COVID-19-associated acute respiratory distress syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayesha Javid, MBBS[2] Sara Mohsin, M.D.[3]

Historical perspective

• The novel coronavirus was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to its high similarity to SARS-CoV, which caused acute respiratory distress syndrome (ARDS) in 2002–2003.
• SARS-CoV-2 virus primarily affects the respiratory system causing a wide variety of respiratory symptoms which can range from symptoms of lower respiratory tract infection to severe hypoxia to acute respiratory distress syndrome within a very short span of time.
• The acute respiratory distress syndrome (ARDS) is a common cause of morbidity and mortality in critically ill COVID-19 infected patients. It is defined by the acute onset of noncardiogenic pulmonary edema, hypoxaemia and the need for mechanical ventilation

Epidemiology and demographics

• Incidence is higher in the elderly and much lower in children
• Higher mortality rate is seen in the elderly.

Pathophysiology

• ARDS arises as a complication of COVID-19 infection due to acute inflammation of the alveolar space which prevents normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response.
• The cytokine storm and the deadly uncontrolled systemic inflammatory response resulting from the release of large amounts of proinflammatory cytokines including interferons and interleukins and, chemokines by immune effector cells resulting in acute inflammation within the alveolar space. The exudate containing plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors will increase alveolar-capillary permeability and decrease the normal gas exchange and plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors.
• The COVID-19 patients with ARDS show elevated levels of IL-6, IFN-a, and CCL5, CXCL8, CXCL-10 in serum as compared to those with the mild to moderate disease.
• This inflammatory process leads to the fibrin deposition in the air spaces and lung parenchyma and contributes to hyaline-membrane formation and subsequent alveolar fibrosis.
• Patients infected with COVID‐19 also exhibit coagulation abnormalities. This procoagulant pattern can lead to acute respiratory distress syndrome.

Diagnosis

Laboratory findings

• Blood plasma has elevated levels of IL-6, IL-1, tumour necrosis factor-α (TNF α) and C-reactive protein.
• Thrombocytopenia.
• Increased D-dimer levels. The elevated level of D-dimer is strongly associated with a higher mortality rate.
• Increased fibrin degradation products.
• Increased fibrinogen.
• Prothrombin time and activated partial thromboplastin time may be slightly elevated.

Imaging studies

• Chest CT scan shows characteristic ground-glass opacities (GCO). This indicates the presence of exudate in the bronchoalveolar airspace.
• Lung biopsy shows fibrin deposition.

Signs and Symptoms

• Dyspnea: The onset of dyspnea is relatively late around the 6th day.
• Acute Hypoxemia due to respiratory failure is a dominant finding.
• Hypercapnia could be present but it is rare.

Treatment

Fluid and electrolytes management

• Studies have shown that in ARDS, conservative fluid management may help patients by reducing oedema formation.
• Conservative fluid management with buffered or non-buffered crystalloid is recommended for ARDS patients.
• The conservative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay. However, its effect on mortality remains uncertain.

Corticosteroids

• Recent studies have shown that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients. In England, a non-peer-reviewed randomized trial was issued as a press release suggesting a potential survival benefit from dexamethasone in hospitalized patients with COVID-19 who require oxygen.
• The Society of Critical Care Medicine (SCCM) provided a conditional, weak recommendation in favor of glucocorticoids in patients with COVID-19 who have severe ARDS; with a partial arterial pressure of oxygen/fraction of inspired oxygen PaO2:FiO2] <100 mmHg). This recommendation suggest benefit in patients with moderate to severe ARDS which is refractory to low tidal volume ventilation.

Mechanical Ventilation

• Mechanical ventilation along with supportive therapies are the mainstay of treatment of ARDS.
• Invasive mechanical ventilation (ie, ventilation via an endotracheal tube or tracheostomy with breaths delivered by a mechanical ventilator) is preferred for patients with ARDS, particularly those with moderate or severe ARDS (ie, arterial oxygen tension/fraction of inspired oxygen PaO2/FiO2 ≤200 mmHg on positive end-expiratory pressure (PEEP) ≥5 cm H2O).
• It is recommended to use low tidal volume ventilation (LTVV) with 4 to 8 mL/kg predicted body weight [PBW]. Several meta-analyses and randomized trials that report a mortality benefit from LTVV in patients with ARDS.
• The aim is to maintain oxygen saturation between 90% to 96%. The severe hypoxemia of the COVID-19 ARDS best responds when Positive end-expiratory pressure (PEEP) is high with Pplat ≤30 cm H2O. It is beneficial if the physician starts with higher than usual levels of PEEP (10 to 15 cm H2O).

Anticoagulant or thrombolytic therapy

• Fibrinolytic drugs such as tissue-type plasminogen activator (tPA) degrade pre-existing fibrin in the lungs.
• Nebulizer plasminogen activators may provide more targeted therapy to degrade fibrin and improving oxygenation in critically ill patients. It is in Phase II of the clinical trial.

Prevention

• The ARDS patients have an increased risk of hospital-associated venous thromboembolism (VTE).
• Due to this reason, it is advised to take low molecular weight heparin (LMWH) prophylactically in patients who do not have the contraindications. Studies have shown that the heparin, either unfractionated or LMWH, can also reduce inflammatory biomarkers hence could help in reducing the inflammation.