A Systematic Review of Cases of Acute Respiratory Distress Syndrome in the Coronavirus Disease 2019 Pandemic

The outbreak of coronavirus disease 2019 (COVID-19) was declared a global pandemic after it spread to 213 countries and has the highest total number of cases worldwide. About 80% of COVID-19 infections are mild or asymptomatic and never require hospitalization but about 5% of patients become critically ill and develop acute respiratory distress syndrome (ARDS). The widely used management for ARDS in COVID-19 has been in line with the standard approach, but the need to adjust the treatment protocols has been questioned based on the reports of higher mortality risk among those requiring mechanical ventilation. ﻿Treatment options for this widespread disease are limited and there are no definitive therapies or vaccines until now. Although some antimalarial and antiviral drugs may prove effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their safety and efficacy are still under clinical trials. We conducted a systematic review of case reports on ARDS in SARS-CoV-2 infection to summarize the clinical presentation, laboratory and chest imaging findings, management protocols, and outcome of ARDS in COVID-19-positive patients. We need ﻿more data and established studies for the effective management of the novel SARS-CoV-2 and to reduce mortality in high-risk patients.


Introduction And Background
An outbreak of a cluster of cases of pneumonia with an unknown cause was first reported in late December 2019 in Wuhan in the Hubei Province of China. This respiratory illness during the coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. COVID-19 was declared a global pandemic on January 30, 2020, after it spread to 213 countries, areas, or territories including the US, where the first case was reported on January 12, 2020 [1,2]. Community transmission of COVID-19 in the US was first reported in February that spread widely later on through close person-to-person contact via respiratory droplets, and through the infected surface to a person's eyes, nose, or mouth [3]. As a result, active surveillance, contact tracing, quarantine, and strict social distancing were implemented worldwide to contain the transmission of the virus [1]. The overall cumulative COVID-19 incidence in the US was 119.6 cases per 100,000 population on April 7 [3].

Pathophysiology
SARS-CoV-2 is a positive single-strand enveloped ribonucleic acid (RNA) virus that contains viral membrane E type glycoprotein that binds and enters sensitive cellular receptors by endophagocytosis in organ systems including epithelial cells in the respiratory tract [10]. The novel beta coronavirus strain that causes COVID-19 is in the same subgenus as the SARS virus of the 2003 outbreak [11]. There is only sporadic information on the pathophysiology of the disease at an early and evolving stage of the pandemic outbreak. In previous animal models and human studies on SARS pathology, it is mentioned that the SARS-CoV protein binding to angiotensin-converting enzyme 2 (ACE2) could lead to acute lung injury through ACE2 downregulation and angiotensin (AT) 1a receptor stimulation [12,13]. Animal studies found that elastase, a major protease induced in lung inflammation, might also be involved in SARS pathogenesis [12,13]. Clinical pathology of autopsy cases of SARS helped in the significant understanding of the nature of the disease. The overall pathological changes in the lungs were of diffuse alveolar damage-causing ARDS [10]. Microscopic examination of pulmonary lesions revealed extensive bilateral consolidation, hemorrhagic infarction, desquamative pulmonary alveolitis and bronchitis, hyaline membrane formation, and viral inclusion bodies in alveolar epithelial cells [10]. Imaging findings range from no abnormalities to bilateral lung consolidation on chest radiographs or peripheral ground-glass opacities on CT scan [5].

Clinical presentation
The included four case reports were published between February and April 2020; two of them were from China, one was from Singapore, and one was from the US [6][7][8][9]. A total of six patients with COVID-19 were studied for the development of critical illness and/or ARDS. Patients were adults with an age range of 44 to 75 years.
The most common initial presentation of COVID infection was a history of two to seven days of cough with or without fever, chills, dyspnea, and fatigue [6][7][8][9]. One of the patients from Iran was detected incidentally on a chest CT scan when he presented to the emergency room for follow-up of a two-weekold rib fracture from a fall with pain unresponsive to over-the-counter painkillers [9].

Disease course and outcomes
The course and development of critical illness or ARDS were similar in most cases with the patient's condition deteriorating within 48-72 hours of initial presentation. Most of them developed dyspnea and severe hypoxemia with declining oxygen saturation (SaO 2 ) during the second week of illness requiring oxygen supplementation or assisted ventilation. The patient who was diagnosed accidentally at early stages of infection was immediately treated with oseltamivir 75 mg twice daily (BID) and hydroxychloroquine 400 mg stat, based on the Iranian interim guideline for "clinical management of COVID-19", though the patient developed fever and dyspnea three days later [9]. Management was switched to a focused antiviral treatment regimen with oseltamivir 75 mg and lopinavir/ritonavir 400/100 mg BID and the patient gradually improved attaining normal oxygen saturation without the need of intubation or supplemental oxygen [9].
All six patients were tested positive for SARS-CoV-2 using the reverse RT-PCR assay of a respiratory specimen. In two of the six cases, a detailed laboratory investigation revealed lymphopenia and elevated C-reactive protein [7,8]. In one of the cases, flow cytometric analysis showed decreased peripheral cluster of differentiation (CD) 4 cells and CD8 cells [7]. Liver and renal function tests showed an elevated aspartate transaminase/alanine transaminase ratio and lactate dehydrogenase levels, and lung biopsy showed bilateral ARDS [7,8]. Three cases of critically ill, mechanically ventilated patients with ARDS required continuous monitoring of D-dimer and fibrinogen levels since it involved treatment with a fibrinolytic agent: tissue plasminogen activator (tPA) [6]. Chest x-ray and chest CT scan on admission showed predominant bi-basilar ground-glass opacities in all six patients [6][7][8][9].

Management
Treatment modalities and clinical management options for COVID-19-induced ARDS were variable among these patients but mainly supportive and similar to standard ARDS management. Infection control measures that included patient placement in isolation wards and standard contact and airborne precautions were pre-requisite. Oxygen supplementation was a standard protocol for most patients who developed dyspnea and hypoxemia. Antiviral therapy was tried in three of the six cases mentioned either as lopinavir/ritonavir 500 mg BID or in combination with oseltamivir as 400/100 mg BID [7][8][9]. One patient died of hypoxemia and sudden cardiac arrest (patient was on the do-not-resuscitate code status), but the other two showed marked improvement after receiving treatment [7][8][9]. The other medication commonly used (in four of six cases) was hydroxychloroquine stat 400 mg, in combination with either azithromycin or oseltamivir (75 mg) [6,9]. Empiric broad-spectrum antibiotics such as moxifloxacin were used in two mechanically ventilated patients to prevent secondary infection; however, one patient developed ventilator-associated pneumonia that necessitated the use of culture-guided antibiotics [7,8]. Corticosteroids, such as intravenous methylprednisone, were administered in one patient to decrease lung inflammation [7].
The study on tPA treatment for COVID-19-associated ARDS, which involved measuring the partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio for oxygenation status, reported one out of three cases had 100% improvement post-tPA but the effect was transient [6]. This case series also mentions the use of anticoagulants like heparin with tPA infusion to decrease the risk of bleeding [6]. There are few in vivo studies on the use of plasminogen activators for the prevention of acute lung injury in animal studies, and so more trials are required to determine the optimal dosing and therapeutic effects of tPA [14,15]. Vasopressors such as norepinephrine, phenylephrine, and vasopressin have been proved effective for hemodynamic support, sedation, and chemical paralysis [15][16][17]. Few studies have summarized the use of non-ventilatory interventions as rescue therapy in non-compliant patients with refractory hypoxemia [16,17]. A descriptive summary of all case reports that met our inclusion criteria is shown in Table 1.

Study
Demographics Initial

Current evidence on treatment
About 80% of patients with COVID-19 have mild disease and never require hospitalization, and about 5% of patients become critically ill, with the risk of ARDS being highest in ICU patients [5,18]. There could be a high risk of mortality (about two-thirds) in ventilated patients according to new data from the United Kingdom's Intensive Care National Audit and Research Center (ICNARC), but this was unclear [19]. Other less frequent complications include acute cardiac injury, acute kidney injury, and septic shock, followed by multi-organ failure [20]. Of the six patients in our review, two died from complications within one to two weeks of clinical presentation [6,7]. The reported causes of death included cardiac arrest even after receiving invasive ventilation and chest compression and the other patient in Wang et al.'s study died due to multi-organ failure with secondary bacterial infection [6,7]. The other four patients showed a good prognosis with no inpatient death.
Antiretroviral protease inhibitors, such as lopinavir/ritonavir, and antimalarials like hydroxychloroquine, for which US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA), were used in all studies but randomized clinical trials (RCTs) to assess their efficacy and safety are still ongoing [21]. Sanders et al. suggested that remdesivir can be a promising therapy for COVID-19 as it has already shown broad antiviral activity in both in vitro and in vivo studies against related viruses: Middle East respiratory syndrome (MERS)-CoV and SARS-CoV [22]. Oseltamivir has no role in COVID-19 treatment and corticosteroids that have been widely used in many patients in China may potentially prolong the course of illness by causing delayed viral clearance [22]. Antimalarial drugs like chloroquine or hydroxychloroquine monotherapy or combination therapy with azithromycin may prove effective, especially in severe disease, but these benefits need to be determined with RCTs that are already underway [22,23]. So treatment options are limited and there are no definitive therapies or vaccines until now and additional studies are needed to evaluate their effectiveness [22].
According to previous reports from China and new ICNARC findings from England, mortality was higher among those requiring mechanical ventilation than those who did not and appears higher than that for patients treated in ICU for other types of viral pneumonia [19,24]. The widely used management for ARDS in COVID-19 has been in lines with the standard approach, but treatment protocols need to be adjusted according to the characteristics of disease pathophysiology, making more gradual positive endexpiratory pressure changes for the atypical type of ARDS seen with COVID-19 [19].

Conclusions
Our systematic review of published cases of ARDS in COVID-19-positive patients will help healthcare professionals to clearly understand and implement updated treatment strategies and confront the COVID-19 pandemic and its medical consequences. Nonetheless, we need more RCTs and treatment guidelines for developing effective management of the novel SARS-CoV-2 and thus improve survival and reduce mortality in high-risk and critical patients.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.