al. Nature Reviews Immunology 2020-04-28
    https://www.nature.com/articles/s41577-020-0311-8

    However, these four bodies of work suggest no reasons for the weakened and dysreguated (destructivly inflammatory) mechanisms which drive severe symptoms with COVID-19.

    Here are two of the numerous articles which indicate very clearly – to me at least – that vitamin D deficiency plays a crucial role:

    A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency
    Gerry K. Schwalfenberg Mol. Nutr. Food Res. 2011, 55, 96–108
    https://doi.org/10.1002/mnfr.201000174 (Payalled.)
    https://sci-hub.tw/10.1002/mnfr.201000174

    Vitamin D and Endothelial Function
    Do-Houn Kim et al. Nutrients 2020, 12(2), 575
    https://www.mdpi.com/2072-6643/12/2/575

    It is well known that there is a surge in Kawasaki disease triggered by COVID-19. In the recent articles about this which I have read, none of the authors seemed to be aware of the crucial, and surely causative, role of extreme vitamin D deficiency in this condition. The following article from 2016 is of the utmost importance for all clinicians:

    Severe vitamin D deficiency in patients with Kawasaki disease:a potential role in the risk to develop heart vascular abnormalities?
    Stefano Stagi et al. Clinical Rheumatology volume 35, pages 1865–1872 (2016)
    https://link.springer.com/article/10.1007/s10067-015-2970-6 (Paywalled.)
    https://sci-hub.tw/10.1007/s10067-015-2970-6

    The patients were 21 girls and 58 boys, average age 5.8 years. Their average 25OHD levels were 9.2ng/ml, while age-matched controls averaged 23.3ng/ml. In the patients who developed severe coronary artery abnormalities, the average 25OHD level was 4.9ng/ml (sd 1.36).
    These children, due to the decisions made by adults, were struggling to live with vitamin D 25OHD in their bloodstream 10% to 20% of what is normal for hunter gatherers in Africa. https://www.ncbi.nlm.nih.gov/pubmed/22264449

    Another, more difficult to fix, cause of immune system pro-inflammatory dysregulation, though not of weakness, is that our immune systems evolved multiple overly-aggressive mechanisms to cope with our ancestor’s helminths (intestinal worms) which secrete compounds which pervasively downmodulated many immune responses. Now, for good reason, we have no helminths and in general, subject to individual genetic and developmental variation, many aspects of our immune system are overly agressive and self destructive. One important paper regarding this is https://www.semanticscholar.org/paper/Multiple-sclerosis-and-the-hygiene-hypothesis.-Fleming-Cook/c3ad39654adf2b578768482576bb0ad81f03d268 . You can find many more by searching Google Scholar for the two words “helminths inflammation” (without the quotes).

    Please see my pages http://aminotheory.com/cv19/ and http://aminotheory.com/cv19/icu/ where these are all linked to and discussed, along with other articles from the Philippines and Indonesia which show a sharp dichotomy for mild vs. severe symptoms, and survival vs. death, for COVID-19 patients according to their vitamin D 25OHD levels being above or below 30ng/ml.

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