A series of autopsies conducted by the team of ASIP member, Dr. Richard Vander Heide, revealed surprising cardiac changes in COVID-19 patients. He recently was an invited speaker for the ASIP COVID-19 Webinar on the topic of Autopsy Insights into the Pathogenesis of COVID-19, where he had proposed the mechanism that the cardiac manifestations in sick COVID-19 patients are likely due to small microthrombi and/or stress on an already diseased heart from the pulmonary stress/diffuse alveolar damage and not due to primary myocarditis. See the transcript here. The team of LSU Health pathologists led by Dr. Vander Heide, an experienced cardiovascular pathologist, identified key pathological changes that shine light on COVID-19 pathogenesis. The team found that unlike the first SARS coronavirus, SARS-CoV-2 was absent in the heart muscle cells. Occluding blood clots in the coronary arteries were also found to be missing.
James Musser, MD, spoke with The New York Times about how COVID-19’s genetic code plays a vital role in controlling the virus.
Since last March, a team of researchers led by Dr. James Musser, chair of the department of pathology and genomic medicine at Houston Methodist Hospital, have been sequencing the viral genomes drawn from patients — 20,000 genomes so far. This new study has found that every coronavirus variant of concern to researchers around the world has been circulating in Houston at a low level for at least six to eight weeks. Houston is the first U.S. city to find all of the variants, including those recently reported in California and New York and the ones found in Brazil, Britain and South Africa.
I was very fortunate in that I transitioned from an academic postdoc to an industry scientist right before the pandemic hit the US. In fact, I had one week of normalcy at my new job before my city was shut down. Luckily, R&D is considered “essential” in my city, so I was able to continue working on a modified basis. While I am eternally grateful for my luck, timing, and privilege, it goes without saying that for the foreseeable future, STEM PhDs undergoing job transitions will have unforeseen difficulties. In fact, just trying to resume benchwork after shutdown is anxiety-provoking, and researchers are concerned for their careers. This recent blog post highlights the struggles postdocs are currently going through. While the solidarity is comforting, the article suggests trainees may want to reconsider careers, even if temporarily. For those on the job market, there may be more opportunities in industry, (particularly in startups, solely based on my own experiences), than academic positions, so postdocs and other academicians may begin looking for exit strategies, as discussed here. The bottom line is: these are unprecedented times, and we don’t know how the STEM job market will fare, so we need to be resilient and flexible.
Do you have any advice to share with those looking for jobs during this time? Or have other interests to contribute to this blog? If so, contact Morgan at email@example.com
Due to the heavy volume of participation and the extent of engagement from the attendees, we followed up with our speakers Drs. L. Maximilian Buja (LMB) and Richard Vander Heide (RVH), who diligently responded to the questions that could not be addressed due to time limitations.
RVH: That is my current hypothesis. We are still testing the hypothesis. My last slide outlines my thinking.
You mentioned intravascular megakaryocytes in lung from COVID19 patient? isn’t it? Could you explain it?
LMB: It is now known that there is traffic of megakaryocytes via the venous system from bone marrow to lung. The pulmonary megakaryocytes are an important source of platelet production along with megakaryocytes of the bone marrow. It has been documented that there is an increase in megakaryoctyes in diffuse alveolar damage.
See: Mandal RV et al. Exp Molec Pathol 2007;83:327-331.
A major theme of our webinar is that the DAD in severe COVOD-19 respiratory diseases is a particularly exaggerated and florid form of DAD which includes marked increase in pulmonary megakaryocytes and pulmonary platelet production.
RVH: Yes the degree to which we see the megakaryocytes indicates that it is unique to COVID-19
You mentioned vacuoles in lung phagocytes. Any idea what these are? Immunogold and EM might help here?
LMB: Vacuolization of alveolar macrophages is a rather common and non-specific finding. Immunogold is challenging but with proper reagents could provide sensitive localization of viral products.
RVH: I agree it would theoretically be possible but difficult in post mortem tissue.
It seemed to me that the major pathology was the microangiopathy causing variety of lesion in different organs. Just wondering when the virus is inhaled, what is the initial pathology seen in the lung before causing microangiopathy? or microangiopathy is the first event seen and later leading to hyaline membrane formation and necrosis of the spenumocytes?
LMB: We are limited because the pulmonologists around the world are not doing endobronchial biopsies because of safety concerns. My thought is that the virus induces initial damage to endothelium and type-II pneumocytes leading to rapidly developing capillary leak resulting in hyaline membranes and essentially simultaneous activation of the intra-capillary thrombotic process.
RVH: I agree; it seems that why COVID is so lethal is that it get into the deep pulmonary tissues before typical influenza type viral infection. The exact sequence is not known but likely DAD process is initiated first.
Also, concerning platelets in the lung capillaries – were these based on H&E of just CD61 staining, given that CD61 could also stain capillary endothelial cells. How often is this ([latelet thrombi) found in all of your patients and were these associated with systemic thrombocytopenias??
LMB: The CD61 positive structures are all intra-capillary and not lining the capillaries. They consist of larger megakaryocytes and small bodies representing platelets. Also, See response to question 2. Paradoxically, at least to me, Mandal et al found that patients with DAD and blood platelet counts of over 350,000 per cubic cm had increased survival.
To Dr Vander Heide, what type of co-infection did you find in lungs (e.g. sarcocystis pn) of some patient?
LMB: We had some cases with superimposed bacterial bronchopneumonia.
RVH: We have seen superimposed bronchopneumonia but it is not common in our cohort. We have not seen other viral infections but have not looked.
Interested in Dr Buja’s slide from China suggesting viral and atypical co-pathogens in COVID. We have just finished and are submitting for publication a study of over 100 COVID ICU patients where we have specifically looked for bacterial co-pathogens, including viruses and mycoplasma using molecular methods. We found a very small proportion of viral co-infection only; a high rate of false Positive mycoplasma serology, not proven with molecular diagnostics. What is the US experience and specifically, are late lung complications considered specific for COVID, or long-term ventilation and critical illness?
LMB: As I mentioned in my talk, the high viral co-infection in the Chinese series was during the winter. I think this is going to be less of an issue in the USA in the spring and summer months, at least. I am very worried about the combo of COVID and influenza going into the fall months.
The data regarding co-infection is cited in a reference in Geng YJ et al.
Geng YJ, Wei ZY, Qian HY, Huang J, Lodato R, Castriotta RJ. Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019. Cardiovasc Pathol. 2020;47:107228. doi:10.1016/j.carpath.2020.107228
Another nice review is Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review [published online ahead of print, 2020 Mar 27]. JAMA Cardiol. 2020;10.1001/jamacardio.2020.1286. doi:10.1001/jamacardio.2020.1286
I think the complications are going to be those generic to severe DAD.
RVH: I agree
How do pulmonary findings compare to those of SARS-infection? I mean SARS versus SARS-cov2.
LMB: General similarities but this new SARS-Co-V2 is worse. I discuss this with references in my paper shown above.
RVH: Yes, the DAD findings are very similar but the clots, both large and small, are not typical of SARS.
Comparison also with Resp Syncytial Virus in lung?
LMB: RSV produces generally a much milder morphological pattern of interstitial pneumonitis.
RVH: I agree.
Had you seen increases numbers of iron-laden macrophages within the lung.
LMB: We haven’t stained for hemosiderin. But not obvious on H&E.
RVH: Good question; we have not seen it despite the large amount of hemorrhage we see in most cases. I think it is the acuity of the bleed that explains the lack of hemosiderin.
Do you believe that inappropriately activated monocytes might play a part in lung damage?
LMB: Absolutely. See the McGonagle articles. Also:
Morphoproteomics and Etiopathogenic Features of Pulmonary COVID-19 with Therapeutic Implications: A Case Study . Robert E. Brown1, Dwayne A. Wolf2, Robert L. Hunter1, Bihong Zhao1, and L. Maximilian Buja,
RVH: Please see our Lancet study and my last slide; we think a cytokine storm is an important component of severe COVID-19 disease. The factors that lead to activation of the cytokine storm in some but not other patients will likely provide insight into the clinical course of the disease.
You mentioned vacuoles in lung phagocytes. Any idea what these are? Immunogold and EM might help here?
LMB: See answer to question 10.
Do you have IHC or EM evidence of SARS-CoV-2 viral infection of endothelial cells or pericytes in the LUNG. Please describe the evidence.
LMB: See the references cited in my paper and the electron micrograph in Dr. Vander Heide’s paper – Fox SE et al.
RVH: We have not seen virus in pulmonary endothelial cells; to date only pneumocytes. The pericyte and endothelial cell lie underneath the basement membrane so it may take some close EM examination to determine the difference between the two.
Have you done viral protein staining in heart? Is that myofiber degeneration correlate with viral staining?
LMB: We have performed some IHC for viral nucleocapsid staining in the heart. We have seen some localization primarily in interstitial cells. As Dr. Vander Heide emphasized the cardiomyocyte injury appears to be secondary to endothelial and interstitial cell infection.
RVH: To date, we have not seen virus in a myocyte.
What stain are you using to identify granulocytes? How do we know that basophilic degeneration in cardiac myocytes is not occurring because of underlying CVD?
LMB: Granulocytes best identified by good old H&E morphology. Basophilic degeneration is a non-specific finding. The more pertinent lesion is multifocal single cardiomyocyte cell necrosis related to the microvascular changes described by Dr. Vander Heide – swollen cardiac capillary endothelial cells and lots of neutrophils in the capillaries.
RVH: We used a myeloperoxidase stain to look for granulocytes. Works well. Agree, basophilic degeneration is non-specific but that occurred in a young patient.
Can it be ischemic necrosis of the cardiomyocytes?
LMB: Patients present with elevated serum troponin before going into shock. The multifocal cardiomyocyte damage is likely due to MICROVASCULAR ischemia due to changes at the arteriolar to capillary level.
RVH: Yes; please see my last slide on the hypothesis. We feel it is small vessel disease that underlies the small troponin elevations seen in most patients.
Brown pigment in cardiomyocytes: ceroid-lipofuscin pigment?
LMB: Always have some peri-nuclear lipofuscin in cardiomyocytes. I didn’t show my preliminary IHC of heart because I am still in the process of sorting out true staining of cardiomyoctyes.
RVH: We see a lot of lipofuscin in the myocytes; we have not specifically investigated it but I would render a soft guess that it is increased if anything.
Any evidence if the virus is localized within the cardiomyocytes?
LMB: None yet. See the Tarazzi reference Question 6.
RVH: Not to date.
Is the glomerular thrombosis the result of SARS-2 cytopathic effect on the glomerular endothelium? Do you see evidence of tubular renal damage (hypoxic or direct cytopathic effect)? What’s the pathogenesis of the liver damage? Did you see any lesion in the brain?
LMB: Only a minority of cases have rip roaring glomerular capillary thrombosis, undoubtedly due to viral infection of endothelium. Most renal failure is due to secondary acute tubular necrosis.
See: Menter T, Haslbauer JD, Nienhold R, et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi:10.1111/his.14134
RVH: We see a lot of virus in the renal tubular cells and we believe there is a cytopathic effect of the virus above and beyond typical acute tubular necrosis seen in terminal patients and patients with hypotension.
Please identify the specific cells in which direct cytopathic effects of the COVID-19 virus have been demonstrated.
LMB: Virus has been found by IHC, in situ hybridization and/or EM in endothelial cells in several organs as well as in type II pneumocytes.
RVH: At this time, I think renal and pulmonary involvement (including respiratory epithelium) can lead to direct damage specific to the virus. The other changes seen in the liver, brain, spleen, and lymph nodes could be secondary changes.
Have you seen any ocular involvement? Choroiditis
LMB: Beyond my expertise. We initially were reluctant to harvest brain because of risk of release of contaminated bone dust. We have now, however, taken a couple of brains.
RVH: We have not looked.
With that amount of thrombi, including medium- and large-sized vessels, how long do you think can a patient live once thrombosis starts to “block| the whole circulatory system?
LMB: Not long. Early anticoagulant and antithrombotic treatment is critical in my view. See: guidelines recently published for prevention, antithrombotic therapy and follow-up for thrombotic and thromboembolic disease in COVID-19 patients. See Bikdeli B et al. J Am Coll Cardiol. Doi:https//:doi.org/10.1016/j.jacc.2020.04.031
RVH: I agree. I think once it start, it is a vicious cycle.
The thrombotic microangiopathy — is it any different between adults and children?
LMB and RVH: Do not know.
Have you had any pediatric case? If yes, was it similar to adults or any unique finding?
LMB and RVH: No.
Hypotheses, Co-Morbidities, and Underlying Mechanisms:
We understand that there is no evidence for viremia. What is the hypothesis for endothelial cells being infected?
LMB: I disagree. There has to be viremia. There is good evidence by EM and IHC for infection of endothelial cells.
See the proposed three stages of disease. Akhmerov A, Marban E Circ Res doi:10.1161/CIRCRESAHA.120.317055
RVH: There almost certainly has to be a viremia to have the systemic effects.
Endothelial dysfunction as in defected activation in response to viral infection? Are there evidence of ICAM-1 up regulation or type I interferons around the swelling endothelium? Is the hypothesis that neutrophil transmigration is specifically unregulated in response to covid in the most severe cases?
LMB: See hypothesis papers by McGonagle D et al. And Ackermann et al.
Also, guidelines recently published for prevention, antithrombotic therapy and follow-up for thrombotic and thromboembolic disease in COVID-19 patients. See Bikdeli B et al. J Am Coll Cardiol. Doi:https//:doi.org/10.1016/j.jacc.2020.04.031
RVH: We have not looked specifically. The neutrophil response is a unique observation and I think that the activated platelets lead to the extracellular traps.
Is there any hypotheses regarding the mechanism of expansion of megakaryocytes in the bone marrow? They are released into the venous circulation and so are likely simply trapped in the pulmonary capillaries and don’t need a stimulus, but they must be proliferating for some reason? Is there expansion of any myeloid, lymphoid or erythroid populations in the bone marrow? Thank you.
LMB: See response to question 2. We have not been taking bone marrow until recently. Dr. Vander Heide reported hypercellularity of the bone marrow.
RVH: yes we see upregulation of megakaryocytes in the bone marrow and I suspect the response is secondary to viral infection and may be responsible for the associated coagulopathy
Do you think that administration of TNF-alfa inhibitors could improve the outcome of the more severe clinical signs?
LMB: Yes. See McGonagle articles.
RVH: Yes, people are trying different anti-cytokine therapies and even steroids.
With regard to lymphocytic cuffing and interstitial pneumonitis, has lymphocrypt virus been investigated as a comorbidity?
LMB: Frankly, I never heard of lymphocrypt virus, so the answer is no.
RVH: I have not heard of that organism either.
Any thoughts on why only a subset of those with chronic lung disease /cardiovascular disease susceptible, while those e.g. with asthma, smoking, COPD, etc. seem not to be so much at risk?
LMB: There is no question that patients with chronic cardiovascular and/or pulmonary disease are at increased risk. But fatal cases have occurred in previously healthy young patients.
RVH: we have seen death in all those kinds of patients. I think COPD patients have limited reserve and may succumb more easily. The co-morbidities we see include obesity, HTN, Type2 DM, and kidney disease (which runs with HTN and DM). I agree the presence in younger patients is interesting and similar in some ways to the 1918 influenza pandemic.
Treatment and Therapy:
Can we start anti-coagulant therapy and immunosuppressants from the beginning of hospitalization in patients without any comorbidities?
LMB: Yes. See: Bikdeli B et al. J Am Coll Cardiol. Doi:https//:doi.org/10.1016/j.jacc.2020.04.031
RVH: I think this is already being done.
Did any of the treatments modify the pathology?
LMB: This is a work in progress that is going to take ongoing clinicopathological correlation in more cases. Importantly several cases from Houston and LSUNO were early deaths without compounding influences of mechanical ventilation, etc.
RVH: I agree.
Any genetic predisposition?
LMB: All acquired diseases involve environmental factors interacting with a genetically predisposed host. In this case, genetic factor may be level of expression and isotype of ACE2 receptor and HLA antigens influencing TOLL receptors. Environmental factor is dose of the virus.
RVH: I think this is an important and necessary area of investigation.
Any genetic predisposition for severe inflammatory cascade?
RVH: Yes, see above answer; should be investigated.
Aren’t COVID toes a manifestation of the skin changes?
LMB: See Magro C et al. Translational Research https:doi.org/10>1016/j.trsl.2020.04.007 Three cases with thrombotic microangiopathy in the skin.
These patients with megakariocytes hyperplasia have anemia? did you find many changes in bone marrow or virions particles inner it?
LMB: Patients don’t have anemia. Dr. Vander Heide reports bone marrow hypercellularity. Not sure about identification of virus in the bone marrow.
RVH: I don’t see unexplained anemia that may be explained by the virus.
There are several cases in tropical countries, what do you think about it?
LMB: This virus does not care about race, ethnicity, country of origin, etc. Not likely to have a summer lull like with influenza.
RVH: The world will be infected especially in this day of easy travel.
The EM of virion looks like clathrin coated vesicles. How can you be sure they are virions?
LMB: All vesicular structures reported as virus likely are not virus. Need to see the right size of about 100 nanometers and the spike protein. See: Calomeni E et al. Multivesicular bodies mimicking SARS-CoV-2 in patients without COVID-19. Kidney Internatl. https:doi.org/10.1016/j.kint.2020.05.003.
In my paper, in retrospect, Figure 12B is probably one of these multivesicular bodies. However, I think Figure 12C is a real virus particle.
RVH: This is an area of controversy. We compare our viral particles to control tissues harvested at the same time so we are fairly confident that they are viral particles but in post mortem tissue it is not easy to entirely sure.
Can you say more about the nucleocapsid IHC – how specific is this (?compared with non-COVID-19 coronaviruses)?
LMB: I don’t know about cross-reactivity of our IHC for original SARS versus SARS-CoV-2, but I think there is selectivity versus influenza.
RVH: I would defer to the company making the antibody.
Do you think the ventilator may cause some lesion?
LMB: Undoubtedly patients with hospital course with high dose oxygen, ventilator and ECMO have complex pathology. But some of our cases are pure COVID-19 without these interventions.
RVH: I agree.
Do you have the viral load data of these patient?
LMB: No. And I don’t know anyone has this type of data. Testing for virus and antibody level is far from high specificity and sensitivity.
RVH: No data.
Have you seen any peripheral manifestations of vascular changes / thrombosis? Gangrenous changes in hands / feet?
LMB: Haven’t seen peripheral gangrene. Have seen thrombi in peritesticular veins.
RVH: We have not seen any as of yet.
Have you seen any patient who was healthy until Covid19 (absolutely with no other commodities like obesity, DM, hypertension, coinfection?
LMB: Unfortunately, Yes. Dr. Vander Heide presented several cases of relatively young folks with some increased weight but not severely obese. Two of our cases died outside of hospital after a short illness.
RVH: Yes, there are some patients that just succumb within days of first symptoms.
CD31 (PECAM) also stains activated platelets so they could be platelet microthrombi adherent to the endothelium/intima rather than or as well as swollen endothelium.
LMB: It is both – damaged/swollen endothelium plus fibrin/platelet microthrombi.
RVH: I agree.
I am curious about localization within the brain. What can you tell us about that?
LMB: See: Li YC et al. J Med Virol 2020 doi: 10.1002/jmv.25728 and Paniz-Mondolfi A et al. J Med Virol 2020 doi: 10.1002/jmv.25915
RVH: We have not looked.
Have you seen anything by EM within the swollen type II pneumocytes?
LMB: In my autopsy material, I could not find virus in the lung but did find an occasional virion in renal glomerular epithelial cell – See figure 12 c in my paper. See the EM of lung in Dr. Vander Heide’s paper. Not yet published, by IHC we did find viral protein in some pneumocytes.
RVH: Yes, we haves seen viral particles in the lung pneumocytes. We have seen them in renal tubular epithelium as well.
Have you seen putative virions in pericytes?
LMB: See answer to question 1 (Endothelium).
Comment on the megakaryocytes. We see intrapulmonary and intravascular megakaryocytes in animals, especially dogs in cases of bacterial infection and sepsis. This is particularly evident when the lymphoid organs follicles are depleted of lymphocytes. Perhaps when you see megakaryocytes in your human patients these patients have secondary bacterial conditions or a systemic depletion – utilization of leukocytes due to the virus.
LMB: See answer to question 1 (Lung Pathology).
Cytokine Storm/Immune Response:
From IHC for Sars-Cov-2, the infected cells are very few. How such low infection could cause whole body cytokine storm? What is your thought?
LMB: We are looking at autopsy cases several days to weeks into the course of illness. This is after the acute infective and viremic phase. Much of what we are seeing is the effect of hyper-inflammation triggered by the virus. Identifiable virus likely much higher earlier on.
RVH: I agree.
Is there evidence for complement deposition in the lung?
LMB and RVH: We have no direct evidence, but I think it has to be. We could consider doing IFC/IHC for C4d and C3d like we do for antibody-mediated rejection in post-transplant biopsies. The endothelial swelling shown by Dr. Vander Heide in the COVID-19 hearts is very similar to that seen in the “endotheliitis” in AMR.
The levels of the cytokines in COVID-19 are very low compared to a septic patient, or patients treated with CAR-T cells. How confident are you that a cytokine storm actually is present.
LMB: Blood levels of Il-6 and other cytokines are definitely increased. I am sure there are levels of storms. In New Orleans and Houston, we have squalls, tropical storms and hurricanes categories 1 to 5.
RVH: I think the seriously ill patients/ patients that die have high cytokine levels. Obviously, not all people infected with the virus develop large increases.
Do you think there is a direct viral damage to endothelium or is this indirect via cytokines?
LMB: There is good published evidence of virions inside of endothelial cells. Elevated cytokines including IL-6 and TNF-alpha probably contribute.
RVH: See my last hypothesis slide I think it could be either or both.
Do you think that serosae (pleura, peritoneum) could also be target for the virus or would that be rather secondary to inflammatory syndrome?
LMB: We have observed a lymphocytic epicarditis in the heart. Not impressed with pleuritis and peritonitis. However, one of our medical examiner cases had an empyema. Probably had bacterial pneumonia leading to empyema with cotemporary COVID with DAD in the opposite lung.
RVH: We have also seen lymphocytic epicarditis in the heart. Any pleuritic that we see (not much) is likely a secondary change to the lung damage/inflammation.
Barth RF, Xu X, Buja LM. A Call to Action: The Need for Autopsies to Determine the Full Extent of Organ Involvement Associated With COVID-19 [published online ahead of print, 2020 Apr 10]. Chest. 2020;S0012-3692(20)30687-5. doi:10.1016/j.chest.2020.03.060
Buja LM, Wolf DA, Zhao B, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities [published online ahead of print, 2020 May 7]. Cardiovasc Pathol. 2020;48:107233. doi:10.1016/j.carpath.2020.107233
Brown RE, Wolf DA, Hunter RL, Zhao B, Buja LM. Morphoproteomics and Etiopathogenic Features of Pulmonary COVID-19 with Therapeutic Implications: A Case Study Annals of Clinical & Laboratory Science, vol. 50, no. 3, 2020 In press.
Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans [published online ahead of print, 2020 May 27]. Lancet Respir Med. 2020;S2213-2600(20)30243-5. doi:10.1016/S2213-2600(20)30243-5
Dr. Buja is Professor of Pathology and Laboratory Medicine and Distinguished Teaching Professor at the McGovern Medical School of the University of Texas Health Science Center at Houston. His scholarly focus is on pathogenesis of cardiovascular diseases. He is an advocate of the importance of the autopsy in medicine and has written several timely articles advocating for the autopsy.
ASIP member Dr. Joseph Roche (Wayne State University) recently published a paper in FASEB J. along with co-author Dr. Renuka Roche (Eastern Michigan University). Their paper hypothesizes a bradykinin [BK] model for COVID-19 complications and they suggest use of the FDA-approved BK blocker in the treatment of patients with COVID-19 respiratory disease. The abstract from the paper is given below and the final paper can be downloaded from FASEB J. using the link provided
Abstract As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157,970 deaths out of 2,319,066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)- bradykinin- and bradykinin-mediated inflammation → injury → inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.