The Top 5 Things We Need To Conquer COVID-19

By Andrew L. Concoff, MD, FACR, CAQSM

In this, the last of the installments of the 19 Things We Need, we have finally made it to the Top 5.

Here we have the most urgent and essential questions that will make or break our further response to the pandemic. Perhaps not surprisingly, these items are all science-related rather than policy-directed. In the end, good pandemic policy takes a back seat to, and cannot be crafted without detailed scientific knowledge. The novelty of SARS-CoV-2 necessitates a great deal of foundational investigation before such policy can be enacted; we simply still have much to learn. Yet the pace of scientific progress toward that understanding has been amazing to behold. By turning the full force of the international scientific community to the task, after just over five months, a Google Scholar search for COVID-19 now returns 219,000 results. With this tremendous pace of inquiry, it won’t be long until this list is obsolete. So, in an effort to summarize the critical questions about the disease before additional research makes me start over, here are the Top 5 of the 19 Things We Need to Conquer COVID-19.

5. Nuanced understanding of the implications of asymptomatic infection and pre-symptomatic transmission

  • Asymptomatic infection70,99,100
    1. Frequency of asymptomatic COVID-19 infection unknown
      • Mild symptoms may not be noted or reported complicating assessment
    2. Defined as individuals who never develop symptoms despite demonstrating IgG serologic evidence of past infection
    3. Critical insights from those that process the infections without the development of symptoms
      • Immune response
      • Genetic/genomic background
      • Possible insights toward treatment
  • Pre-symptomatic transmission
    1. Defined as the period of viral shedding and infectiousness prior to the onset of symptoms
    2. Demonstrated in SARS-CoV-2 and Influenza viruses but not SARS
    3. What percentage of pre-symptomatic, “stealth” spread contributes to new infections?
      • 44% (CI 25-69%) of new infections are thought to be transmitted from those who are pre-symptomatic70
  • Stealth spread severely complicates the entire public health approach to COVID-19 as peak viral loads and infectivity occur within a few days before to a few days after symptom onset mimicking influenza and in contradistinction to SARS70
    • Markedly limits the effectiveness of screening regimens predicated upon signs and/or symptoms as stand-alone efforts without extensive testing
      1. Fever screening
      2. Symptom checklists
      3. “Stay at home if you feel sick”
    • Mandates repeated, highly accurate laboratory testing of the population that includes asymptomatic individuals as the only method to effectively identify roughly half of those at risk for spread (actively infected and contagious but pre-symptomatic)
      • In response to identifying six new cases of COVID-19 this weekend in Wuhan, the Chinese government is evaluating the feasibility of testing all 11 million residents of Wuhan over a period 10 days101
    • By limiting diagnostic testing to those with symptoms, COVID-19 statistics across the US have been inaccurate:102,103
      1. Mortality rate – overestimated or underestimated?
        • Prior reports of mortality are case fatality rates:
          1. Milder cases certainly missed
          2. But many COVID-19 related deaths outside of hospital settings not counted
          3. Relationship to COVID-19 of deaths attributed to other causes (e.g., MI, CVA) may not be clear
        • Serologic testing allows estimation of infection fatality rate:
          1. Defined as the number of deaths in relation to the true total number of infections in the population
            • Modeled at 1.3%103
          2. Always significantly lower than the case fatality rate:  the number of deaths as a function of the number of proven cases given smaller denominator
      2. Prevalence and incidence – significantly underestimated to date
        • Only limited, symptom-based diagnostic testing has been performed in the US
          1. Asymptomatic and mild cases missed
  • Lack of availability of adequate diagnostic tests at the onset of the pandemic necessitated limitation of testing to those with certain characteristic symptoms of moderate severity
    1. Necessitates alternative approaches to determine population-based rates of COVID-19 spread
      1. A posteriori serologic testing demonstrating IgG antibodies indicative of past infection104
        • Individual testing to reflect personal risk/history of infection
          1. Positive tests used to indicate:
            • Prior infection
            • Potential as donor for convalescent serum
            • Potential use in return to work scenarios
          2. The concept of “immunity licenses” for use in determining return to work is increasingly viewed as implausible105
            • Threshold levels of neutralizing antibodies that confer protection has yet to be determined
              1. Require parallel studies to establish which antibody titer correlates with protection
                • At least one such test104 documented a high correlation between the ELISA threshold and the SARS-CoV-2 microneutralization IC50 (n=12, Pearson’s r – 0.9279; p<0.0001)
            • Immunity conferred by antibodies may be only relative, not absolute
        • “Serosurveys”23
          1. Population level testing in a given area to reflect the seroprevalence of disease
          2. Recently reported in New York
            • 13.9% state residents had evidence of prior infection
            • 21% of those in New York City were seropositive
            • North County demonstrated only 1.2% Seropositivity
          3. Demonstrates the hazard of state-level data: 
            • All COVID-19 epidemiology issues vary at the local level, but policy is typically set (by necessity) at the state level
        • The FDA’s policy of “regulatory flexibility”, designed to hasten access to serologic testing by foregoing formal FDA review of test clinimetrics has now been recognized to have backfired, allowing the market to be flooded by tests that failed to perform adequately when tested106
          • The FDA has responded by requiring that test manufacturers submit data demonstrating that tests meet “specific performance thresholds” for rates of false positive and false negative results54
    2. Waste-water assessments SARS-CoV-2 titers may represent complementary population-level indicators of COVID-19 infection
      • SARS-CoV-2 is shed in stool107
      • SARS-CoV-2 can be measured in sewage, at times even prior to the identification of the first local case108
      • A recent study in Massachusetts109 found significantly higher estimated percentage of SARS-CoV-2 positive stools that the confirmed case numbers suggesting a higher population prevalence than previously appreciated
      • May reflect better sensitivity to COVID-19 cases of milder severity
      • First antigen based (rather than PCR-based) diagnostic test was recently approved110
      • Likely cheaper and more scalable than prior PCR-based diagnostic tests
      • Highly specific, less sensitive than PCR tests
        • False negative tests will be a concern
          1. Follow-up PCR tests may be necessary in concern exists for false negative result
  • Pre-vaccination diagnostic testing may be required to avoid complications associated with vaccination during active, asymptomatic, or pre-symptomatic infection (see Thing #4 below)

4. Expeditious vaccine development

  • Requirements:
    1. Effectiveness
    2. Safety
      • Potential of hazard from vaccination during active infection
        1. Pre-vaccination diagnostic testing may be necessary to confirm the absence of asymptomatic disease pre-symptomatic disease
          • In SARS, anti-Spike (S) Protein IgG Antibody seroconversion has been identified as potentially hazardous4
            1. Development of ARDS in SARS was found to coincide with IgG seroconversion in 80% of patients91
            2. Earlier development of Neutralizing-Anti-S antibodies associated with a higher likelihood of death from SARS92
              • Fatal infections:  patients reached peak anti-S neutralizing antibody levels at an average of 14.7 days
              • Non-fatal infections: patients reached peak anti-S-neutralizing antibodies at an average of 20 days
      • Prior vaccines for dengue fever and SARS were abandoned after making those vaccinated more susceptible to severe forms of the disease93
      • An inactivated vaccine would be more widely applicable than live, attenuated versions, particularly among the immunocompromised
  • Accelerating the timetable for availability of vaccine94,95,96
    1. Over 100 projects worldwide
    2. The previous record for development of a vaccine
      • 4 years for Mumps
    3. Estimated expedited time to availability had been 12-18 months per Dr. Anthony Fauci
    4. Trump administration’s “Operation Warp Speed” will attempt to reduce time to vaccine availability
      • Goal: 300 million vaccine doses by January 2021
      • 14 projects selected for support
    5. Representative current vaccine development projects95
      • Oxford Vaccine
        1. Adenoviral vector vaccine
        2. Had head start from prior work toward developing MERS vaccine
        3. Good initial results recently reported in macaques
        4. Started safety trials in volunteers
      • Sinovac Vaccine
        1. Reported initial success in April with vaccine administration protective of subsequent COVID-19 exposure in monkeys
      • CanSino
        1. Adenoviral vector vaccine
        2. Started volunteer trials
      • Innovio
        1. Pure DNA vaccine
      • Moderna
        1. Pure RNA vaccine
      • Which vaccine platform will yield the best results quickly?
        1. Traditional approaches versus innovative efforts
  • Is SARS-CoV-2 vaccine development likely to succeed?  Is repeated vaccination likely to be necessary?
    • Determined, in-part, based upon rate of viral mutation
      1. Initial reports: mutation rate appeared low, amenable to vaccination97
      2. Controversial recent study24 indicates D614G Spike protein mutation may:
        • Outcompete other SARS-CoV-2 serotypes as has become more dominant over time through increased transmissibility
          1. Possible mechanisms of increased transmissibility:
            • Structural
              1. May decrease the interaction between the S1 and S2 subunits, thereby facilitating S1 shedding from S2
              2. May allosterically improve the ease of movement of the receptor-binding domain (RBD) from the “down” to the “up” position (required to interact with the ACE2 receptor)
            • Immunologico-structural
              1. D614 is embedded within an active immunologic epitope
                • Induced chronic B-cell memory responses in convalescent sera from SARS-CoV
              2. Antibodies against this epitope in SARS-CoV mediate antibody-dependent enhancement (ADE) in rhesus macaques:  
                • D614G mutation may cause a conformational change in Spike protein that increases receptor binding, fusion activation, or ADE antibody elicitation
                • May impact neutralizing antibody sensitivity
                • May create susceptibility to re-infection following recovery
          2. Cannot rule-out alternative theory of “Founder effect” if D614G initially infected a particularly vulnerable population (e.g., nursing home residents)
  • If a vaccine is successfully developed, it is likely96 that a period of production levels inadequate to immunize the entire population will occur.
    1. Which higher risk groups should be prioritized to receive the vaccine first?
      • Older patients
      • Ethnic/racial minorities
      • Those with co-morbidities
      • Non-seroconverters with high occupational exposure
        1. Health care workers
        2. Other workers deemed essential
  • Public relations to confront opposition and ensure adoption
    1. Focused community-based outreach efforts targeting high risk and/or disenfranchised, populations that would not otherwise be tested68
      1. Nursing homes
      2. Correctional facilities
      3. Homeless shelters
      4. Minority communities
      5. Poor, urban communities

3. Treatments of proven efficacy from robust clinical trials

  • To date, no treatments have been proven effective for COVID-19 infection prevention or treatment
  • Prior to the development of a vaccine, the public policy decisions and the availability of effective treatments will determine the magnitude of the damage done by the COVID-19 pandemic
  • Treatments by phase of disease
    1. Preventative treatments for high-risk occupations / exposures
      • Determining whom to treat and the timing, thereof, is challenging given asymptomatic and pre-symptomatic infection (see Thing #5, above)
        1. Prophylactic treatment based upon exposure would likely address early infection events including viral binding to receptors, viral replication, or boosting initial innate immune response (see Thing #1, below)
    2. Treatments for mild/moderate or early COVID-19 with risk factors for severe disease:
      • Purpose:  prevent hospitalization and complications
      • Antiviral treatments may work better early in disease when viral replication and viral loads are highest
    3. Treatments for severe COVID-19:
      • Purpose: limit ARDS/Cytokine storm/ prevent intubation and/or death
      • Immunomodulating medications may work best later in disease when viral loads and replication have decreased but immune system hyperactivity becomes a greater concern (See Thing #1, below)
  • Expert consensus recommendations have been made and should be followed for the non-pharmacologic management of critically ill patients74
  • Candidate Treatment Medications by Class:
    1. Repurposed medications75, 76
      1. Antimalarials
        • Hydroxychloroquine
        • Chloroquine
          1. Utility of antimalarials in prophylaxis remains unclear77
          2. Largest, retrospective observational study of HCQ to date from New York Presbyterian hospital (N=1,376) demonstrated no benefit toward risk of combination of intubation or death78
            • HCQ not recommended for routine use in COVID-19
            • Non-randomized, not conclusive
              1. RCTs recommended
              2. >20 additional studies are on-going
          3. FDA Issued a warning regarding prolonged QT interval particularly when used with macrolide antibiotics
      2. Targeted immunomodulators
        • IL-6 Inhibitors
        • Tocilizumab
          1. IL-6 levels found to be lower among survivors of hospitalization than fatalities
          2. Initial favorable results from uncontrolled trials
        • JAK-inhibitors
          1. Baricitinib
            • Machine learning suggests opportunity to limit endocytosis of viral bound ACE2
          2. TD-090379
            • Lung-selective, nebulized JAK inhibitor
            • Phase I trial planned
        • IL-1 receptor antagonist
          1. Anakinra
            • Recent retrospective cohort study80 of high-dose anakinra vs. standard care for COVID-19 associated ARDS with hyperinflammation (n=27) at 21 days
              • Clinical improvement was noted in 72% of Anakinra treated patients
              • Results favored Anakinra over standard care:
                1. Survival: 90% vs 56% (p=0.009)
                2. Mechanical ventilation-free survival (72% vs 50% (p=0.15)
          2. Anakinra may be the preferred medication in COVID-19-related cytokine storm81
            • Compared to tocilizumab, as anakinra is considered:
              1. Less myelosuppressive
              2. Less hepatotoxic
              3. Has shorter half-life
              4. Does not mask infection (Fever, CRP)
            • Compared to JAK-inhibitors, as anakinra is considered:
              1. Safer given blockade of single, rather than numerous cytokine pathways
              2. Though less convenient given the subcutaneous versus oral route of administration 
      3. Colchicine
        • Phase III trial planned
      4. Antivirals
        1. Likely best used early in disease (during period of greater viral replication rather than late disease during immune-predominant phase) and in combination:
          1. In an open label, phase 2 study,82 early triple combination of IFN beta-1b, lopinavir-ritonavir, and ribavirin was superior to lopinavir-ritonavir alone
            • N=127
            • Triple therapy had shorter median time to negative nasopharyngeal swab [7 (IQR 5-11) vs 12 (8-150)]; hazard ratio 4.37 [95% CI 1.86-10.24], p=0.001
            • Side effects were mild
              1. Self-limited nausea and diarrhea
              2. No difference in frequency between group
            • Future recommend study design:
              1. Triple therapy plus IFN vs IFN alone to determine triple therapy efficacy without IFN
        2. Antiviral COVID-19 Treatments sourced from other Viral Infections:
          •  HIV:
            1. Lopinavir/ritonavir
              • One published, Chinese RCT83 among inpatients
                • No benefit vs standard care (n=199)
            2. Darunavir/clobicistat
          • Influenza
            1. Osteltamivir
            2. Baloxavir
            3. Umifenovir
            4. Favipiravir (experimental)
          • Other antivirals
            1. Remdesivir (Ebola)
              • Often cited as the most likely antiviral to succeed
              • Negative study84
                1. RCT from 10 Chinese hospitals
                2. n = 237
                3. Symptom onset to enrollment 12 days or less
                4. Oxygen sat 94% or less on room air
                5. IV Remdesivir
                  • Day 1; 200mg
                  • Day 2-10: 100mg
                  • vs. Placebo
                6. Primary outcome:
                  • Time to improvement of two levels on an ordinal scale from 1=discharged to 6-death
                7.  Results:
                  • No difference Hazard ratio 1.23 [95% CI 0.87 – 1.75]
              • “Positive” study – The Adaptive COVID-19 Treatment Trial:85
                1. Details of trial not yet released
                2. By Gilead report only:
                  • N= 1,063
                  • Impact on mortality 8% vs placebo 11.6 % vs placebo 8% (NS by report only)
                  • Reduced hospital stays to average discharge by day 11 versus day 15 (four days)
                  • Is this really a “positive” study?
              • FDA Authorized Remdesivir under an Emergency Use Authorization on May 1, 2020:86
                1. SpO2 < 94% on room air
                2. In-patient setting via IV
                3. Now considered standard-of-care treatment
              • 19 additional Remdesivir studies are underway, including many testing Remdesivir in combination with other drugs
              • Gilead, the manufacturer of Remdesivir, has donated its entire stockpile of the drug to the US Government for use in combating COVID-1987
            2. Galidesivir (Hep C, Ebola, Marburg)
            3. Ribavirin (RSV, Hep C, Hemorrhagic fevers)
            4. Azvudine (Hep C, HIV)
            5. Nitazoxanide (Anti-parasitic/anti-viral)
      5. Immune checkpoint inhibitor
        • Camrelizumab and thymosin
      6. Antiparasitic88
        • Ivermectin
      7. Immunosuppressive agent
        • Sirolimus
    2. Passive immunity
      • Convalescent serum
        1. Transfer of neutralizing antibodies to:
          • The critically ill
          • Highest risk exposures?  (e.g., Among health care workers)
          • May cause damage if inadequate levels of antibody or in the absence of innate immune response through antibody-dependent enhancement (ADE) of viral infection (see Thing #1, below)6
      • Intravenous immunoglobulin (IVIG)6
        1. Potential treatment for secondary inflammation/cytokine storm
          • Block viral-neutralizing antibody binding to FcR
            1. Limit inflammation
            2. Limit inflammatory cytokine production
            3. Prevent / treat ADE of viral infection (see #1, below)
          • Well-recognized non-specific anti-inflammatory effects
    3. Novel drugs:
      • Novel antibody-based treatments89
        1. Llama-derived, single-domain antibodies
        2. Directed against the viral spike protein to prevent initial entrance into e pithelial cells or subsequent ACE2 shedding (see Thing #1 below)
        3. Cross-reactive with SARS-CoV-1 and MERS
      • Furin inhibitors
      • Mavrilibumab (GMCSF)
      • Selinexor [Selective Inhibitor of Nuclear Export (XPO1 Inhibitor)]
      • RNA-based approaches
        1. mRNA-1273
        2. siRNA
      • Other novel drugs identified by a recent large-scale drug repurposing study90
        • Four, novel cysteine protease inhibitors
          1. MDL-28170
          2. Z LVG CHN2
          3. VBY-825
          4. ONO 5334
      • Apilimod (PIKfyve kinase inhibitor)
      • MLN-3897 (CCR1 antagonist)
      • Leronlimab (CCR5-Inhibitor)
      • Other drugs/mechanisms of note79
        1. Aviptadil (Caspase 3 inhibitor)
        2. APN-01 (recombinant human angiotensin converting enzyme 2)
        3. Inflarx NV (anti-C5a antibody)
        4. Interferon-based treatments
        5. Surfactants:
          • KL4 Surfactant
          • AT-100 (recombinant human surfactant protein D)

2. Detailed Understanding of the Epidemiology of COVID-19 Infection52

  • Determination of community point prevalence and incidence of COVID-19
    1. Capturing milder cases
      • Robust, symptomatic surveillance plus targeted asymptomatic population diagnostic sampling
      • Population serologic sampling
        1. New York State recently reported results53 (See Thing #5 above)
        2. Inaccuracy of tests represents a challenge to their utility54 (see Thing #5 above)
      • Monitoring of sewage levels of SARS-CoV-2 (See #5 above)
    2. Capturing severe cases
      • Post-mortem testing to provide accurate mortality rates
        1. Pre-hospital deaths from myocardial infarction, stroke, etc. may be COVID-19 related
    3. Testing of household contacts of patients with disease
      • Time course of transmission
      • Risk factors for transmission
    4. Development of the “severity pyramid”
      • Aggregation of testing from numerous settings
    5. Hospital case control studies
      • Detailed risk-profiling predictive of suffering severe manifestations and/or death:
        1. Putative, but unproven, risk factors of poor outcome:55
          • Demographic and lifestyle:
            1. Male
            2. Over 60 years of age
              • Of note, type I interferon responses decrease with age11 including those induced by viral infection12 (see Thing #1 below)
            3. Smoking
            4. Other
          • Comorbidity-associated:
            1. Diabetes mellitus
            2. Hypertension
              • Low renin-hypertension, common among African Americans,56 may link the renin-angiotensin-aldosterone system (RAAS) to poor outcomes in COVID-19
            3. Coronary artery disease
            4. Chronic obstructive pulmonary disease
            5. Immunocompromise57,58
              • From underlying disease
              • Associated with underlying disease activity
              • Recent single-center study59 found no evidence of enrichment of hospitalized population for those with systemic autoimmune disorders.
                1. Limited number of cases may not allow accurate assessment of risk among less common autoimmune conditions/medications
              • All major rheumatologic organization have recommended staying on prescribed antirheumatic medications
                1. Greater hazard likely is stopping medications resulting in disease flare requiring corticosteroid dosing (see below)
          • Medication-related:
            1. ACE-inhibitors and ARBs
              • Initial concerns that ACE-inhibitors and ARBs could worsen COVID-19 via increased ACE2 receptor expression60 are likely unfounded
              • A protective effect of ACE-inhibition through increased ACE2 expression25,26 appears more likely as was suggested by a small Chinese study61 (n=41; 17 on ACEI/ARB, 25 on non-ACEI/ARB)
                1. Twice the percentage of patients on Non-ACEI/ARB (12/25) 48% developed severe disease as those on ACEI/ARB (4/17) 24% (NS)
                2. Peak viral load was significantly lower in the ACEI/ARB group than the non-ACEI/ARB group
            2. Corticosteroids62
              1. Decreased viral clearance, and increased mortality
              1. Mechanism may involve suppression of already inadequate interferon activation (see Thing #1 below)
              1. Not currently recommended for Acute Respiratory Distress Syndrome (ARDS) nor for COVID-19
              1. Doses for non-COVID-19 diseases should be used at the minimum necessary dose during the pandemic
            3. Immunocompromising medications63
              • Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs)
              • Targeted immunomodulators (TIMs)
              • Theoretical concern has not panned out to date
              • Potential exists for protective effect from more severe disease by limiting robustness of humoral immunity (see #1 below)
            4. Chemotherapy64
              • Past use
              • Current use
          • HLA-Associations65
            1. HLA-B*46:01 likely confers increased risk for COVID-19 (as found previously for SARS)
            2. HLA-B*15:03 could enable cross-protective T-cell immunity from prior non-SARS-CoV-2 coronavirus exposure
          • Other
    6. Genomic / epigenomic sources of accelerated, severe disease among those without recognized risk factors:
      1. Candidate molecules
        • Interferon I responses3
        • ACE2-associated abnormalities66
          1. Serum ACE2 level
          2. ACE2 polymorphisms
          3. Angiotensin II level
          4. Serum renin in hypertension67
        • Furin levels, serum
          1. Elevated with HTN
          2. Elevated with DM
          3. Elevated by certain medications
        • Serum Surfactant Protein D
          1. Known prognostic factor in A/H1N1 virus infection68
      2. Associated with “cytokine storm”69
        • Perforin mutations
        • Specific cytokines or cytokine triggers
          1. Interferon gamma
          2. Interleukin 1
          3. Interleukin 6
          4. GMCSF
          5. Other cytokines and chemokines
    7. Further temporal shedding studies
      1. Goal: establish time-course of contagiousness
      2. Best current study70 is based upon only 77 infection-infectee pairs
    8. Convalescent patient monitoring
      1. Does infection confer long-lasting immunity?
      2. What is the etiology of the “False Dawn” phenomenon of recovery?71
        • Patients are improving to the point of hospital discharge and becoming asymptomatic for days only to develop recurrent symptoms
        • Etiology is unclear
    9. Explanatory investigations of the marked variation in local and regional prevalence of COVID-1972
      1. Known risk factors do not explain current differences in prevalence
        • Age
        • Population density
        • Weather
    10. What data thresholds best direct changes in the aggressiveness of social distancing by identifying the least restrictive rules of social interaction to limiting the development of second (and subsequent) waves across different COVID-19 prevalence rates?
      1. Critical period is delayed 2-3 weeks after policy changes when the rate of hospitalization may begin to change to reflect the new policy
        • Assessment of policy changes requires aggressive testing in the weeks after changes made
        • Monitoring for changes from newly established baseline incidence must continue, thereafter
    11. To optimize both the health and economics of our population, should social distancing policies differ for seniors and non-seniors to account for the marked variation in disease severity and economic impact of these groups?
      1. Recent innovative study73
        • Represents the first effort at hybrid modeling designed to simultaneously investigate:
          1. Differential disease risks by age
            • Hospitalization outcome by degree of saturation of healthcare capacity
              1. Recovery
              2. Death
          2. Economic impact of public policy designed to control spread:
            • Severity of social distancing policies
            • Differential productivity by age
        • Findings:
          1. Non-strict quarantine policy and releasing the entire population when disease levels begin to regress yields: a
            • “Second wave” of infections
            • Excess hospitalizations for capacity
              1. Increased death toll
          2. An extremely strict seniors-only quarantine coupled with extremely gradual withdrawal of mandatory quarantine for non-seniors controls the outbreak
            • Limits economic damage
            • Avoids oversaturating hospitals
              1. Reduced death toll
          3. Strict isolation policies that reduce contagiousness attributable to asymptomatic spread (as compared to loosely enforced policies):
            • Reduce the total number of hospitalizations
              1. Reduce the death toll
            < /li>
  1. Deeper understanding of the tissue-, cellular- and molecular-level viral-host interactions, immune responses, and the manifestations of COVID-19 infection
  • Three-phase model of COVID-19 therapeutics
    1. Prevention of initial infection
    2. Post-infection, initial immune response
    3. Secondary immune response, “cytokine storm”
      • Only experienced by a minority of those affected
  • Relationship between magnitude of initial inoculum, viral titers, and subsequent course1
  • What aspects of the host immune response to SARS-CoV-2 lead to more severe manifestations of COVID-19?2,3
    1. Prognostic Clinical Risk Scores for COVID-19 have been developed:
      • Best recent example:4
        1. Developed (n=1590) to predict composite endpoint of:
          • Admission to ICU
          • Invasive ventilation
          • Death
      • Preliminarily validated (n=710) [Validation cohort AUC = 0.88 (95% CI, 0.84-0.93)]:
      • Based upon 10 Predictors:
        1. Abnormal Chest x-ray
        2. Age
        3. Hemoptysis
        4. Dyspnea
        5. Unconsciousness
        6. Number of Co-Morbidities
        7. History of Cancer
        8. Neutrophil-to-Lymphocyte Ratio
        9. Lactate dehydrogenase level
        10. Direct Bilirubin Level
      • Online Risk Calculator is available at:
      • Recent review of prior models5 indicates that they:
        1. Are poorly supported
        2. Are at high risk of bias
        3. Likely overestimate real-world performance
    2. Detailed understanding of the immune dysregulation leading to “cytokine storm”
      • Consequences of SARS-CoV-2 evasion of the initial innate immune response and the resultant dysfunctional alterations in the temporal patterns of host immune response
        1. Hazard associated with delayed innate immune system activity coupled with early, adaptive immune system involvement
          • Early, but inadequate, humeral responses may lead to antibody-dependent enhancement (ADE) of viral infection6
            1. ADE causes increase in target cell infection by uptake of infectious virus-antibody complexes through FcR binding
              • Causes infection of immune cells including macrophages
            2. Second mechanism suggested via antibody binding induced conformational change receptor-binding domain identified in SARS7
            3. Increased humoral response may result in numerous negative effects related to immune complex formation/deposition:8
              • Complement activation leading to tissue damage and inflammation
              • Immune cell recruitment leading to proinflammatory cytokine expression
              • Mast cell degranulation leading to vasodilation and edema
            4. The generation of specific, pathologic autoantibodies may be more likely with an unbalanced humoral response
              • Anti-ACE2 autoantibodies have been associated with pulmonary hypertension and digital ischemia among patients with autoimmune disease.9  
                1. The generation of Anti-ACE2 antibodies may be associated with complications in COVID-19
              • Anti-Spike protein antibodies in SARS have been demonstrated to cross react with pulmonary epithelial cells, resulting in cytotoxicity.10
                1. Similar antibodies may be present in COVID-19 given the significant S-protein sequence homology between SARS-CoV-1 and SARS-CoV-2
      • Inadequate initial type 1 interferon response sets the stage for subsequent, late overly aggressive second phase of pro-inflammatory cytokine expression
        1. In general, Type 1 interferon responses have been recognized to decrease with aging11
          • Type 1 Interferon responses to viral infection have also been recognized to decrease with aging12
            1. Likely explanation for increased prevalence of cytokine storm and greater mortality with aging
        2. Critical cases of COVID-19 are marked by upregulation of type I IFN signaling genes including IFNAR1, JAK1, TYK2 but a marked downregulation of IFN-stimulated genes including MX1, IFITM1, IFIT213
          • Interestingly, ACE2 has been identified as one such SARS-CoV-2 stimulated gene14
            1. Inadequate IFN response to infection may limit ACE2 production contributing to numerous downstream COVID-19 effects (see below)
        3. Lack of IFN signaling through STAT1 secondary to inactivation by SARS-CoV-1 ORF6 protein has been implicated in reduction, and functional exhaustion, of T-cells among elderly patients15
          1. However, ORF6 in SARS-CoV-2 truncated, may not have same functionality
        4. Surfactant protein D (SF-D), which selectively recognizes the SARS Spike protein,16 may be a link from inadequate innate immune response to COVID-19 pathology
          1. SF-D is recognized to play an important role in the initial innate immune response to viral infection through:17
            • Binding viral particles for opsonization, leading to phagocyte clearance
            • Microbial aggregation which is thought to enhance the efficiency of neutrophil traps
            • Neutralization of infectivity
            • Dampening microbe-induced innate signaling
            • Activation of the complement pathway18
            • SF-D has been demonstrated to attenuate renal injury in a murine model of pneumonia-induced sepsis by modulating:19
              1. Apoptosis
              2. Inflammation
              3. NF-kB signaling
            • SF-D delays Fas- and TRAIL-mediated apoptosis in T-Cells20
              1. Thus, inadequate SF-D activity may contribute to deficient T-cell survival
          2. Epidemiologic associations SP-D to recognized risks for COVID-19 severity17
            • SF-D polymorphisms have been associated with diabetes, metabolic syndrome, and atherosclerosis through effects of endothelium
            • Serum SP-D levels have been associated with:
              1. Mortality in a variety of pulmonary disorders including ARDS
              2. All-cause and cardiovascular mortality
              3. Metabolic disease
          3. Recombinant human SF-D is entering human trial for COVID-19
      • Late, enhanced and poorly controlled innate immune system activation leading to “cytokine storm”
        1. In SARS and MERS, the following processes are thought to yield the unrestrained inflammation in “cytokine storm”8,21
          • Inadequate initial innate immune response
          • Rapid viral replication / greater viral loads
            1. Create greater endothelial and vascular cytopathic effects
            2. Higher levels of cytokines and chemokines
            3. Large scale infiltration of uninfected inflammatory cells into the lungs
          • Infection of alveolar type I and Type II pneumocytes rather than airway epithelial cells alone
          • Associated in animal studies with lung pathology and host susceptibility
          • Rebound, excessive innate immune responses
            1. Contributes to uninfected inflammatory macrophage and monocyte accumulation
          • Inflammatory macrophage/monocyte and neutrophil accumulation
            1. Predominant source of cytokines and chemokines
    3. Neutralizing antibodies
      1. To which epitopes must antibodies bind to effectively neutralize viral particles and resolve infection?
      2. Does the premature development of neutralizing antibodies (or early treatment with convalescent plasma) increase the risk of organ damage and mortality as seen in SARS?
        • Adoptive transfer of Anti-S-IgG neutralizing antibody in macaques, mice, and African green monkeys reviewed in 6 resulted in:
          1. Decreased viral loads, however,
          2. Repeat challenge with inactivated SARS-CoV caused vaccine-induced pulmonary injury
            • Putative mechanism:
              • ADE and diffuse alveolar hemorrhage
          3. Similarly, SARS-CoV vaccine-induced pulmonary injury has been reported in multiple animal models
            • Care should be exercised in the timing of treatment with convalescent serum
            • Concern m ay exist for lung injury with re-exposure after treatment with convalescent serum
        • Anti-S-IgG-initiated toxicity occurs through binding to the Fc receptors on monocytes/macrophages resulting in3
          1. Inflammatory cytokine production
          2. Activation of the classical complement pathway
          3. Antibody-dependent, cell-mediated toxicity
          4. Increased viral replication from ADE 
      3. Do all patients with confirmed COVID-19 that recover from seroconvert according to antibody tests?
        • A Chinese study22 was unable to identify neutralizing antibodies from 30% of those who had recovered from COViD-19
          1. Higher titer neutralizing antibodies were seen among elderly and middle aged than young patients
          2. Neutralizing antibody titers were positively correlated with CRP and negatively correlated with lymphocyte counts
        • A more recent study of mildly affected COVID-19 patients from New York23 found:
          1. Seroconversion was noted among:
            • Over 99% of those with confirmed disease [all but 3/1,343 (0.22%)]
            • 37.4% of suspected patients
          2. Seropositivity developed:
            • From 7-50 days after symptom onset (median 24 days)
            • From 5-49 days from symptom resolution (median 15 days)
            • Optimal time for widespread antibody testing = 3-4 weeks after symptom onset and at least 2 weeks after symptom resolution
            • Whether IgG antibodies conferred immunity was not determined
          3. Prolonged nasopharyngeal PCR positivity was noted among 19% of subjects despite symptom resolution and may represent:
            • Shedding of nonviable virus
            • Shedding of nonviable virus or fragments coated by antibody or engulfed by immune cells
            • Asymptomatic carriers
            • On-going active, contagious disease
      4. Key Questions:
        • Is immunity following SARS-CoV-2 lifelong?
          1. If not,
            • How long does the immunity conferred by convalescence from COVID-19 last?
            • What level of neutralizing antibody is necessary to achieve and maintain immunity?
            • Do specific mutations such as D614G risk loss of immunity / make individual susceptible to second infection?24 (see Thing #4, above)
        • Does the development of neutralizing antibodies signal the end of contagiousness, even if viral shedding persists, given coating of virus by antibody?
  • What are the relationships between Viral-ACE2 binding, the host immune response, and specific COVID-19 disease manifestations as mediated by changes in:
    1. The Renin-Angiotensin-Aldosterone System (RAAS)?25,26
    2. The Kinin-Kallikrein system?27,28
    3. Complement Activation?29
  • Specific organ manifestations:
    1. Pulmonary Disease
      • ACE2 in Acute Lung injury and ARDS-like involvement
        1. ACE2 has been demonstrated to be protective of severe acute lung failure30
        2. ACE2 Binding and Inflammation6
          • SARS-CoV-2 binding has been demonstrated to downregulate ACE2
            1. The catalytically active ACE2 ectodomain is shed
          • In a murine model, local reduction in ACE2 levels altered the balance of the RAAS, favoring ACE over ACE2, resulting in:
            1. Increased inflammation
            2. Vascular permeability
            3. Pulmonary edema
            4. Neutrophil accumulation
            5. Diminished lung function
          • SARS-CoV-2 Binding and IL-1 exposure causes ACE2 shedding, as sACE2, from the pulmonary epithelia by ADAMTS17 and may cause:
            1. Increased TNF-alpha production
            2. Increased pathogenicity
        3. In a small Chinese study31 (n=12), angiotensin II levels from patients with COVID-19 were:
          • Markedly elevated
          • Linearly related to:
            1. Viral load
            2. Lung injury
      • ACE2 inhibition and pulmonary edema from activation of the Kinin-Kallikrein system27,28
        1. ACE2 mechanism of pulmonary edema was initially thought to be from the impact of high angiotensin II – mediated pulmonary vasoconstriction
        2. Lack of evidence of experimental increase in hydrostatic pressure argues against angiotensin II as source
        3. ACE2 inactivates des-ARG9-bradykinin
        4. Decreased ACE2 levels from COVID-19 may remove the inhibition of des-Arg9-bradykinin, a potent ligand of bradykinin receptor B1 on endothelial cells, the inducible receptor that is upregulated in the setting of inflammation
        5. Activation of B1 receptors triggers vasopermeability and vasodilation leading to angioedema
          1. Bradykinin receptor antagonism has been suggested as a COVID-19 treatment
      • Role of surfactant protein D (SF-D) deficiency in COVID-19 respiratory failure
        1. Inadequate SF-D response is a possible link between inadequate innate immune system activity and respiratory failure related to alveolar collapse (see above)
      • Pulmonary Intravascular Coagulopathy (PIC)32 (see below)
      • Activation of the complement cascade29
        1. Case series: 5 patients were described with skin and/or lung involvement:
          1. Respiratory failure
          2. Purpuric skin rash
        2. Marked deposition of C5-9, C4d, and Mannose binding lectin-associated serine protease 2 (MASP2) in the microvasculature consistent with complement induced microvascular injury
        3. Pathology:
          1. Lungs:
            • Pauci-inflammatory septal capillary injury
            • Septal capillary mural and luminal fibrin deposition
            • Neutrophilic infiltrate of the inter-alveolar septa
            • No viral cytopathic changes noted
            • No evidence of classic ARDS:
            • No prominent diffuse alveolar damage, hyaline membranes, inflammation, type II pneumocyte hyperplasia
          2. Skin: 
            • Pauci-inflammatory thrombotic vasculopathy with deposition of C5-9 and C4d in grossly normal and involved skin
          3. Co-localization of SARS-CoV-2 spike glycoproteins with C4d and C5-9 in inter-alveolar septa and cutaneous microvasculature  
        4. Generalized activation of:
          1. Alternative
          2. Lectin-based pathways
        5. Possible triggers
          1. Hypoxemia
          2. Catastrophic anti-phospholipid antibody syndrome
          3. Atypical hemolytic uremic syndrome
          4. Purpura fulminans
          5. Atrophic papulosis
          6. ACE2 downregulation leading to increased angiotensin II-induced ROS formation
      • “Silent hypoxia”33
        1. Patients presenting with limited symptomatology but remarkably low peripheral oxygen saturation
        2. Oxygen saturation below 75% typically results in loss of consciousness
        3. Levels in COVID-19 often in the 70-80% range without symptoms
          1. Occasional lower levels below 50%
        4. Rationale for the disconnect between degree of hypoxia and symptoms remains unclear
      • Key questions:
        1. How are the numerous, underlying pulmonary pathologies best distinguished and treated in each individual patient?
        2. What is the explanation for the lack of symptomatology at low peripheral oxygen saturations in “silent hypoxia”?
    2. Cardiovascular manifestations34
      • Myocardial injury as evidenced by elevated high-sensitivity cardiac troponin I or new ECG changes was identified among
        1. 7.2% of patients in Wuhan overall
        2. 22% of those requiring ICU care
        3. Two patterns of injury
          • Noncardiac presentation with rise in troponin I four days after symptom onset
            1. Timing coincides with other inflammatory markers including D-Dimer, ferritin, IL-6, LDH
            2. Consistent with Cytokine Storm
          • Cardiac predominant presentation
            1. Viral Myopericarditis (as seen in MERS) or stress cardiomyopathy
          • Shock 8.7%
          • Mechanism unclear:
            1. Direct infection via myocardial ACE2 receptors
            2. Cy tokine storm
              1. Hypoxia induced cardiac myocyte apoptosis
            3. Myocardial infarction
      • Dysrhythmias
        1. Present in 16.7%
        2. Etiology:
          • Disease associated
          • Medication-induced
            1. Prolonged Q-T Interval
              • Antimalarials
              • Macrolide antibiotics
            2. Other
      • Kawasaki-like vasculitis among children35
        1. 100 cases by the end of 4/2020, predominantly European
        2. Kawasaki Disease
          • Clinical diagnosis based upon:
            1. Fever > 5 days
            2. Peripheral edema
            3. Cutaneous changes
              • Erythema and desquamation
              • Rash
            4. Conjunctivitis
            5. Oral changes
              • Cheilitis
              • Glossitis
              • Pharyngitis
            6. Cervical lymphadenopathy
            7. Dreaded complication is coronary vasculitis
          • Cause unknown
            1. Temporal association with viral infections
              • Including coronavirus HCoV-NL63 has been previously suggested though not confirmed
        3. Most cases improved rapidly over by four days
          1. Some required:
            1. Mechanical ventilation
              • 10/23 cases from two studies combined
            2. Cardiac Support
          2. Treatments included
            1. IVIG
            2. Antibiotics
            3. Methylprednisolone
            4. Aspirin
        4. Differences COVID-19 Associated Syndrome and Kawasaki Disease
          1. COVID-19 patients were older
            1. Median age 9 vs 3yrs
          2. Greater frequency of gastrointestinal symptoms
      • Key questions:
        1. Does myocardial injury typically represent viral myocarditis or non-specific cardiac involvement from cytokine storm?
          • How frequently is COVID-19 related cardiac sudden death and how often is it missed in assessing COVID-19 related mortality?
            1. Does COVID-19 cause sudden death from coronary vasculitis with coagulopathy among those with pre-existing ASCAD?
              • Is coronary vasculitis present in COVID-19 patients without other Kawasaki manifestations?
                1. Are COVID-19 Coronary vasculitis-related myocardial infarctions being misclassified as non-COVID-19?
          • What is the mechanism behind the development of Kawasaki-like COVID-19 manifestations?
            1. Why are only children affected?
              • Why is the age distribution for COVID-19 Kawasaki-like manifestations skewed older than traditional Kawasaki disease?
    3. Hematologic abnormalities
      • Coagulopathy
        1. One study found that 31% of critically ill COVID-19 patients in the ICU have thrombotic complications36
          • 14% suffered pulmonary emboli
        2. Spectrum of disease
          • Pulmonary Intravascular Coagulopathy (PIC)32
            1. Significant microvascular thrombosis and hemorrhage
            2. Extensive alveolar and interstitial inflammation
            3. PIC is distinct from DIC
              • Lung-limited thrombosis (vs multi-organ in DIC)
              • Intrapulmonary hemorrhage (vs generalized in DIC)
              • Equivocal transaminase elevation (marked elevation ion DIC)
              • No Anemia (versus DIC)
              • Normal to low platelet count (Markedly low in DIC)
              • Occasional hemophagocytosis (detectible in 80% of DIC)
              • Minimal or no PT elevation (marked in DIC)
              • Fibrinogen normal to slightly elevated (decreased in DIC)
          • DIC manifestationsmeeting criteria for Sepsis induced coagulopathy (SIC)37 (See below)
          • Subendothelial activation and kallikrein activity27:
            1. Elevated D-dimer
            2. Edema or pulmonary edema without thrombosis or microangiopathy
          • Antiphospholipid Antibody Syndrome:
            1. Antiphospholipid antibodies with possible anti-phospholipid antibody syndrome have been identified in COVID-1938
              • Mechanism of antiphospholipid antibody generation by viruses is likely molecular mimicry39 between viral surface proteins and elements of the clotting cascade
            2. Lupus anticoagulant40 and related hypercoagulable state has also been identified
              1. DRVVT and lupus anticoagulant-sensitive aPTT positive 53%
              1. DRVVT positive alone 21%
              1. Lupus anticoagulant-sensitive aPTT positive alone 18%
            3. Catastrophic antiphospholipidantibody syndrome may occur in some patients with thrombotic complications in COVID-19
          • Treatment with anticoagulation is challenging given risks imposed by concomitant pulmonary hemorrhage
            1. Anticoagulant therapy resulted in decreased mortality in the setting of criteria for sepsis induced coagulopathy (SIC) with markedly elevated D-Dimer41
            2. Expert consensus anticoagulation recommendations have been made including post-hospital discharge prophylaxis for venous thromboembolism42
      • Cytopenias
        1. Thrombocytopenia43
          • Marker of increased risk of:
            1. Severe disease (5X risk)
            2. Mortality
            3. Likely multifactorial / variable by individual in terms of etiology
              1. Direct infection of bone marrow elements
              1. Low grade DIC
              1. Consumption in lung
              1. Mechanical ventilation damage
        2. Lymphopenia   
          • Peripheral lymphopenia in SARS-CoV-2 seen in over 80% of those with COVID-1944 may be caused by:6
            1. Apoptosis
            2. Pyroptosis
            3. Massive pulmonary infiltration (sequestration)
          • May serve as prognostic indicator of more severe disease
      • Key questions:
        1. How is each of the myriad of coagulopathic manifestations best distinguished and treated?
        2. Which form of anti-coagulation should be standard for hospitalized patients and for how long should it be continued?
        3. Do cytopenias serve as prognostic markers and/or biomarkers of treatment response?
    4. Gastrointestinal involvement45
      • Gastrointestinal symptoms are not uncommon
        1. Diarrhea 2-36%
        2. Vomiting 1-12%
      • Patients may present with GI symptoms
      • ACE2 is expressed in the GI tract
      • SARS-CoV-2 can be identified
        1. By staining viral nucleocapsid protein in cells of the gastric, duodenal, and rectal epithelium
        2. Via viral RNA in stool
        3. Stool samples may remain positive after respiratory samples have cleared
          1. Viral shedding from the GI tract may last long after symptoms resolve
        4. Fecal-oral transmission and fecal aerosol infection have been documented
      • Liver injury with increased liver enzymes in 15-53% of cases
        1. Mechanism unclear
          • Direct viral infection
          • Immune-related injury
          • Drug hepatotoxicity
          • Infection of cholangiocytes
      • Key Questions:
        1. How frequently does transmission occur via the fecal-oral route?
        2. What is the consequence for contagiousness of the prolonged fecal shedding of SARS-CoV-2 long after symptom regression?
    5. Neuropsychiatric manifestations46
      1. Affect 36% of all patients
      2. 46-84% of those with severe disease
      3. SARS-CoV-2 may spread from the olfactory bulbs to the brain
      4. ACE2 receptors are present on brain cells
        1. Headache
        2. Dizziness
        3. Guillain-Barre Syndrome
        4. Encephalitis
        5. Stroke
        6. Anosmia
        7. Ageusia
        8. Muscle weakness
        9. Hallucinations
      5. Key questions:
        1. Do neuropsychiatric manifestations reflect CNS infection by SARS-CoV-2?
        2. Are there long-term neuropsychiatric sequelae from such infection or the immune response it generates?
    6. Dermatologic manifestations47
      • Five distinct COVID-19 rashes have been identified
        1. Maculopapular eruptions
          • 47% of cases
          • More severely affected patient
        2. Urticaria, pruritic
          • To body or palms
          • 19% of cases
        3. Asymmetrical chilblain-like lesions to the hands or feet
          • Painful or pruritic
          • Typically seen in younger patients, later in the course of milder disease
          • 19% of cases
        4. Small vesicles (blisters) around the trunk and limbs
          • Middle aged patients
          • Early in disease
          • 9% of cases
        5. Livedo or necrosis
          • 6% of cases
          • More severely affected patients
      • Key Questions:
        1. What does the dermatopathology of each lesion indicate about the etiopathogenesis of skin disease in COVID-19?
        2. Are the skin manifestations effective prognostic markers for disease severity and/or outcome?
    7. Renal involvement48
      • Among 710 hospitalized patients in Wuhan:
        1. Proteinuria 44%
        2. Hematuria 26.9%
        3. Increased plasma creatinine 15.5%
        4. Increased BUN 14.1%
        5. Acute renal injury 3,2%
      • Etiology:
        1. Hypoxic damage?
        2. Hypovolemia
        3. Direct effect of SARS-Cov-2 infection in the kidney
          • ACE2 receptors are present in the kidney
          • The RAAS has been implicated in the progression of renal disease49
            1. Angiotensin II is produced by renal cells in high concentration
              1. Thought to contribute intra-renally to:
                • Proteinuria
                • Inflammation through NF-KB
                • Proliferation of Mesangial cells, glomerular endothelial cells, and fibroblasts
                • Apoptosis
                • Fibrosis
            2. Aldosterone and renin also contribute to fibrosis
      • Key questions:
        1. How often is renal damage in COVID-19 from direct SARS-CoV-2 to ACE2 binding in the kidney?50
        2. How much of the renal damage in COVID-19 related to:
          • Hypercoagulability from complement activation?51
          • Immune-complex deposition?8
          • RAAS imbalance?
        3. Do ACE-inhibitors or ARBs reduce the incidence of renal injury in COVID-19?

Stay safe, stay healthy, stay United. 


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