Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a pandemic with the United States now carrying the highest number of cases and fatalities. Although vaccines and antiviral agents are the main focus of therapy, here we present a plausible hypothesis to leverage our understanding of neuroimmunomodulation to intervene in the pathophysiology of the disease to prevent death.

1. Potential treatment to mitigate COVID-19
Pandemic
Dr. Sanjiv K Hyoju MD
Surgeon and Research professional
University of Chicago
Coronavirus Cases:
5,719,556
Deaths:
353,079
Recovered:
2,456,573
No disclosure to be made

2. COVID-19 is an emerging, rapidly evolving situation
Let’s brainstorm together to mitigate pandemic until we figure out the definitive treatment ?? Vaccine ??
NO DISCLOSURE
No disease is more difficult to study than pandemic virus. It comes, it spreads, it
vanishes with unexampled suddenness.
First made online in 3/29/2020
14:41:00

3. Outline:
☛ Immunopathology of COVID-19
☛ Immunomodulatory response of sympathetic nervous system interacting
with immune cells via β2 adreno receptor and Norepinephrine
☛ Effect of civilization and dietary modification on Sympathetic nervous
system
☛ Speculation (Viral infection and sympathetic hyperactive stage)
☛ Hypothesis
☛ Possible hypothetical treatment
☛ Case report.

4. ☛ Immunopathology of COVID-19
Cytotoxic lymphocyte reduction and exhaustion is key component for COVID-19
progression
Cytotoxic lymphocytes such as cytotoxic T lymphocytes (CTLs) and natural killer (NK)
cells are necessary for the control of viral infection, and the functional exhaustion of
cytotoxic lymphocytes is correlated with disease progression
CD8+ T cell counts and NK cells were decreased significantly in Mild disease and
Severe disease patients

5. COVID -19 infection is capable of producing an excessive immune reaction in the host
(CYTOKINE STORM).
The protagonist of this storm is interleukin 6 (IL-6) leading to extensive tissue damage,
cytokine release syndrome characterized by fever and MOF.

6. The sympathetic neurotransmitter norepinephrine modulates the level of T and B lymphocyte activity
by binding to the beta2-adrenergic receptor (beta2AR).
☛ Immunomodulatory response of sympathetic nervous system interacting
with immune cells via β2 adreno receptor and Norepinephrine

7. Norepinephrine (NE) modulates the functions of memory CD8 T cells by
inducing inflammatory cytokine production and reducing activation-
induced memory CD8 T cell expansion.
• Memory CD8 T cells express more beta 2 adrenergic receptors than naïve cells.
• NE treated memory CD8 T cells produce more inflammatory cytokines.
• NE treated memory CD8 T cells produce less growth-related cytokines.
• Memory CD8 T cells from adults with high NE have more
inflammatory cytokine expression.

8. Immune response mediated through β2 Adrenergic receptors via Norepinephrine
is altered in chronic stress situation
T cell T cell

9. Sympathetic nervous system increases proinflammatory cytokines and
exacerbates Influenza A virus pathogenesis
6-OHDControl
Sympathetic tone ablation reduce mortality following lethal IAV
infection, significantly reduced lung inflammation

10. Sympathetic tone ablation either chemically using 6-OHD or beta blocker
Nadolol increases Antiviral T Cell Responses in Vivo
Nadolol
6-OHD

11. β2-adrenergic signals downregulate the innate immune response and reduce
host resistance to Cytomegalovirus infection
Mice treated with β2-adrenergic agonist are more susceptible to CMV infection β2-
adrenergic receptor deficiency resulted in better clearance of the virus, less tissue
damage and greater resistance to CMV due to higher level of IFN-𝛄 production and
stronger resistance to CMV
CMV infected β2-adrenergic receptor KO
Control, CMV infected β2 agonist treatment
uni: not infected
MCMV: CMV infected

12. Central sympatholytic drug Clonidine has an inhibitory effect on the
replication of various influenza virus strains suppress lung edema and
improve survival in a murine lethal infection model.

13. Diet such as western diet and age are most important factor that lead to
chronic increase in SNS activity predisposing to various comorbid condition
such as diabetes, Hypertension and Obesity
Sympathetictone

14. Viral infection act as stressor “it activate sympathetic nervous system”
☛ Viral infection and sympathetic hyperactive stage

15.  Like other respiratory virus, Covid-19 infection
activate sympathetic nervous system of body
 In chronic stress condition, viral infection
dysregulated immune system mediated through
increase Norepinephrine release due to
sympathetic hyperactivity via beta 2
adrenoreceptors
 Magnitude of Sympathetic hyperactivity
determine the outcome during the course of
Covid-19 infection.
☛Speculation

16. ☛Hypothesis
Chronic sympathetic hyperactive people with comorbid condition who then contract
SARS-CoV-2 virus can potentially drive the infection toward a fatal outcome due to
excessive catecholamine release and cytokine spillage

17. Attenuation of sympathetic activity with currently available drugs such as of a2
agonist ( Clonidine) and  blockers ( Propranolol) may be a plausible mechanism to
override the T cell exhaustion, cytokine spillage and impaired clearance of virus.

18. Evaluation of the hypothesis
Inclusion criteria:
• SAR-CoV-2 + patient presented
with symptoms of fever, myalgia,
cough, headache, GI symptoms.
Exclusion criteria:
• Allergic to drug,
• Significant heart block
• BP<90mm Hg at presentation

19. CASE REPORT
Management of COVID-19 fever with
Clonidine and Propanolol.

20. Age: 64 yrs.
Gender: Female
Presenting symptoms:
 Intermittent High grade Fever up to 105ºF
 Chills
 Headache
 Myalgia
Past medical history
 Chronic hypertension
 Hypothyroidism
 Hyperlipidemia
Medication:
 Amlodipine + Losartan tab
 Thyroxine tab
 Vitamin supplement
Post menopausal
No past surgical history

21. Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17
Fever
Headache
Malaise
Cough
94.0
96.0
98.0
100.0
102.0
104.0
106.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Body temperature
0
20
40
60
80
100
120
140
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Heart Rate
Symptoms evolution
Clinical sign during course of illness

22. Day 5 Day 8 Day 11
WBC 6450/µl 4640/µl 8310/µl
Hb 13.2 gm% 11.9 gm% 13.0 gm%
PLT 112000/µl 192000/µl 362000/µl
Neutrophil 67% 65% 60%
Lymphocyte 27% 27% 35%
ESR 50 64 52
FDP d-dimer 1.61µg/ml ( <0.5)
CRP ++
Widal test Negative
Dengue NS1 Ag +
Ab
Negative
Blood c/s Negative
Serum Ferritin
511ng/ml ( 6.24-
264)
721ng/ml ( 6.24-
264)
Random glucose
9 ( 3.8-7.8)mmol
L
5.8( 3.8-7.8)mmol
L
6.1( 3.8-7.8)mmol L
Urea
4.6 (1.6-7.6) mmol
L
3.3 (1.6-7.6) mmol
L
4.5 (1.6-7.6) mmol L
Cr
90 (40-110) mmol
L
80 (40-110) mmol
L
66 (40-110) mmol L
Bilirubin ( Total) 3.0 (3-21) gm/L 8.0 (3-21) gm/L 2.0 (3-21) gm/L
AST 131 (5-40) U/L 138 (5-40) U/L 96 (5-40) U/L
ALT 124 (5-45) U/L 153 (5-45) U/L 142 (5-45) U/L
ALP 248 (<306) U/L 300 (<306) U/L 293 (<306) U/L
LDH 430 ( <460) U/L 489 ( <460) U/L 495 ( <460) U/L
CPK 126 (<195) 67 (<195)
Serum electrolyte WNL WNL WNL
Laboratory Investigation
• Lower WBC count, High FDP d-dimer, CRP++
Increase serum Ferritin, AST, ALT, and LDH
are well corelate with COVID-19 infection, since
other potential cause of high grade fever has
been rule out
• Due to social stigma and difficulty to get test
patient denies for COVID testing, however, choose
to remain in strict isolation in home, follow rules to
prevent possible transmission to other house
members.
• COVID antibody test was done 4 weeks following
recovery IgG is negative.

23. Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17
Clonidine
Propranolol
Azithromycin
Treatment initiation
 Till day 7 paracetamol 650 mg every 4 hours alternate with Ibuprofen 400 mg every 4 hours
 On 7th day of fever, Amlodipine and Losartan were hold, Clonidine 0.1mg once daily HS started and continue
till day 15.
 On day 9, propranolol 10 mg started and continue till day 15
 On day 9, Azithromycin 500mg stat followed by 250mg OD was started and continue till day 13
 During entire course of treatment : every 4 hours Vital monitoring was done.
 Strict isolation was maintained up to 3 weeks following onset of fever.
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17
Fever
Headache
Malaise
Cough

24. Outcome
 Symptomatically patient improved following 48hrs of Clonidine treatment.
 Fever went down to 98ºF. Cough resolved.
 Patient looks much better by day 11.
 Repeat CBC demonstrate raising WBC count, down trending of liver enzyme.

25. For detail Please refer to hypothesis manuscirpt on below link.
https://www.sciencedirect.com/science/article/pii/S0306987720314274
Email : skhyoju@gmail.com
THANKS
Sanjiv Hyoju MD
@SanjivHyoju
Sanjiv Hyoju