Essentials of ARDS in Viral Infections

CME INDIA Presentation by Dr. Gagan Gunjan, Asst. Professor (Gen. Med.), RIMS, Ranchi.

Based on Presentation at APICON.

• Acute Respiratory distress syndrome is an inflammatory lung parenchymal injury caused by various direct or indirect insults to pulmonary alveoli leading to exudative non-hydrostatic pulmonary edema.
• In 1967, Ashbaugh and colleagues were the first to give a clinico-pathological description of the ARDS in twelve adult patients.
• These infections can be classified as pulmonary ARDS or extrapulmonary ARDS based on direct/Indirect involvement.
• Incidence of ARDS varies extremely from country to country, being lowest in Brazil (10.1 per 100,000 person-years) to highest in USA (78.9 per 100,000 person-years).
• Unfortunately, there is no such population survey based data published from India showing incidence of ARDS.
• According to a multinational observational study representing a large data from 29,144 ICU patients across 50 countries, ARDS was present in 10.4% of patients admitted to ICU and 23.4% of patients on mechanical ventilator.
• With the advent of- multiplex nucleic acid amplification assays for the detection of viral pathogens, increasing numbers of viral etiologies have been elucidated among the critically ill patients.
• Respiratory viruses which can cause ARDS can be grouped into two types: pandemic and non-pandemic respiratory viruses.
• Influenza viruses (H5N1, H1N1), Severe Acute Respiratory Syndrome Corona viruses (SARS-CoV), Middle East Respiratory Syndrome (MERS) Corona viruses are notable examples of pandemic respiratory viruses which can result in severe form of ARDS compared to non-pandemic respiratory viruses.
• Respiratory viruses usually cause ARDS in people who are
• Immuno-compromised, in extreme of ages, having severe co morbidities, hematopoietic cell transplant recipients or those with exaggerated host response.
• The most common viruses detected from viral pneumonia were Influenza and Rhinovirus while Respiratory syncytial virus infection was noted in the pediatric age group.

Most common types of viruses causing pneumonia are divided according to the genetic material they contain and their pandemicity.

Pathophysiology

• Pathophysiology of ARDS in patients with viral infections is not entirely clear.
• This is due to variable interaction between host factors and host immune response to viral antigen, which governs the severity of pneumonia or ARDS.
• Respiratory virus first invades nasal and bronchial epithelium, this invasion causes injury to respiratory airway and alveolar endothelium. Damage to alveolar endothelium results in increased endothelial permeability and recruitment and infiltration of leucocytes, which stimulate production of reactive oxygen species and nitric oxide that damage the epithelial-endothelial barrier.
• In lungs, diffuse alveolar damage (DAD), a pathological hallmark of ARDS, has been observed in direct viral invasion of cells and lytic effects.
• Few components of coagulation and fibrinolytic system are also activated in viral induced lung injury. These pathological events are translated to high incidence of both hemorrhagic and venous thromboembolic events.
• Another unique difference in viral and bacterial etiology of ARDS is the small lymphocytes as predominant immune cells at the site of lung injury. Due to cytokine-induced lymphocytic sequestration, lymphopenia ensues.
• Few viruses (HSV, VZV and CMV) remain in dormant state in ganglia or reticuloendothelial tissue and may become reactivated in the state of immunosuppression, especially in later stage of prolonged sepsis, characterized by immune-paralysis stage.
• Interestingly, in cases where ARDS results from inflammatory host response rather than direct cytopathic effect of virus, the antiviral therapy alone has limited value as has been observed in case of COVID-19 where SARS CoV-2 primarily injures the vascular endothelium.

Clinical features

• Clinical features of virus induced ARDS are often non-specific, vague and overlapping.
• It is not uncommon for such patients to present with features of both ARDS as well as underlying cause.
• Symptoms appear within few days after the exposure to inciting factor and is often characterized by fever, cough, sore throat, myalgia, chills or rigors.
• Watery diarrhoea is also common along with abdominal pain, nausea and vomiting especially in illness caused by enterovirus and corona viruses.
• In case of Progressive symptoms of breathlessness, increased requirement of oxygen, increased work of breathing and alveolar infiltrates on chest imaging within 6 to 72 hours of an inciting event, ARDS should be highly suspected.
• On examination, patients may have tachypnea, tachycardia, and diffuse crackles, wheeze.
• In severe case, confusion, respiratory distress, cyanosis, and diaphoresis may be evident.

Mimics of ARDS

There are a number of conditions that may present as acute hypoxaemic respiratory failure with bilateral alveolar opacities and mimic ARDS. Some of the important mimics are being mentioned here: –

(a) Acute cardiogenic pulmonary edema: It usually involves left ventricular systolic or diastolic dysfunction, but it may also occur due to fluid overload, hypertension, or severe renal disease.

It can be distinguished from ARDS by evidence of cardiac dysfunction, elevated right-sided filling pressures or related radiographic abnormalities.BNP or NT-pro BNP is usually elevated. In doubtful cases, bedside transthoracic echocardiography may be performed to seek evidence of cardiac dysfunction.

(b) Diffuse alveolar haemorrhage (DAH): Almost two-third patients with DAH will present with hemoptysis. On FOB, frothy hemorrhagic secretions are visible throughout the airways. BAL cytology, though non-specific, may show hemosiderin-laden macrophages.

(c) Inflammatory or autoimmune conditions: Several specific acute inflammatory conditions may mimic ARDS which mainly include acute eosinophilic pneumonia, pulmonary vasculitis, acute interstitial pneumonitis, acute fibrinous organizing pneumonia, cryptogenic organizing pneumonia. These conditions can be ruled out by serology, BAL specimens, ANA, C-ANCA, P-ANCA or lung biopsy.

(d) Malignancy: Hematological malignancies such as leukaemia, lymphoma and pulmonary secondaries of solid tumours may be mistaken for ARDS.

(e) Others: Few embolic syndromes (fat embolism syndrome, amniotic fluid embolism syndrome) may present with hypoxemia and bilateral opacities. BAL examination may reveal fat or amniotic fluid debris. Air embolism can be suspected when patients experiencing sudden-onset respiratory distress in the setting of a known risk factor, intravenous catheter insertion, or trauma

Diagnostic criteria

• The ARDS Definition Task Force has defined ARDS in 2012 known as Berlin’s criteria, which consists of
  • Acute rapid onset (within 7 days) of ARDS,
  • Impaired oxygenation status (PaO/FiO2 ratio<300 mmHg with positive end expiratory pressure, PEEP≥5 cmH₂O),
  • Characteristic radiological opacities (diffuse, bilateral, and fluffy), and non-cardiac origin of pulmonary edema (not explained by cardiac dysfunction or fluid overload).
• Severity of ARDS: –
  • Mild ARDS -PaO2/FiO2 ratio is in between 200 to 300 mmHg,
  • Moderate ARDS – PaO2/FiO2 ratio between 200 to 100 mmHg.
  • Severe ARDS -PaO2/FiO2 ratio≤100 mmHg, high mortality rate.
• In the past-diagnosis was purely on clinical ground. But now, Association of ARDS to viral etiology is confirmed by isolation of intact virus particles from cell culture or viral antigen detection by immuno-fluorescence, or multiplex RT-PCR. 
• Among all these, most commonly performed and most rapid test is the multiplex RT-PCR, which gives comparable diagnostic accuracy to cell line culture (gold standard) and immuno-fluorescence techniques.
• The best sample for highest diagnostic yield is obtained from broncho-alveolar lavage (BAL), which is not always possible due to highly infectious nature.
• Bacterial & fungal culture, lung histopathology should also be performed to look for coexisting infections leading to ARDS.

Laboratory tests

• Haematological profile – leukopenia, lymphopenia and thrombocytopenia are seen, which are markers of severity of viral illness.
• ABG analysis shows hypoxemia, which is often initially accompanied by acute respiratory alkalosis which later, is replaced by hypercapnic respiratory acidosis (due to contraction of baby lung of ARDS).
• Metabolic acidosis with hyper-lactatemia may also develop due to the precipitating sepsis or associated organ injury.
• Routine biochemical examination may manifest the evidence of organ injury (acute kidney injury or liver dysfunction) reflective of severe hypoxemia or associated shock and systemic inflammation (hypoalbuminemia, raised C-reactive protein).
• The prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be prolonged and D-dimer is elevated in severe viral illness and ARDS, suggesting prognostic importance of coagulation parameters.

Radiology

• Radiological findings in viral ARDS are variable and nonspecific and graded according to the severity of ARDS.

• The initial chest radiograph may be normal or may reveal typically bilateral diffuse alveolar opacities with dependent atelectasis.
• Computed tomography (CT) of the chest may show widespread patchy and/or coalescent airspace opacities that are usually more apparent in the dependent lung zones. The opacities can be subtle (e.g., patchy ground glass), particularly in early ARDS, but can become consolidative in appearance as severity worsens.
• Lung ultrasound has emerged as non-invasive, radiation free, reproducible and promising tool with reportedly higher sensitivity (83 to 92%) for the diagnosis of ARDS compared with CT chest

Management

• Management of ARDS in viral illness is mainly supportive while Specific management includes anti-viral drugs, immunotherapies and steroids.
• Respiratory support: Main issue in ARDS is worsening gas exchange and hypoxemia due to development of intra pulmonary shunt. Therefore, reversal of hypoxemia is the key principle in the management, which can be accomplished by respiratory support in the form of various oxygen delivery devices.
• Role of NIV and HFNOT: Both NIV and HFNOT are noninvasive oxygen delivery devices which are associated with improved outcomes in acute hypoxemic respiratory failure (AHRF) patients compared to invasive mechanical ventilation.
• Before intubating an ARDS patient who has moderate hypoxemia, a trial of NIV or HFNOT may be warranted.
• The need for tracheal intubation in ARDS arises in cases of  severe metabolic acidosis, moderate to severe ARDS, patient in shock state, hypotension, severe dyspnea  & multi organ dysfunction syndrome.
• Ventilatory settings: – for ARDS lung includes low tidal volume (TV),protective lung ventilation (TV, 4-8 mL/kg of predicted body weight) and frequent monitoring and maintaining of plateau pressure (Pplat) below 30 cmH2O to ensure safety to baby lung.
• Low TV may result in hypercapnia and respiratory acidosis, A little of hypercapnia is permissible till pH of arterial blood is maintained above 7.20.
• Positive end expiratory pressure (PEEP) is kept high 10-20 cmH₂O) provided patient is euvolemic and free of neurological insult.
• Frequent ABGs are performed to monitor PaO2/FiO2 ratio, PaCO2 and pH in ARDS patients on mechanical ventilattion.
• Severe hypoxemia in ARDS (<150) should trigger institution of more aggressive approach such as prone position ventilation, extra corporeal membrane oxygenation (ECMO) and use of lung recruitment maneuver (inspiratory hold at 40 cm H2O for 40 seconds).
• Role of awake prone: This novel strategy arrests the progressive basilar atelectasis and has been practiced recently to improve oxygenation in COVID-19 patients. The patients, who do not respond to HFNOT, may be made prone early.
• Proning improves PaO₂ and decreases CO₂ retention in patients with severe ARDS. A multicentric trial (PROSEVA) has shown significant mortality improvement with proning when performed for the duration of 16 hours a day.
• This strategy has been shown to be successful and prevented intubation among 64% of patients.
• Extra corporeal membrane oxygenation (ECMO): This life-support measure has been used as recue therapy in patients with severe ARDS in the times of SARS (2002), H1N1 (2009, 2014-16), MERS (2012-14) and presently COVID-19 (2019-20) pandemic.
• Main issues are its unavailability, huge cost, being resource-intensive and requirement of expertise.
• Fluid management:The society of critical care medicine, 2020 guidelines recommend to use restricted fluid and to use dynamic tests of fluid responsiveness to determine the need of fluid.
• Role of corticosteroid: In H5N1 and H1N1 influenza ARDS, routine use of steroid was discouraged citing higher rate of nosocomial infections. Similarly, corticosteroids did not show any benefit but led to delayed viral clearance in a multicenter study performed in patients (n=309) with the MERS.
• Recently Oxford University released findings of RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial in which dexamethasone reduced the mortality by one-third in the patients on mechanical ventilator.
• Antiviral treatment can reduce the viral load, viral shedding and reduce the disease transmission to close contacts. It has also shown proven benefit in radiologic clearance in ARDS. Once, respiratory virus is detected in respiratory or blood sample, antiviral treatment may be started.
• In pandemic times, empirical antiviral without waiting for result is warranted to improve the outcome. However, the efficacy of antiviral is maximized if administered within 48 hours of symptom onset. Specific antiviral drugs have been listed as below.
• Antimicrobials: In critically ill patients, due to presence of various indwelling catheters, prevention and treatment of nosocomial infection is of equally important while managing virus induced ARDS.

Other pharmacological treatments

• Anti-cytokine drug: Two drugs, Aviptadil (concentrated in the lung 40%), and Remestemcel-L are being repurposed and investigated as therapeutics in COVID-19 ARDS (CARDS). Both down-regulate the synthesis of pro-inflammatory cytokines in the lung.
• Immunotherapies: Palivizumab (monoclonal antibody) with intravenous immunoglobulin (IVIG) has been recommended in preventing RSV induced severe pneumonia in high risk infants and young children.
• Interferons-alpha-2a with ribavirin has been shown to improve survival in severe MERS-CoV infection.
• Convalescent plasma, due to its immunotherapeutic potential, has been successfully used in SARS, MERS, Ebola virus disease and COVID-19.

CME INDIA Learning Points

• The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients
• It is   defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation.
• ARDS occurs most often in the setting of
  1. Pneumonia
  2. Sepsis
  3. Aspiration of gastric contents
  4. Severe trauma
• Mortality remains high at 30–40% in most studies.
• Diagnosis is based on
  1. Consensus syndromic criteria.
  2. Modifications for under-resourced settings and in paediatric patients.
• Treatment
  1. Lung-protective ventilation.
  2. No specific pharmacotherapies have been identified.

CME INDIA Tail Piece

Definitions of ARDS in adults

2012 Berlin definition (4)

• Timing: respiratory failure within 1 week of a known insult or new and/or worsening respiratory symptoms
• Origin: respiratory failure not fully explained by cardiac function or volume overload (need objective criterion such as echocardiography to exclude hydrostatic oedema if no risk factor is present)
• Imaging: bilateral opacities on chest radiograph or CT not fully explained by effusion, collapse or nodules
• Oxygenation: acute onset of hypoxaemia defined as PaO₂/FiO₂ <300 mmHg on at least PEEP 5 cmH₂O^a
  • PaO₂/FiO₂ of 201–300 mmHg is mild ARDS
  • PaO₂/FiO₂ of 101–200 mmHg is moderate ARDS
  • PaO₂/FiO₂ ≤100 mmHg is severe ARDS

2016 Kigali modification(5)

• Timing and origin: as in the Berlin definition
• Imaging: bilateral opacities on chest radiography or ultrasonography scan not fully explained by effusion, collapse or nodules
• Oxygenation: SpO₂/FiO₂ <315; no PEEP requirement

References:

1. Luyt CÉ, Combes A, Trouillet JL, Nieszkowska A, Chastre J. Virus-induced acute respiratory distress syndrome: epidemiology, management and outcome. Presse Med. 2011 Dec;40(12 Pt 2):e561-8. doi: 10.1016/j.lpm.2011.05.027. Epub 2011 Nov 16. PMID: 22094172; PMCID: PMC7125714
2. Luyt, CE., Bouadma, L., Morris, A.C. et al. Pulmonary infections complicating ARDS. Intensive Care Med 46, 2168–2183 (2020). https://doi.org/10.1007/s00134-020-06292-z
3. Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 (2019). https://doi.org/10.1038/s41572-019-0069-0
4. Ranieri, V. M. et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 307, 2526–2533 (2012).
5. Riviello, E. D. et al. Hospital incidence and outcomes of the acute respiratory distress syndrome using the Kigali Modification of the Berlin Definition. Am. J. Respir. Crit. Care Med. 193, 52–59 (2016)

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