COVID-19-associated pulmonary hypertension

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Sara Zand, M.D.

Synonyms and keywords: Pulmonary hypertension, PH, COVID-19, SARS-COV-2, ARDS

Overview

Pulmonary hypertension (PH) is determined as an increase in mean pulmonary arterial pressure (mPAP) of 25 mm Hg or greater at rest. It occurs due to pulmonary arterial remodeling and vasoconstriction prompting an increase in pulmonary artery pressure and finally leading to 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 is underestimated. Pulmonary hypertension is a rare disease and studies about PH during SARS-CoV disease in 2003 implied the role of inflammation in this process.

Historical Perspective

• In 2003, the association between corona infection and pulmonary hypertension was established during SARS-CoV epidemic.

Classification

• Pulmonary hypertension in COVID-19 may be classified into two subtypes:

1. Pulmonary hypertension due to lung disease or hypoxia.
2. 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.
• The pathogenesis of PH in COVID-19 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 hemostasis of blood pressure and electrolyte balance and inflammatory response.
• Renin is a protease that is generated in the kidney and cleaves angiotensinogen to angiotensin1, Then angiotensin converting enzyme (ACE) cleaves angiotensin 1 to angiotensin 2.
• Angiotensin 2 is a key factor of RAS and has two receptors including type 1 and type 2.
• 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.
• 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.
• Lack of ACE2 causes elevation in angiotensin 2 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.
• Phosphorilized ACE2 is a much more stable form in which it converts angiotensin 2 to angiotensin 1-7 and increases the bioavailability of endothelial nitric oxide synthase-derived NO.
• Lack of phosphorilized ACE2 causes vasoconstriction and pulmonary hypertension.
• 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.
• Endothelin-1 caused downregulated ACE2 expression in lung epithelial cells and reduced pulmonary vasoconstriction.
• 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 COVID-19.

Coronavirus virion structure [1]

Causes

• Factors contributing to the microthrombi formation in the pulmonary artery in COVID-19 include:

1. Hypoxia following diffuse alveolar and interestitial inflammation. Hypoxia may induce endothelial dysfunction and activation of coagulation cascade in small vessles.
2. ACE2 receptor expression downregulation after attaching the spike site of COVID-19 to pneumocytes type2.
3. Activation of the innate coagulation cascade in older age.
4. Mechanical ventilation may induce immune micro thrombosis in small arteries.
5. Bacterial superinfection.

Differentiating COVID-19-associated pulmonary hypertension from other Diseases

• Pulmonary intravascular coagulopathy causing pulmonary hypertention in COVID-19 must be differentiated from disseminated intravascular coagulation (DIC) based on clinical features and lab data:

	Disseminated intravascular coagulopathy	Pulmonary intravascular coagulopathy
Onset	Acute	Subacute
Pulmonary involvement (%)	50%	100%
Thrombosis	Multi-organ clotting	Mainly lung
Bleeding	Generalised	Intrapulmonary microhaemorrhage
Liver function	Decreased fibrinogen and other clotting factors; increased transaminase +++	Preservation of liver synthetic function; +/−
Anemia	+++	−
Thrombocytopenia	+++	Normal or low
cytopenia	++	No.may be lymphopenia is a finding of COVID-19
Creatine kinase	+	+
Troponin T	+	++
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

• Data on the incidence of pulmonary hypertension in COVID-19 patients is limited.
• There is no racial predilection to pulmonary hypertension in COVID-19.
• Male are more commonly affected by COVID-19 than female, therefore, the prevalence of pulmonary hypertension induced by Covid-19 is higher in the male gender.

Risk Factors

• Common risk factors in the development of pulmonary hypertention in COVID-19 include the following:
  • Male sex
  • Hypertension
  • Obesity
  • Diabetes

Screening

• There is insufficient evidence to recommend routine screening for pulmonary hypertension in COVID-19.

Natural History, Complications, and Prognosis

• Severe COVID-19 infection induces cytokine storm which leads to activation of the coagulation cascade and thrombotic process.
• Inflammatory markers including IL-1,IL-6 and tumor necrosis factor and ferritin concentration, cause pulmonary endothelial dysfunction and thromboinflammatory process.
• 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 fibrinolysis and plasminogen activation inhibitor 1.
• Thrombosis and hemorrhage occur in small vessels of the lung and thrombin generation and fibrin deposition enhances in the bronchoalveolar system.
• These show the severity of inflammation.
• D-dimer level correlated with severe COVID-19 and indicates activation fibrinolysis and plasmin generation.
• COVID-19 downregulates ACE2 on pneumocytes type2 which are adjusted pulmonary vascular bed, then vasculopathy and thrombosis happens.
• Prognosis is generally poor in older patients and in patients with high level of fibrin degeredated factors, including, D-dimer and cardiac troponin T due to right ventricular failure.
• COVID-19 associated pulmonary hypertension is a chronic progressive disease with a high mortality rate.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of pulmonary hypertension is made when at least three of the following diagnostic criteria in right heart catheterization (RHC) are met:
• Mean PAP≥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
  • Lightheadedness
• Less common symptoms include:
  • Syncope

Physical Examination

• Physical examination in PH may be remarkable for:
  • Rales
  • Dullness or decreased breath sound due to pulmonary congestion or effusion.
  • Central cyanosis due to hypoxia.
  • Holosystolic murmur with increased intensity during 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 output and peripheral vasoconstriction.
  • Abdominal distention
  • Lower extremity edema (seen in advanced disease and right ventricular failure).
  • Racing pulse

Laboratory Findings

• Laboratory findings consistent with the diagnosis of pulmonary hypertension in COVID-19 include:

1. Increased D-dimer (due to pulmonary vascular bed thrombosis with fibrinolysis).
2. Elevated concentration of cardiac enzymes due to right ventricular strain induced by pulmonary hypertension.
3. Normal fibrinogen 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

• Chest x-ray may be helpful in the diagnosis of pulmonary hypertension in COVID-19. Findings on chest x-ray suggestive of pulmonary hypertension include:
  • Enlarged main pulmonary artery.
  • Prunning or attenuation of the peripheral vasculature.
  • Right ventricular enlargement especially in lateral view.
  • With other evidence of lung involvement in COVID-19.

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 COVID-19.. Findings on CT scan suggestive pulmonary hypertension in COVID-19 in comparison with baseline chest CT scan include:

1. Pulmonary artery dilation above 27mm in women and 29mm in men.
2. Increased median Pulmonary Artery/Aorta ratio from 26mm to 31mm after SARS-COVID infection.

• In one study, pulmonary artery dilation was correlated with high level of D-dimer and pulmonary artery thrombosis and poor outcome in COVID-19.

MRI

• Cardiac MRI is one of the most accurate method in the diagnosis of pulmonary hypertension. Findings on MRI for evaluation of pulmonary hypertension include :
  • Assessment of 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 pulmonary hypertension without the ventilation portion due to difficulty in disinfecting the ventilation system in COVID-19 pandemic.
• If lung perfusion image is normal, chronic thromboembolism is ruled out and further invasive catheterization may be avoided.

Other Diagnostic Studies

• There are no other diagnostic studies associated with pulmonary hypertension in COVID-19.

Treatment

Medical Therapy

• The mainstay of therapy for pulmonary hypertension in Covid-19 including:

1. Pulmonary vasodilation.Nitric oxide has antiviral and anti inflammatory effect in SARS-CoV .
2. Supplement oxygen for correction of hypoxia and prevention of pulmonary vasoconstriction to maintain oxygen saturation above 92%.
3. Avoidance of inhaled prostacyclin for prevention of spreading COVID-19 and using the parenteral form for the protection of health care providers.
4. Endothelin receptor antagonist agents.
5. Anticoagulation therapy if there is evidence of thromboembolic mechanism.
6. Correction of hypotension with fluild and inotropic agents in order to avoid decreased RV coronary perfusion and RV ejection fraction.
7. Correction of acidosis, hypercarbia, hypothermia, hypervolemia.
8. Intubation is not recommended due to the effect of positive pressure ventilation in increasing RV preload and also vasodilatory effect of sedation agents impending systemic hypotension and hemodynamic collapse.
9. 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.
10. 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 COVID-19 include keeping social distancing and maintaining the medication used for pulmonary hypertension.

Secondary Prevention

• There are no established measures for the secondary prevention of pulmonary hypertension in COVID-19.

References

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