Current issues and trends in Respiratory therapy

Olabisidam

article11.pdf

Home >Applied Sciences homework help >Current issues and trends in Respiratory therapy

2020 Year in Review: Pharmacologic Treatments for COVID-19

Jessica L Saunders and Michael D Davis

Introduction

Methods

Discussion

Remdesivir

REGN-CoV-2

Optate

Dexamethasone

Oxygen

Inhaled Pulmonary Vasodilators

Summary

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus

2 infection, has led to a pandemic of acute respiratory illness. Pharmacologic treatments for

COVID-19 have included treatments that target infection prevention, prevention of viral replica-

tion, reduce inflammation, and manage symptoms of respiratory failure caused by the disease.

This is a review of key pharmacologic treatments for COVID-19 based on peer-reviewed articles

Introduction

The novel coronavirus, severe acute respiratory syn-

drome coronavirus 2 (SARS-CoV-2), was first identified in

Wuhan, China, at the end of 2019.1 Since that time, it has

affected > 100 million people around the world, which led

to > 2 million deaths.2 The virus causes an acute respira-

tory illness that the World Health Organization has termed

coronavirus disease 2019 (COVID-19). Due to the severity

and effects of this illness, great efforts have been under-

taken to identify effective pharmacologic therapies to pre-

vent infection, prevent viral replication, prevent damaging

inflammation, or to manage the symptoms of respiratory

failure caused by the virus.

This review includes 6 pharmacologic treatments currently

being used in the management of patients with COVID-19.

Remdesivir, REGN-CoV-2 (Regeneron Pharmaceuticals,

Tarrytwon, NY), and Optate (Airbase Breathing Company,

Indianapolis, IN) directly target viral infection and replication.

Dexamethasone is a corticosteroid that reduces inflammation

after infection. Oxygen and inhaled pulmonary vasodilators

are used to treat and manage respiratory symptoms in patients

with COVID-19. The purpose of this article is to review the

literature available in the past year with regard to these phar-

macologic therapies for COVID-19. Recent pharmacologic

treatment strategies for COVID-19 are also summarized.

Dr Saunders is affiliated with the Indiana University School of Medicine,

Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana.

Dr Davis is affiliated with the Wells Center for Pediatric Research/

Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children

at Indiana University School of Medicine, Indianapolis, Indiana.

Dr Davis is funded by the National Heart, Lung, and Blood Institute 1 PO1

HL128192 and the Indiana Clinical and Translational Sciences Institute UL

1 TR002529; he also is a patent holder of Optate and a co-founder of

Airbase Breathing Company. Dr Saunders is funded by the Cystic Fibrosis

Foundation First and Second Year Clinical Fellowship Grant.

Correspondence: Michael D Davis RRT PhD FAARC, Wells Center for

Pediatric Research/Pulmonology, Allergy, and Sleep Medicine, Riley

Hospital for Children at Indiana University School of Medicine, 1044 West

Walnut Street, R4-472, Indianapolis, IN 46202. E-mail: [email protected].

DOI: 10.4187/respcare.09153

RESPIRATORY CARE � JULY 2021 VOL 66 NO 7 1167

Methods

Pharmacologic agents included in the National Institutes of

Health COVID-19 Treatment Guidelines3 with the most sup-

porting evidence at the time of this publication were included

in this review. A PubMed search was conducted to identify

articles published in 2020 that related to these COVID-19

pharmacologic treatments. Searches were conducted by using

the key words “remdesivir,” “REGN-CoV-2,” “Optate,”

“dexamethasone,” “oxygen” and “inhaled pulmonary vasodi-

lators” in conjunction with “COVID-19.” A summary for

each of the reviewed pharmacologic agents, based on the

findings of this literature search, is included below.

Discussion

Remdesivir

Remdesivir is an intravenous prodrug of an adenosine

analog that incorporates into viral RNA and results in pre-

mature termination. It has a broad-spectrum antiviral activ-

ity against several viruses, such as respiratory syncytial

virus, Nipah virus, Ebola virus, Middle East respira-

tory syndrome, and severe acute respiratory syndrome

coronavirus-1 (SARS-CoV-1).4-6 Remdesivir was

authorized for emergency use by the FDA in May of

2020 for hospitalized adults with severe COVID-19.

This emergency use authorization led to a double-

blind, randomized, placebo controlled trial sponsored

by the National Institutes of Health.7

This initial trial enrolled hospitalized adults with con-

firmed cases of COVID-19 and evidence of lower respira-

tory tract infections, treated them with either 10 d of

remdesivir or placebo, and monitored their time to recov-

ery.7 In this study, the subjects who received remdesivir

had a significantly decreased median recovery time versus

the subjects who received the placebo (95% CI 9–11 d vs

95% CI 13–18 d) (Fig. 1).7 The subjects who received

remdesivir were also more likely to have clinical improve-

ment at day 15 (odds ratio 1.5, 95% CI 1.2–1.9; after adjust-

ment for disease severity) when compared with those treated

with placebo.7 Although there was no statistically significant

difference in mortality noted between the 2 groups, the

investigators concluded that remdesivir shortened the time to

recovery and hastened clinical improvement when compared

with the placebo group and may have prevented progression

to more serious illness in some cases.7

A subsequent trial evaluated different courses of remde-

sivir (5 vs 10 d), compared against each other and the stand-

ard of care.8 The subjects who received 5 d of remdesivir

had significantly higher odds of having a better clinical sta-

tus than those who received standard care alone (odds ratio

1.65, 95% CI 1.09–2.48; P ¼ .02). Of note, those who received 10 d of remdesivir therapy did not show a statisti-

cally significant difference when compared with the stand-

ard of care group (P ¼ .18) and there was no significant difference in mortality among the 3 groups after 28 d.

Although results of repeated studies suggest that remdesivir

is a promising therapy for COVID-19, ongoing studies are

needed to determine whether it reduces mortality.8

REGN-CoV-2

REGN-CoV-2 is an antibody cocktail that prevents viral

entry into human cells via the angiotensin-converting

enzyme 2 receptor. It is made up of 2 noncompeting, neutral-

izing human immunoglobulin G1 antibodies, REGN10933

and REGN10987, that target the SARS-CoV-2 spike pro-

tein.9 Viruses mutate frequently, which may result in new

mutant viruses that are not affected by a specific antibody, a

process known as viral escape. By combining $ 2 antibod- ies, a therapy is less vulnerable to viral escape because the

virus would have to mutate in multiple specific ways.10

Initial trials evaluated the effects of 8.0 or 2.4 g of REGN-

CoV-2 compared with placebo on non-hospitalized subjects

with COVID-19. The subjects who received either dose of

REGN-CoV-2 had a significantly decreased SARS-CoV-2

viral load than those who received the placebo (95% CI

�1.02 to �0.11) (Fig. 2). In addition, medical visits for COVID-19 were significantly decreased in the subjects who

received REGN-CoV-2 than in those who received the pla-

cebo (95% CI �29 to 11).11 As with remdesivir, further stud- ies are needed to determine the effects of REGN-CoV-2 on

mortality in patients with COVID-19.

Optate

Optate is an inhaled isotonic, isosmotic, alkaline medica-

tion designed to safely raise airway pH without irritating

Placebo Remdesivir

M ed

ia n

re co

ve ry

ti m

e (d

)

Fig. 1. Remdesivir shortens the time to recovery in patients with co-

ronavirus disease 2019 (COVID-19). The subjects who received remdesivir had a median recovery time of 10 (95% CI 9–11) d com-

pared with the subjects who received the placebo whose median recovery time was 15 (95% CI 13–18) d. Data from Reference 7.

PHARMACOLOGIC TREATMENTS FOR COVID-19

1168 RESPIRATORY CARE � JULY 2021 VOL 66 NO 7

the airway epithelium. Raising intracellular pH partially

prevents activation of SARS-CoV-2 in normal primary

human airway epithelial cells, which decreases viral repli-

cation by altering endosomal trafficking and preventing vi-

ral entry and replication.12 Optate has previously been

shown to be safe to inhale in healthy human subjects and in

those with stable airways disease.13 These studies also dem-

onstrated that Optate raised airway lining fluid pH, with it’s

airway epithelial extracellular pH. In 2020, in vitro studies

demonstrated that Optate also safely increases intracellular

pH of normal primary human airway epithelial cells.

Optate also ablated SARS-CoV-2 viral infection and repli-

cation in normal primary human airway epithelial cells af-

ter 48 h compared with placebo (P < .001) (Fig. 3). Due to

its demonstrated safety profile in humans and antiviral

effects in vitro, Optate inhalation may be well suited for a

clinical trial in patients with COVID-19 infection.14

Dexamethasone

Dexamethasone is a potent corticosteroid with anti-

inflammatory properties that has often been used as a sup-

plemental treatment for viral pneumonia.15 Inflammation

is a known component of COVID-19, which leads to rat-

ionale of dexamethasone as a potential therapy.16 The

RECOVERY Trial Collaborative Group17 performed a

randomized controlled, open-label trial that compared sub-

jects treated with oral or intravenous dexamethasone (6 mg

daily for up to 10 d) to those who received the standard of

care alone and assessed mortality at 28 d. They found that

those who received dexamethasone had significantly

decreased mortality within 28 d versus those who received

the standard of care (22.9 vs 25.7%; age-adjusted rate ratio,

0.83; 95% CI 0.75–0.93; P < .001) (Fig. 4). The subjects who required mechanical ventilation at the time of random-

ization also had lower mortality rates when receiving dexa-

methasone therapy versus the standard of care (29.3 vs

41.4%; rate ratio 0.64, 95% CI 0.51–0.81) (Fig. 4).

Similarly, those who received noninvasive oxygen therapy

at the time of randomization had lower mortality rates

when they were randomized to the dexamethasone group

(23.3 vs 26.2%; rate ratio 0.82, 95% CI 0.72–0.94) (Fig. 4).

Of note, this decrease in mortality was not noted in the sub-

jects who did not require oxygen therapy at the time of ran-

domization (17.8 vs 14.0%; rate ratio 1.19, 95% CI 0.92–

1.55) (Fig. 4).17

P FU

/m L

(fo ld

c ha

ng e)

V ita

l t ie

r ( P

FU /m

Time post-infection (h) 0 0

Limit of detection

Control Optate

101

102

103

* *

24 48 72 96 120 Control Optate

0.5

1.5 A B

Fig. 3. Optate decreases severe acute respiratory syndrome coro- navirus 2 (SARS-CoV-2) viral replication in Vero E6 and normal pri-

mary human airway epithelial (NHAE) cells. A: PFUs were measured in culture media from control and Optate-treated Vero E6 cells

infected with SARS-CoV-2. Optate ablated viral infection in the Vero E6 cells (P <.001). B: Control and Optate-treated primary NHAE cell cultures were infected with SARS-CoV-2, PFUs in culture media

were analyzed under similar conditions for 120 h, starting from 24 h after infection. After the infection was established (24 h), viral infec- tion was ablated in the Optate-treated cells (P <.001). PFU, Plaque

forming units. From Reference 14.

M or

ta lit

y at

d ay

2 8

(% )

Ox yg

No ox

yg en

Standard care Dexamethasone

Al l s

ub jec

Inv as

ive ve

nti lat

ion

Fig. 4. Dexamethasone decreases mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). Shown is the effect of dexamethasone on 28-d mortality according to respiratory support

at the time of randomization. Subgroups included all the subjects, those who were undergoing mechanical ventilation, those who were

receiving supplemental oxygen, and those who were receiving no oxygen at the time of randomization. Data from Reference 17.

–0.5

–1

–1.5

–2

–2.5

Pl ac

eb o

2.4 g 8 g

Co mb

ine d

Le as

t-s qu

ar es

m ea

n ch

an ge

(lo g�

� c op

ie s/

m L)

Time-weighted average change in viral load from day 1 to 7

Fig. 2. REGN-CoV-2 significantly decreases the viral load compared

with placebo. The time-weighted average change in viral load from day 1 to day 7. The subjects who received REGN-CoV-2 had a sig-

nificantly decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load than those who received the placebo (95% CI �1.02 to �0.11). Data from Reference 11.

PHARMACOLOGIC TREATMENTS FOR COVID-19

RESPIRATORY CARE � JULY 2021 VOL 66 NO 7 1169

Oxygen

Hypoxic respiratory failure is a severe complication of

SARS-CoV-2 and affects �19% of patients with COVID- 19.18 The Surviving Sepsis Campaign COVID-19 panel

issued several recommendations with regard to oxygen use

in adults with COVID-19, including

• start supplemental oxygen if SpO2 < 92% (weak recommendation),

• start supplemental oxygen if SpO2 < 90% (strong recommendation),

• maintain SpO2 # 96% in patients with acute hypoxemic respiratory failure who required oxygen (strong

recommendation).19

There is some rationale for heightened caution of the

overuse of supplemental oxygen therapy in patients with

COVID-19 due to concern for upregulation of SARS-CoV-

2 receptor expression in airway epithelium. Increased

receptor expression could lead to increased susceptibil-

ity to SARS-CoV-2 infection. Myti et al20 compared levels

of messenger RNA for genes encoding SARS-CoV-2 recep-

tors in lung cells of mouse pups and preterm human infants

exposed to chronically elevated FIO2 (>0.5). Levels of 2 dif- ferent SARS-CoV-2 receptors, transmembrane serine protease

2 (TMPRSS2) and transmembrane serine protease 11D

(TMPRSS11D), were both increased in the groups treated

with high FIO2 (P < .001) (Fig. 5). Increased levels of SARS- CoV-2 receptors could increase susceptibility to infection;

however, further studies that determine the effects of oxygen

on SARS-CoV-2 infection in vivo are warranted.20

–2

–4

–6

–8

� C

t ( vs

. P ol

r2 a)

AC E2

TM PR

ES S1

TM PR

ES S2

TM PR

ES S1

AC E2

TM PR

ES S1

TM PR

ES S2

TM PR

ES S1

AC E2

TM PR

ES S1

TM PR

ES S2

TM PR

ES S1

AC E2

TM PR

ES S1

TM PR

ES S2

TM PR

ES S1

AC E2

TM PR

ES S1

TM PR

ES S2

TM PR

ES S1

P2 P3 P5 P10 P14

*** * ***

* ** **** ****

******

� C

t ( vs

. P ol

r2 a)

–2

–4

–6

–8

–10 Control BPD Control BPD Control BPD Control BPD

ACE2 TMPRSS1 TMPRSS2 TMPRSS11D

Fig. 5. Steady-state levels of lung messenger RNA (mRNA) transcripts encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) entry receptors and co-receptors in experimental animals and clinical subjects chronically exposed to elevated FIO2 . A: mRNA levels of

Ace2, Tmprss1, Tmprss2, and Tmprss11d in mouse pup lungs (5 animals per group) at post-natal day (P) 2, 3, 5, 10, and 14, and then exposed to room air (FIO2 0.21) (white bars) or hyperoxia (FIO2 0.85) (black bars) for the first 14 d of postnatal life. B: mRNA levels were similarly deter-

mined for ACE2, TMPRSS1, TMPRSS2, and TMPRSS11D in the lungs of infants without (control, n ¼ 8 subjects) (white bars) or with broncho- pulmonary dysplasia (BPD) (n ¼ 10 subjects) (black bars). Data reflect mean DCt 6 SD. Pairwise comparisons were made between the 21% O2 and 85% O2 groups by using unpaired Student t test (A), and between the control and BPD groups by using Mann-Whitney U test (B). *P <.05,

**P <.01, ***P <.001, ****P <.0001. ACE2, angiotensin converting enzyme 2; Ct, cycle threshold; TMPRSS1, transmembrane serine protease 1; TMPRSS2, transmembrane serine protease 2; TMPRSS11D, transmembrane serine protease 11D. From Reference 20, with permission.

PHARMACOLOGIC TREATMENTS FOR COVID-19

1170 RESPIRATORY CARE � JULY 2021 VOL 66 NO 7

Inhaled Pulmonary Vasodilators

Inhaled pulmonary vasodilators have been shown to

improve oxygenation and _V/ _Q mismatch in patients with ARDS, which could lead to benefits in patients with

COVID-19. Inhaled pulmonary vasodilators include in-

haled nitric oxide, prostacyclins, and prostacyclin analogs.

At the time of this publication, the Surviving Sepsis

Campaign for COVID-19 panel did not recommend the

routine use of inhaled pulmonary vasodilators for patients

with COVID-19; they did recommend a trial of inhaled pul-

monary vasodilators for adults on mechanical ventilation

and with severe ARDS and hypoxemia secondary to

COVID-19 and refractory to optimized ventilation and

other rescue strategies. However, this is a weak recommen-

dation with low-quality evidence.19

Franco et al21 explored the mechanism of action of sev-

eral inhaled pulmonary vasodilators and current ongoing

clinical trials. They discussed the potential benefits of nitric

oxide for patients with COVID-19 by directly treating en-

dothelial dysfunction/ _V/ _Q mismatch, improving cardiac

reserve, and by direct antiviral effects. Currently, a clinical

trial is underway to assess these benefits as well as the

safety of pulsed inhaled nitric oxide in subjects with

COVID-19 who require supplemental oxygen.22 Studies are

also ongoing that evaluate the effects of inhaled prostacy-

clin therapy on outcomes for adults on mechanical ventila-

tion with COVID-19.23

Summary

In 2020, several pharmacologic agents were identified

and trialed for use in patients with COVID-19. Several of

these treatments target viral replication, inflammation, and

symptom management. Due to the ongoing nature of this

novel pandemic, recommendations for treatment of patients

with COVID-19 are ever evolving. The most up-to-date

guidelines from the National Institutes of Health can be

found at https://www.covid19treatmentguidelines.nih.gov/,

Accessed March 17, 2021. Knowledge of therapeutic options and best practice of their use is crucial for battling

this pandemic. Of note, at the time of this publication, vac-

cination against SARS-CoV-2 is recommended as an effec-

tive prevention of COVID-19.24

REFERENCES

1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features

of patients infected with 2019 novel coronavirus in Wuhan, China.

Lancet 2020;395(10223):497-506.

2. Dong E, Du H, Gardner L. An interactive web-based dashboard to

track COVID-19 in real time. Lancet Infect Dis 2020;20(5):533-534.

3. National Institutes of Health. NIH COVID-19 Treatment Guidelines.

https://www.covid19treatmentguidelines.nih.gov/. Accessed March 30, 2021.

4. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X,

et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734)

is mediated by the viral polymerase and the proofreading exoribonu-

clease. mBio 2018;9(2):e00221-18.

5. Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P,

Hotard AL, et al. GS-5734 and its parent nucleoside analog inhibit

filo-, pneumo-, and paramyxoviruses. Sci Rep 2017;7:43395.

6. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE,

Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epi-

demic and zoonotic coronaviruses. Sci Transl Med 2017;9(396):

eaal3653.

7. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil

AC, et al; ACTT-1 Study Group Members. Remdesivir for the treat-

ment of Covid-19 - final report. N Engl J Med 2020;383(19):1813-

1826.

8. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM,

Soriano Viladomiu A, et al; GS-US-540-5774 Investigators. Effect of

remdesivir vs standard care on clinical status at 11 days in patients

with moderate COVID-19: a randomized clinical trial. JAMA

2020;324(11):1048-1057.

9. Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al.

Antibody cocktail to SARS-CoV-2 spike protein prevents rapid muta-

tional escape seen with individual antibodies. Science 2020;369

(6506):1014-1018.

10. Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, et al.

Studies in humanized mice and convalescent humans yield a SARS-

CoV-2 antibody cocktail. Science 2020;369(6506):1010-1014.

11. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R,

et al; Trial Investigators. REGN-COV2, a neutralizing antibody cock-

tail, in outpatients with Covid-19. N Engl J Med 2021;384(3):238-251.

12. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T,

Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and

TMPRSS2 and is blocked by a clinically proven protease inhibitor.

Cell 2020;181(2):271-280.e8.

13. Davis MD, Walsh BK, Dwyer ST, Combs C, Vehse N, Paget-Brown

A, et al. Safety of an alkalinizing buffer designed for inhaled medica-

tions in humans. Respir Care 2013;58(7):1226-1232.

14. Davis MD, Clemente TM, Giddings OK, Ross K, Cunningham RS,

Smith L, et al. A treatment to eliminate SARS-CoV-2 replication in

human airway epithelial cells is safe for inhalation as an aerosol in

healthy human subjects. Respir Care 2021;66(1):113-119.

15. Zoorob RJ, Cender D. A different look at corticosteroids. Am Fam

Physician 1998;58(2):443-450.

16. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson

JJ, HLH Across Specialty Collaboration, UK. COVID-19: consider

cytokine storm syndromes and immunosuppression. Lancet 2020;395

(10229):1033-1034.

17. RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR,

Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients

with Covid-19. N Engl J Med 2021;384(8):693-704.

18. Wu Z, McGoogan JM. Characteristics of and important lessons from

the coronavirus disease 2019 (COVID-19) outbreak in China: sum-

mary of a report of 72314 cases from the Chinese Center for Disease

Control and Prevention. JAMA 2020;323(13):1239-1242.

19. Alhazzani W, Evans L, Alshamsi F, Moller MH, Ostermann M,

Prescott HC, et al. Surviving sepsis campaign guidelines on the man-

agement of adults with coronavirus disease 2019 (COVID-19) in the

ICU: first update. Crit Care Med 2021;49(3):e219-e234.

20. Myti D, Gunjak M, Casado F, Khaghani Raziabad S, Nardiello C,

Vadasz I, et al. Elevated FiO2 increases SARS-CoV-2 co-receptor

expression in respiratory tract epithelium. Am J Physiol Lung Cell

Mol Physiol 2020;319(4):L670-L674.

21. Franco V, Bradley EA, Badagliacca R, Sabanayagam A, Rajpal S,

Lastinger LT, et al. Pulmonary vasodilators: beyond the bounds of

PHARMACOLOGIC TREATMENTS FOR COVID-19

RESPIRATORY CARE � JULY 2021 VOL 66 NO 7 1171

pulmonary arterial hypertension therapy in COVID-19. Pulm Circ

2020;10(4):2045894020970369.

22. NIH. U.S. National Library of Medicine. ClinicalTrials.gov. A Study

to Assess Pulsed Inhaled Nitric Oxide vs Placebo in Subjects with

Mild or Moderate COVID-19. https://www.clinicaltrials.gov/ct2/

show/NCT04421508. Accessed March 30, 2021.

23. NIH. U.S. National Library of Medicine. ClinicalTrials.gov. VentaProst

in Subjects with COVID-19 Requiring Mechanical Ventilation. https://

clinicaltrials.gov/ct2/show/NCT04452669. Accessed March 30, 2021. 24. Centers for Disease Control. Ensuring COVID-19 Vaccines Work.

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/effectiveness.

html. Accessed March 8, 2021.

PHARMACOLOGIC TREATMENTS FOR COVID-19

1172 RESPIRATORY CARE � JULY 2021 VOL 66 NO 7