COVID-19-associated pulmonary hypertension: Difference between revisions
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[[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 during [[SARS -COV]]ID disease in 2003 implied the role of inflammation in this process.<br /> | [[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 during [[SARS -COV]]ID disease in 2003 implied the role of inflammation in this process.<br /> | ||
==Historical Perspective== | ==Historical Perspective== | ||
The association between COVID infection and pulmonary hypertension was made in 2003 during SARS-COVID epidemic. | The association between COVID infection and pulmonary hypertension was made in 2003 during [[SARS-COVID]] epidemic. | ||
Revision as of 12:17, 8 July 2020
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand,MD
Synonyms and keywords:
Overview
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 during SARS -COVID disease in 2003 implied the role of inflammation in this process.
Historical Perspective
The association between COVID infection and pulmonary hypertension was made in 2003 during SARS-COVID epidemic.
Classification
- Pulmonary hypertension in covid19 may be classified into two subtype:
- Pulmonary hypertension due to lung disease or hypoxemia
- Microvascular thromboembolic pulmonary hypertension
Pathophysiology
- .The SARS-CoV-2 and SARS-CoV virus genomes are highly similar, and patients infected with these viruses have common pathological features.[1]
- 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.
- 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 .[2]and the unbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7) receptor pathway in the RAS system will induce multi-system inflammation.
- angiotensin-converting enzyme 2 (ACE2), and neprilysin hydrolyze angiotensin 2 to anti inflammatory agents including Ang1–7, Ang III, Ang IV, and Ang A.[3]
- 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.[4][5]
- 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.[6]
- 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. [7]
- 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.[8]
- Endothelin-1 caused downregulated ACE2 expression in lung epithelial cells and pulmonary vasoconstriction.[9]
- 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.[10]
Clinical Features
Causes
Factors contributing to constriction and microthrombotic formation in pulmonary artery in covid 19 include:
- Diffuse alveolar and interestitial inflammation causing hypoxia . Hypoxia may induce endothelial dysfunction and activation of coagulation cascade in small [11]
- ACE2 receptor expression downregulation after attaching the sparkle site of covid19 to pneumocytes type2
- Activation of innate coagulation cascade with older age
- Mechanical ventilation may induce immune micro thrombosis in small arteries[12]
- Bacterial superinfection
Differentiating COVID-19-associated pulmonary hypertension from other Diseases
- Pulmonary intravascular coagulopathy causing pulmonary hypertention in covid19 must be differentiated from disseminated intravascular coagulation(DIC) based on clinical features and lab data :[13]
| Disseminated intravascular coagulopathy | Pulmonary intravascular 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 |
| 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 |
| 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
- There is no racial predilection to pulmonary hypertension in covid19.
- male are more commonly affected by covid19 than female ,therefore, the prevalence of pulmonary hypertension induced by covid19 in higher in male gender.
Risk Factors
Common risk factors in the development of pulmonary hypertention in covid 19 are male sex, hypertension, obesity, and diabetes[13]
Screening
There is insufficient evidence to recommend routine screening for pulmonary hypertension in covid19.
Natural History, Complications, and Prognosis
- Severe COVID-19 infection induce cytokine storm which leads to activation of coagulation cascade and thrombotic process.
- Inflammatory markers including (IL)-1,(IL) -6 and tumor necrosis factor and ferritin concentration which cause pulmonary endothelial dysfunction and thromboinflammatory process.[14]
- Hypoxia in COVID-19 pneumonia will cause endothelial dysfunction and expression of active tissue factor on endothelium , macrophage , neutrophils, and finally activation of coagulation cascade and reduction of finbrinolysis and plasminogen activation inhibitor 1.
- Thrombosis and haemorrhage occur in small vessles of the lung and thrombin generation and fibrin deposition enhance in bronchoalveolar system.
- these show the severity of inflammation.
- D-dimer level correlated with severe COVID19 and indicates activation fibrinolysis and plasmin generation.[15]
- covid19 Downregulates ACE2 on pneumocytes type2 which are adjested pulmonary vascular bed, then vasculopathy and thrombosis happens.
- Prognosis is generally poor in older patients and high level of fibrin degeredated factors, including, D-dimer and cardiac troponinT due to right ventricular failure.[16]
- SARS‐Cov‐2 induces in severe cases a cytokine storm that ultimately leads to the activation of the coagulation cascade, causing thrombotic phenomena.[7]
Diagnosis
Diagnostic Study of Choice
The diagnosis of pulmonary hypertension is made when at least three of the following diagnostic criteria are met:
In right heart catheterization(RHC) mPAP≥25 mmHg,pulmonary artery wedge pressure≤15 mmHg, Pulmonary vascular resistance ≥3 wood units
History and Symptoms
The most common symptoms of pulmonary hypertension include exertional dyspnea , chest pain,fatigue,light headness.Less common symptoms include syncope, abdominal distention,lower extremity edema which are seen in advanced disease and right ventricular failure.
Physical Examination
- Physical examination in PH may be remarkable for:
- Rale,dulness or decreased breath sound due 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 veins due to RV dysfunction and TR
- Peripheral edema and ascites
- Low blood Pressure , diminished pulse pressure , cool extremities due to reduced cardiac out put ,prepheral vasoconstriction
Laboratory Findings
- 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
Electrocardiogram
An ECG may be helpful in the diagnosis of pulmonary hypertension. Findings on an ECG suggestive pulmonary hypertension include right atrial enlargement, right axis deviation,right ventricular enlargement with strain pattern
X-ray
An x-ray may be helpful in the diagnosis of pulmonary hypertension in covid 19. Findings on an x-ray suggestive of pulmonary hypertension include
- Enlarged main pulmonary artery,
- Prunning or attenuation of peripheral vasculture and
- Right ventricular enlargement specially in lateral view
- With other evidence of lung involvement in covid19
Echocardiography or Ultrasound
Echocardiography is the first modality in the diagnosis of pulmonary hypertension . Findings on an echocardiography suggestive of pulmonary hypertension include:
- right atrial enlargement,
- right ventricular enlargement and dysfunction,
- small left side chambers,
- interventricular setal flattening,
- tricuspid regurgitation
CT scan
- Chest CT scan even unenhanced may be helpful in the diagnosis of pulmonary hypertension in COVID19.. Findings on CT scan suggestive pulmonary hypertension in COVID19 in comparison with baseline chest ct scan include :[17]
- PA dilation above 27mm in women and 29mm in men.
- Increased median PA/Ao ratio from 26mm to 31mm after SARS-COVID infection
PA dilation correlated with high level of D-dimer and pulmonary artery thrombosis (21)and poor outcome in COVID19 .[18]
MRI
Cardiac MRI is one of the most accurate method in the diagnosis of pulmonary hypertension . Findings on MRI suggestive of pulmonary hypertension include :[19]
assessment the anatomy of the pulmonary arteries
assessment of pulmonary blood flow
assessment of right ventricular size, morphology and function
Other Imaging Findings
Perfusion ventilation scan may be helpful in the diagnosis of chronic thromboembolic pulmonay hypertension with out ventilation portion due to difficulty in disinfecting the ventilation system in COVID19 pandemic. if lung perfusion image is normal , chronic thromboembolism can be rule out and avoidance of further invasive catheterization.[20]
Other Diagnostic Studies
There are no other diagnostic studies associated with pulmonary hypertension in COVID19.
Treatment
Medical Therapy
- Pulmonary vasodilation.Nitric oxide has antiviral associated SARS-COVID and anti inflammatory effect .[23]
- Supplement oxygen for correction of hypoxia to maintain oxygen saturation above %90 ,
- Correction of hypotension with fluild and inotropic agents to avoid decreased RV coronary perfusion and RV ejection.
- Correction of acidosis, hypercarbia, hypothermia, hypervolemia
- Intubation is not recommended due to the effect of positive pressure ventilation to increase RV preload and vasodilatory effect of sedation agents impending systemic hypotension and hemodynamic collapse.
- If intubation is indicated, a vasoactive agent should be given before anesthesia. Etomidate is recommended for general anesthesia due to little effect on cardiac contractility and vascular tone.
- Ventilator should be set with low tidal volumes and moderate positive end-expiratory pressure for minimum airway pressure and sufficient oxygenation and ventilation.
Surgery
Surgical intervention is not recommended for the management of pulmonary hypertension in COVID 19
Primary Prevention
Effective measures for the primary prevention of PH and covid19 include keeping social distancing and maintaining the medication which was used for pulmonary hypertension.
Secondary Prevention
There are no established measures for the secondary prevention of pulmonary hypertension in covid19
References
- ↑ Zhu, Na; Zhang, Dingyu; Wang, Wenling; Li, Xingwang; Yang, Bo; Song, Jingdong; Zhao, Xiang; Huang, Baoying; Shi, Weifeng; Lu, Roujian; Niu, Peihua; Zhan, Faxian; Ma, Xuejun; Wang, Dayan; Xu, Wenbo; Wu, Guizhen; Gao, George F.; Tan, Wenjie (2020). "A Novel Coronavirus from Patients with Pneumonia in China, 2019". New England Journal of Medicine. 382 (8): 727–733. doi:10.1056/NEJMoa2001017. ISSN 0028-4793.
- ↑ Konishi H, Kuroda S, Inada Y, Fujisawa Y (March 1994). "Novel subtype of human angiotensin II type 1 receptor: cDNA cloning and expression". Biochem. Biophys. Res. Commun. 199 (2): 467–74. doi:10.1006/bbrc.1994.1252. PMID 8135787.
- ↑ Chappell MC (October 2012). "Nonclassical renin-angiotensin system and renal function". Compr Physiol. 2 (4): 2733–52. doi:10.1002/cphy.c120002. PMC 4186703. PMID 23720263.
- ↑ Li, Wenhui; Moore, Michael J.; Vasilieva, Natalya; Sui, Jianhua; Wong, Swee Kee; Berne, Michael A.; Somasundaran, Mohan; Sullivan, John L.; Luzuriaga, Katherine; Greenough, Thomas C.; Choe, Hyeryun; Farzan, Michael (2003). "Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus". Nature. 426 (6965): 450–454. doi:10.1038/nature02145. ISSN 0028-0836.
- ↑ Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench MO, Simmons G, Hofmann H, Kuri T, Weber F, Eichler J, Drosten C, Pöhlmann S (January 2010). "Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63". J. Virol. 84 (2): 1198–205. doi:10.1128/JVI.01248-09. PMC 2798380. PMID 19864379.
- ↑ Imai, Yumiko; Kuba, Keiji; Rao, Shuan; Huan, Yi; Guo, Feng; Guan, Bin; Yang, Peng; Sarao, Renu; Wada, Teiji; Leong-Poi, Howard; Crackower, Michael A.; Fukamizu, Akiyoshi; Hui, Chi-Chung; Hein, Lutz; Uhlig, Stefan; Slutsky, Arthur S.; Jiang, Chengyu; Penninger, Josef M. (2005). "Angiotensin-converting enzyme 2 protects from severe acute lung failure". Nature. 436 (7047): 112–116. doi:10.1038/nature03712. ISSN 0028-0836.
- ↑ 7.0 7.1 Zhang, Jiao; Dong, Jianjie; Martin, Marcy; He, Ming; Gongol, Brendan; Marin, Traci L.; Chen, Lili; Shi, Xinxing; Yin, Yanjun; Shang, Fenqing; Wu, Yan; Huang, Hsi-Yuan; Zhang, Jin; Zhang, Yu; Kang, Jian; Moya, Esteban A.; Huang, Hsien-Da; Powell, Frank L.; Chen, Zhen; Thistlethwaite, Patricia A.; Yuan, Zu-Yi; Shyy, John Y.-J. (2018). "AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension". American Journal of Respiratory and Critical Care Medicine. 198 (4): 509–520. doi:10.1164/rccm.201712-2570OC. ISSN 1073-449X.
- ↑ Chen, L.; Liu, P.; Gao, H.; Sun, B.; Chao, D.; Wang, F.; Zhu, Y.; Hedenstierna, G.; Wang, C. G. (2004). "Inhalation of Nitric Oxide in the Treatment of Severe Acute Respiratory Syndrome: A Rescue Trial in Beijing". Clinical Infectious Diseases. 39 (10): 1531–1535. doi:10.1086/425357. ISSN 1058-4838.
- ↑ Zhang H, Li Y, Zeng Y, Wu R, Ou J (2013). "Endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells". Pharmacology. 91 (5–6): 297–304. doi:10.1159/000350395. PMID 23751363.
- ↑ Fox, Sharon E.; Akmatbekov, Aibek; Harbert, Jack L.; Li, Guang; Brown, J. Quincy; Vander Heide, Richard S. (2020). doi:10.1101/2020.04.06.20050575. Missing or empty
|title=(help) - ↑ Ten, Vadim S.; Pinsky, David J. (2002). "Endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction". Current Opinion in Critical Care. 8 (3): 242–250. doi:10.1097/00075198-200206000-00008. ISSN 1070-5295.
- ↑ Engelmann B, Massberg S (January 2013). "Thrombosis as an intravascular effector of innate immunity". Nat. Rev. Immunol. 13 (1): 34–45. doi:10.1038/nri3345. PMID 23222502.
- ↑ 13.0 13.1 McGonagle, Dennis; O'Donnell, James S; Sharif, Kassem; Emery, Paul; Bridgewood, Charles (2020). "Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia". The Lancet Rheumatology. 2 (7): e437–e445. doi:10.1016/S2665-9913(20)30121-1. ISSN 2665-9913.
- ↑ Levi M, van der Poll T (January 2017). "Coagulation and sepsis". Thromb. Res. 149: 38–44. doi:10.1016/j.thromres.2016.11.007. PMID 27886531.
- ↑ Ji HL, Zhao R, Matalon S, Matthay MA (July 2020). "Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility". Physiol. Rev. 100 (3): 1065–1075. doi:10.1152/physrev.00013.2020. PMC 7191627 Check
|pmc=value (help). PMID 32216698 Check|pmid=value (help). - ↑ Zhou, Fei; Yu, Ting; Du, Ronghui; Fan, Guohui; Liu, Ying; Liu, Zhibo; Xiang, Jie; Wang, Yeming; Song, Bin; Gu, Xiaoying; Guan, Lulu; Wei, Yuan; Li, Hui; Wu, Xudong; Xu, Jiuyang; Tu, Shengjin; Zhang, Yi; Chen, Hua; Cao, Bin (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study". The Lancet. 395 (10229): 1054–1062. doi:10.1016/S0140-6736(20)30566-3. ISSN 0140-6736.
- ↑ Spagnolo, Pietro; Cozzi, Andrea; Foà, Riccardo Alessandro; Spinazzola, Angelo; Monfardini, Lorenzo; Bnà, Claudio; Alì, Marco; Schiaffino, Simone; Sardanelli, Francesco (2020). "CT-derived pulmonary vascular metrics and clinical outcome in COVID-19 patients". Quantitative Imaging in Medicine and Surgery. 10 (6): 1325–1333. doi:10.21037/qims-20-546. ISSN 2223-4292.
- ↑ Dolhnikoff, Marisa; Duarte‐Neto, Amaro Nunes; Almeida Monteiro, Renata Aparecida; Silva, Luiz Fernando Ferraz; Oliveira, Ellen Pierre; Saldiva, Paulo Hilário Nascimento; Mauad, Thais; Negri, Elnara Marcia (2020). "Pathological evidence of pulmonary thrombotic phenomena in severe COVID‐19". Journal of Thrombosis and Haemostasis. 18 (6): 1517–1519. doi:10.1111/jth.14844. ISSN 1538-7933.
- ↑ Frazier AA, Burke AP (December 2012). "The imaging of pulmonary hypertension". Semin. Ultrasound CT MR. 33 (6): 535–51. doi:10.1053/j.sult.2012.06.002. PMID 23168063.
- ↑ Galiè, Nazzareno; Humbert, Marc; Vachiery, Jean-Luc; Gibbs, Simon; Lang, Irene; Torbicki, Adam; Simonneau, Gérald; Peacock, Andrew; Vonk Noordegraaf, Anton; Beghetti, Maurice; Ghofrani, Ardeschir; Gomez Sanchez, Miguel Angel; Hansmann, Georg; Klepetko, Walter; Lancellotti, Patrizio; Matucci, Marco; McDonagh, Theresa; Pierard, Luc A.; Trindade, Pedro T.; Zompatori, Maurizio; Hoeper, Marius (2016). "2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension". European Heart Journal. 37 (1): 67–119. doi:10.1093/eurheartj/ehv317. ISSN 0195-668X.
- ↑ Gordon, Claire; Collard, Charles D; Pan, Wei (2010). "Intraoperative management of pulmonary hypertension and associated right heart failure". Current Opinion in Anaesthesiology. 23 (1): 49–56. doi:10.1097/ACO.0b013e3283346c51. ISSN 0952-7907.
- ↑ Pritts, Chad D; Pearl, Ronald G (2010). "Anesthesia for patients with pulmonary hypertension". Current Opinion in Anaesthesiology. 23 (3): 411–416. doi:10.1097/ACO.0b013e32833953fb. ISSN 0952-7907.
- ↑ Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, Zhu Y, Hedenstierna G, Wang CG (November 2004). "Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing". Clin. Infect. Dis. 39 (10): 1531–5. doi:10.1086/425357. PMC 7107896 Check
|pmc=value (help). PMID 15546092.
.