Sandbox:Sara.Zand

antiviral agents

• Remdesivir (initially named GS-5734) is a prodrug and inhibits viral RNA polymerase when intracellularly metabolized to an ATP analogue

• It has been effective on MERS-COV,EBOLA, SARS-COV1.(1)

• Results in SARS-COV2:

1. significant reduction in viral load in bronchoaleolar lavage
2. inhibition of SARS-COV replication in nasal and bronchial airway epithelial cells.

• Indicated only for inhospital setting for adults and children with
• laboratory confirmed COVID-19 disease
• severe COVID-19 disease.

severe COVID-19 disease defined as:

1. SO2ᐸ%94 on room air,
2. need to supplement oxygen,
3. mechanical ventilation,
4. extracorporeal membrane oxygenation (ECMO)

• Contraindications:

severe renal impairment (eGFR <30 ml/min)

severe hepatic dysfunction or alanin transferase (ALT)ᐳ 5-times upper limit

Hydroxychloroquine and Chloroquine

• It has been effective in graft versus host disease lupus erythematosus, rheumatoid arthritis, and malaria

• Mechanism of action: inhibit entry of SARS-COV-2 and prevent fusion of viral spike protein to ACE2 receptor.
• may more effective in the early stage of infection, before COVID-19 lessens ACE2 expression and activity.
• reducing cytokine storm by anti -inflammatory effect on TH-17 related cytokines(IL-6,IL17,IL22)
• recovery of lymphopnea due to anti-inflamatory effect
• The US FDA has issued emergency authorization for the use of chloroquine and ydroxychloroquine for the treatment of COVID-19
• intracellular uptake, was enhanced with combination with Zinc
• high doses of chloroquine 600 mg twice daily for 10 days or total dose of 12 g may be related to cardiac risks.

Lopinavir-Ritonavir or kalerta

• Inhibit the activity of the HIV-1 protease
• there is no benefit in adminstration of lopinavir-ritonavir in COVID-19
• In an open-label randomized controlied trial comparision between patients with COVID-19 recieved either lupinavir-ritonavir 400/100 mg, orally twice daily plus standard of care or standard care alone showed no benefit of adminstration of lopinavir-ritonavir DOI: 10.1056/NEJMoa2001282
• Only one study in korea in the initial phase of outbreak accepted using this combination PMID: 32056407
• side effects: Diarrhea, nausea, asthenia

Umifenovir (Arbidol)

• It has been used in treatment of Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus, influenza A,B   PMID:26739045

• mechanism of action: inhibit the fusion virus to cell membrance and hydrogen binding to membrance phospholipids.PMID: 20527735
• In retrospective cohort study showed improvement in chest ct scan of COVID-19 patients recieved combination of umifenovir and lopinavir-ritonavir.PMID: 32171872
• In prospective study, umifenovir had inferior outcomes in clinical recovery rate and relief of fever and cough , compared with favipiravir https://doi.org/10.1101/2020.03.17.20037432
• safety and efficacy in COVID-19 is under investigation in china with two randomized open trials.

Favipiravir (Avigan)

• It has been used in 2014 in japan for the treatment of influenza resistant to neuraminidase inhibitors and has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus PMID: 28769016 PMID: 31389664
• Mechanism of action: after entering the infected cells and being phosphorylated and inhibits RNA replication.
• SARS-CoV-2 is an enveloped, positive-sense, single-strand RNA virus and studies showed the efficacy of favipiravir on SARS-COV-2.
• A randomized control trial has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%) than that treated with umifenovir (55.86%), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group Doi.org/10.1101/2020.03.17.20037432
• two randomized and non randomized controlled trials are evaluating safety and efficacy of favipiravir for treatment of COVID-19 disease.

Oseltamivir (Tamiflu)

• It has been approved for treatment of influenza A,B viruses and inhibits neuraminidase glygoprotein which is essential for replication of influenza A and B viruses PMID:11270942

• The study in wohan showed no positive outcomes were observed in COVID-19 patients after recieving osetamivir doi:10.1001/jama.2020.1585
• A clinical trial is investigating the effivacy of combination between Oseltamivir with chloroquine and favipiravir . PMID: 32256547

supportive agents

azithromycin

• It has been effective in treatment of Zika and Ebola viruses and prevented severe respiratory tarct infection PMID: 27911847
• mechanism of action is binding to 50S subunit of the bacteria ribosom,then inhibits traslation mRNA.
• effects of azithromycin in treatment of viral respiratory tract infection include:1. antibacterial coverage 2. mmunomodulatory and anti-inflammatory effects doi: 10.1016/j.ijantimicag.2020.105949.

• Many trials in COVID-19 patients showed the effectiveness of azithromycin combined with hydroxychloroquine.

• A trial in france reported %100 viral clearance in nasopharengeal swap after recieving hydroxychloroquin with azithromycin doi: 10.1016/j.ijantimicag.2020.105949.
• data about benefits of azithromycin in COVID-19 disease is still inadequate and needs further evaluation.

Vitamin C (Ascorbic Acid)

Effects in viral agents include:PMID: 29534432

• maturation of T lymphocytes and NK( natural killer) cells which are involved in the immune response to viral agents
• inhibition of reactive oxygen species (ROS) production
• remodulation of the cytokine network in systemic inflammatory syndrome

Study in COVID-19 patients in china showed administration of high dose IV ,Vitamin C (1500mg per day) in moderate and severe cases was correlated with improvement in oxygenation indexes and recovery .PMID: 32328576

Corticosteroids

1. effects of Low doses of methylprednisolone in COVID-19 include: PMID: 30097460 PMID: 32043983

• controlling the hypercytocynemia
• anti inflammation which is caused by infection superimposed in COVID-19

• increase blood pressure when it is low

• decreased risk of death in ARDS complicated COVID-19 PMID: 32167524
• Effects of dexamethason in ARDS complicated COVID-19 include: PMID: 32043986

• decreased ventilation days
• decreased mortality

Due to suppression immunesystem, the role of corticosteroid in COVID-19 would be considered percisely. PMID: 32043983

anti-inflammatory and anti-fibrotic drug, low doses of methylprednisolone (DEPO-Medrol or SOLU-Medrol) have the potential to prevent an extended cytokine response and may accelerate resolution of pulmonary and systemic inflammation in pneumonia PMID: 32043983may improve dysregulated immune response caused by sepsis (possible complication of infection with COVID-19) and increase blood pressure when it is lowPMID: 30097460

in a retrospective cohort study, 201 patients with confirmed COVID-19 who developed ARDS were treated with methylprednisolone (1–2 mg/kg daily IV for 5–7 days) and the results showed that treatment with methylprednisolone may be beneficial for patients who develop ARDS in the reduction of the risk of death. Briefly, of those patients with ARDS who received methylprednisolone treatment, 23 of 50 (46%) patients died, while those who did not receive methylprednisolone, 21 of 34 (61.8%) died [86]. PMID: 32167524

deleterious effects (i.e., inhibition of immune response and pathogen clearance) in patients with COVID-19 PMID: 32043983

Dexamethasone has demonstrated utility on ARDS by decreasing ventilator days and mortality on severe ARDS in patients without COVID-19 PMID: 32043986

Whether the use of corticosteroids provides similar benefit in patients with COVID-19 and ARDS remains to be seen.

[1]

Pulmonary hypertention (PH) is determined as an increase in mean pulmonary arterial pressure(mPAP) of 25 mm Hg or greater at rest.Pulmonary arterial remodeling and vasoconstriction prompting to increase pulmonary artery pressure and finally right heart failure..Few cases of covid 19 with PH were found and it seems due to keeping social distance and quarantine the number of cases are understimated. PH is a rare disease and Studies about PH in SARS -COVID implied the role of inflammation in this process. [[Media:Media:Example.ogg[[Media:File:Example.oggFile:Example.https://www.wikidoc.org/index.php/Copyleft sourcesjpg]]]]

Historical Perspective[edit | edit source]

• Pulmonary hypertension in COVID was first explained in 2004 following epidemic of SARS-COVID

Classification[edit | edit source]

• [Disease name] may be classified according to [classification method] into [number] subtypes/groups:

• [group1]
• [group2]
• [group3]

• Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology[edit | edit source]

• .The SARS-CoV-2 and SARS-CoV virus genomes are highly similar, and patients infected with these viruses have common pathological features.(8)
• The pathogenesis of PH in covid19 is characterized by pulmonary vasoconstriction due to lack of ACE2 and pulmonary microthromboembolism due to local endothelial cell dysfunction .(lancet rheumatology ,dennis mc ganagle)
• Renin angiotensin system (RAS) is responsible for hemeostasis of blood pressure and electrolyte balance and inflammatory response. Renin is a protease which is produced in kidney and cleaves angiotensinogen to angiotensin 1.Then angiotensin convertase enzyme(ACE) cleaves angiotensin 1 to angiotensin 2. Angiotensin2 is a key factor of RAS and has two receptors including type1 and type2 [1].
• angiotensin-converting enzyme 2 (ACE2), and neprilysin hydrolyze angiotensin 2 to anti inflammatory agents including Ang1–7, Ang III, Ang IV, and Ang A .[2]

• Angiotensin-converting enzyme 2 (ACE2) was a receptor of spike protein on SARS corona virus in epithelial cell and after attaching virus the activity of enzyme(ACE2) was decreased and then virus spread quickly[3](12)
• Lack of ACE2 causes elevation in angiotensin2 level causing vascular permeability and lung edema and neutrophil infiltration and further lung deterioration.

• ACE2 has anti inflammation effect and protected the lung from acute lung injury.(4)https://commons.wikimedia.org/wiki/File:SARS-CoV-2_without_background.png#/media/File:SARS-CoV-2_without_background.png
• Phosphorilized ACE2 is much more stable form in which converts angiotensin 2 to angiotensin 1-7 and increases endothelial nitric oxide synthase-derived NO bioavailability ,
• then lack of phosphorilized ACE2 caused vasoconstriction and pulmonary hypertension (5)
• Nitric oxide inhalation for SARS-corona patients was correlated with vasodilation and relaxation of pulmonary artery, reduction in pulmonary artery pressure and improvement in arterial oxygenation. (6)
• Endothelin-1 caused downregulated ACE2 expression in lung epithelial cells and pulmonary vasoconstriction.(7)
• On microscopic histopathological analysis, pulmonary wall edema,hyalin thrombosis , inflammatory cell infiltration of pulmonary microvasculature , vessle thrombosis due to diffuse alveolar damage and septal inflammation are characteristic findings of PH in covid19.(9)

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Differentiating [disease name] from other Diseases[edit | edit source]

• Pulmonary intravascular coagulopathy in covid19 must be differentiated from disseminated intravascular coagulation(DIC) based on clinical features including:(lancet rheumatology)

	Clinical features Disseminated intravascular coagulopathy Pulmonary intravscular coagulopathy
	Onset	Acute	Subacute
	Pulmonary involvement (%)	50%	100%
	Thrombosis	Multi-organ clotting	Mainly lung (occasional CNS and peripheral thrombosis reported; related to DIC evolution?)
	Bleeding	Generalised	Intrapulmonary microhaemorrhage
	Laboratory parameters
	Liver function	Decreased synthetic function including fibrinogen and other clotting factors; raised transaminase +++	Preservation of liver synthetic function; +/−
	Anaemia	+++	−
	Thrombocytopenia	+++	Normal or low
	Immune cell cytopenia	++	No but lymphopenia is a feature of COVID-19 in general
	Creatine kinase	+ (skeletal and cardiac origin)	+ (worse prognosis)
	Troponin T	+	++ with high levels associated with worse outcome
	Coagulation and immunology markers
	Elevated prothrombin time or activated partial thromboplastin time	+++/+++	+ or normal
	Fibrinogen levels	Decreased	Normal or slight increase
	Fibrin degradation products or D-dimer	Increased	Increased
	C-reactive protein	Elevated	Elevated
	Ferritin elevation	+++	Elevated
	Hypercytokinaemia	+++	++

Epidemiology and Demographics[edit | edit source]

• The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
• In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].

Age[edit | edit source]

• Pulmonary hypertension in covid19 is more commonly observed among elderly patients.

Gender[edit | edit source]

• males are more commonly affected with pulmonary hypertension and covid than females

Race[edit | edit source]

• There is no racial predilection for pulmonary hypertension

Risk Factors[edit | edit source]

• Common risk factors in the development of pulmonary hypertention in covid 19 are male sex, hypertension, obesity, and diabetes (lancet rheumato)

Natural History, Complications and Prognosis[edit | edit source]

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include
• Prognosis is generally poor in patients with high level of fibrin degeredated factors, including, D-dimer and cardiac troponinT.(11)

Diagnosis[edit | edit source]

Diagnostic Criteria[edit | edit source]

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

Symptoms[edit | edit source]

• Symptoms of pulmonary hypertension may include the following:

Physical Examination[edit | edit source]

• Physical examination in PH may be remarkable for:

• Rale,dulness or decreased breath sounddue to pulmonary congestion or effusion
• central cyanosis due to hypoxia
• Holosystolic murmur increased with inspiration due to tricuspid regurgitation (TR)
• Diastolic murmur due to pulmonary regurgitation
• Hepatojugular reflux
• Right ventricular S3 due to RV dysfunction
• Distention of jugular veinsdue to RV disfunction and TR
• Peripheral edema and ascites
• Low blood Pressure , diminished pulse pressure , cool extremities due to reduced cardiac out put , prepheral vasoconstriction

Laboratory Findings[edit | edit source]

• laboratory findings consistent with the diagnosis of pulmonary hypertension in covid19 include:(lancet rheumato)

Increased D-dimer(due to pulmonary vascular bed thrombosis with fibrinolysis)

Elevated cardiac enzyme concentration due to right ventriclular strain induced by pulmonary hypertention

Normal fibrinigen and platelet level

Imaging Findings[edit | edit source]

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies[edit | edit source]

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment[edit | edit source]

Medical Therapy[edit | edit source]

• The mainstay of therapy for pulmonary hypertension in covid19 is(10)(13)

Pulmonary vasodilator

Supplement oxygen for correction of hypoxia to maintain oxygen saturation above %90 ,

Hypotension should be corrected with fluild andP inotropic agents to avoid decreased RV coronary perfusion and RV ejection.

Correction of acidosis, hypercarbia,hypothermia, hypervolemia

Intubation is not recommended due to effect of positive pressure ventilation on increased RV preload and vasodilatory effect of sedation agents impending systemic hypotension and hemodynamic collapse.

If intubation is indicated , vasoactive agent should be given before anesthesia. Etomidate is recommended for general anesthesia due to little effect on cardiac contractiliy and vascular tone.

Ventilator should be set with low tidal volumes and moderate positive end expiratory pressure for minimum air way pressure and sufficient oxygenation and ventilation.

Prevention[edit | edit source]

• Effective measures for the primary prevention of PH and covid19 include keeping social distancing and maintaning the medication which was used for pulmonary hypertension.

References[edit | edit source]

4.Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436:112–116

5.Zhang J, Dong J, Martin M, et al. AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension. Am J Respir Crit Care Med. 2018;198(4):509-520. doi:10.1164/rccm.201712-2570OC.

6.Chen L, Liu P, Gao H, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004;39(10):1531-1535. doi:10.1086/425357

7.Zhang, Hongliang, et al. "Endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells." Pharmacology 91.5-6 (2013): 297-304.

8.Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017

9.Fox SE Pulmonary and cardiac pathology in Covid-19: the first autopsy series from New Orleans. medRxiv. 2020; (published online April 10.) (preprint).DOI: 10.1101/2020.04.06.20050575

10.APA Gordon, Clairea; Collard, Charles Da,b; Pan, Weia,b Intraoperative management of pulmonary hypertension and associated right heart failure, Current Opinion in Anaesthesiology: February 2010 - Volume 23 - Issue 1 - p 49-56

doi: 10.1097/ACO.0b013e3283346c51

11.Zhou F Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062

12.Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. doi:10.1038/nature02145

13.Pritts CD, Pearl RG. Anesthesia for patients with pulmonary hypertension. Curr Opin Anaesthesiol. 2010;23(3):411-416. doi:10.1097/ACO.0b013e32833953fb

14.Ten VS Endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction.Curr Opin Crit Care. 2002; 8: 242-250

15.Engelmann BThrombosis as an intravascular effector of innate immunity.Nat Rev Immunol. 2013; 13: 34-45

16.Levi M Coagulation and sepsis.Thromb Res. 2017; 149: 38-44

17.Frazier AA, Burke AP. The imaging of pulmonary hypertension. Semin Ultrasound CT ,MR 2012;33(6):535–551. Crossref, Medline, Google Scholar

18.Spagnolo P, Cozzi A, Foà RA, et al. CT-derived pulmonary vascular metrics and clinical outcome in COVID-19 patients. Quant Imaging Med Surg. 2020;10(6):1325-1333. doi:10.21037/qims-20-546

19.Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317

20.Ji HLElevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility.Physiol Rev. 2020; 100: 1065-1075

21.Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517-1519. doi:10.1111/jth.14844

.22.Chen, Luni, et al. "Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing." Clinical infectious diseases 39.10 (2004): 1531-1535.