Author: Dr Sudhir Singh
MS, MCh (General Surgery), Getwell Hospital, Varanasidownload Article
Coronavirus pandemic due to SARS-CoV-2 infection has created a chaos across the globe causing many causalities. Severe conditions of COVID-19 infection lead to acute respiratory distress syndrome (ARDS) and pneumonia, which can prove to be fatal for the infected individual. Initial alveolar damage is linked to viral infection and damage due to cytokine storm, and which later leads to multi organ dysfunction. The main treatment strategy for pulmonary distress and acute respiratory distress syndrome is to provide oxygenation therapy and ventilation support. Further research is required to identify more specific therapies for COVID-19 related ARDS.
Keywords: SARS-CoV-2, COVID-19, ARDS, Cytokine storm, Oxygen therapy, Ventilation support
The outbreak of novel coronavirus was detected in Wuhan in December 2019 resulted in a worldwide pandemic. On February 11, 2020, the World Health Organization (WHO) formally named it as coronavirus disease 2019 (COVID-19).  Globally, more than 15,654,428 confirmed individuals and over 636,475 deaths, across more than 200 countries, territories or areas have been reported.  As the virus continues to spread at an alarming rate, healthcare workers are seeking effective and actionable management program for affected patients. Most of the people who came in contact with Coronavirus presented with mild symptoms (80.9%), then severe (13.8%), and finally critical (4.7%). Patients with underlying diseases had much higher fatality rates than patients with no underlying diseases (10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, 5.6% for cancer, and 0.9% for none). 
A recent single-center study found that most critically ill patients developed organ dysfunction, where 67% were found to have acute respiratory distress syndrome (ARDS), 29% with acute kidney injury (AKI), 23% with cardiac injury, 29% with liver dysfunction, and 2% with pneumothorax.  According to the opinion of experts’, the patients should also be considered as critical cases if they are suffering from high respiratory frequency (RR ≥ 30 bpm) and low oxygen index (arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤ 200 mmHg) under high-flow nasal cannula oxygen therapy (HFNC). The experts drew up sections on the management of COVID-19 disease, mostly based on their experience in Wuhan.
Figure 1: Percentage of higher fatality rates in patients with underlying diseases
As late in the year 2019, when most people were diagnosed with pneumonia kind of symptoms due to unknown reason, it led to the rigorous findings for cause of such situation. This lead to the discovery of newly emerged SARS-CoV-2 causing COVID-19. The disease spreads from person to person through airborne droplets carrying SARS-CoV-2 viruses, or via coming into contact with any kind of surfaces contaminated with the strains of this coronavirus. 
After the individual host comes into contact with SARS-CoV-2, the virus enters inside the body through mouth, nose or eyes into lungs, and starts multiplying there causing infection. Majority of infected individuals are asymptomatic or show mild symptoms. Other infected patients start observing symptoms related to respiratory distress, shortness of breath, fever, fatigue, muscle pain, dry cough, sore throat, loss of smell or taste, nausea, vomiting and diarrhea. The patients with other kind of comorbidities like pulmonary and cardiovascular issues, obesity, diabetes, asthma, hypertension, lung fibrosis, COPD and interstitial lung diseases develops severe kind of disease characteristics.  If not treated properly, the symptoms worsen and after this the disease progresses leading to acute respiratory distress syndrome (ARDS) preceded by acute lung injury (ALI), or maybe even death. Patients with ARDS require oxygen therapy and ventilation support along with ongoing treatment, based on their condition and progress of recovery.
SARS-CoV-2 is a positive sense single stranded RNA virus. It encodes spike S protein which binds to the ACE2 receptor on cell surface of host cell and promotes fusion by endocytosis. Upon entering the host cell like any other virus, SARS-CoV-2 uses host cells machinery to synthesize viral proteins and replicates viral genome. 
After entering the human body, viruses trigger the series of immune responses such as, apoptosis, autophagy, activating innate immunity and various other stress responses. Initially if the person has strong immunity, then bodies innate immune system comes into play by activating antiviral defense mechanism such as antiviral T cells and natural killer (NK) cells, and releasing of interferons (IFN) by infected cell. 
In earlier study on SARS and MERS, it was observed that these viruses have evolved a method to delay interferon production by virus infected cell. This resulted in severe lung injury and enhanced inflammatory responses, leading to the production of outburst of inflammatory cytokines, known as cytokine storm. This correlates with the disease severity and poor prognosis of COVID-19 patients. 
Transcriptomic RNA-sequence analysis of COVID-19 patients has revealed that several immune pathways and pro-inflammatory cytokines CXCL, CCL2, CXCL2, CCL8, IL33, and CCL3L1 in bronchoalveolar lavage fluid (BALF) and TNFSF10, CXCL10, IL10, TIMP1, C5, IL18, AREG, and NRG1 in peripheral blood mononuclear cells (PBMC) were induced by SARS-CoV-2 infection, suggesting a sustained inflammation and cytokine storm. Importantly, SARS-CoV-2 infection–induced excessive cytokine release correlates with lung tissue injury and COVID-19 pathogenesis. 
The patients who develop severe disease condition are linked most likely due to genetics, epigenetics or other factors. COVID-19 is well known to effect respiratory system, but other organ system also including organs like heart and brain. Many neurological symptoms have been reported in patients and infection due to SARS-CoV-2 has been found in brainstem of infected humans as well as experimental animals. 
Figure 2 : Schematic representation of clinical features versus pathogenic inflammatory cytokine response in SARS-CoV-2 infections.
The statements regarding the evidences on how to cope with current pandemic situation were drawn up by a group of 16 front-line intensive care experts in China who fought against the COVID-19 in Wuhan. The quality of evidence was assessed using the methodology described in grades of recommendation, assessment, development, and evaluation (GRADE). 
According to the GRADE method and summary of the results, experts drew up 46 statements. Of these guidelines, 5 had a high level of evidence (GRADE 1±), 21 had a low level of evidence (GRADE 2±), and 20 were expert opinions.
As the front-liners of the COVID-19 outbreak response, health care workers are exposed to a high risk of infection. Therefore, health care workers must follow the standard precautionary principles and try their best to ensure the personal protection, hand hygiene, ward management, environmental ventilation, and sanitization of the object surface, in order to prevent nosocomial cross-infection.
Plasma treatment tends to lower the upper respiratory tract virus load and decreases serum cytokines levels in patients with severe virus infection. A study performed in 10 severe COVID-19 patients found that convalescent plasma treatment could improve clinical outcomes, improve immune function, and promote absorption of lung lesions. 
Respiratory failure is the primary organ dysfunction, which worsens the prognosis of COVID-19 patients. Oxygen therapy and respiratory support are the major treatments for COVID-19-induced ARDS. Due to inflammatory and necrosis-induced small airway occlusion, which was confirmed by autopsy of COVID-19-induced ARDS, positive pressure ventilation is important to restore the collapsed airway and to improve the gas exchanges. However, high end-inspiratory pressure increases stress and strain to normal alveoli and increases the risk of lung injury. Oxygen therapy and respiratory support for COVID-19-induced ARDS should balance airway recruitment and risk of lung injury.
Noninvasive ventilation support (NIV) and high-flow nasal cannula oxygen therapy (HFNC) are important treatment options for COVID-19-induced mild and moderate ARDS. The mechanisms of the two treatments are positive end-expiratory pressure, decreased respiratory workload, decreased incidence of intubation, ease of use, and higher comfort. In a randomized trial of adult patients admitted to the ICU for acute hypoxemic, non-hypercapnic respiratory insufficiency, continuous positive airway pressure (CPAP) delivered by face mask was associated with an early improvement in oxygenation. 
Due to the nature of virus infection, it is not logical to use prophylactic antibiotics, and there is no evidence that this treatment option could reduce the incidence of the secondary infection. On the other hand, according to the management guidelines of COVID-19 from WHO and China empiric antibiotic treatment should only be given to the patient based on the clinical diagnosis (community-acquired pneumonia, healthcare-associated pneumonia or sepsis), local epidemiology and susceptibility data, and treatment guidelines. 
There is some evidence that immunotherapy may be effective against novel coronavirus infection. An article published on the MedRixv website stated that the mortality of COVID-19 patients might be negatively related to the number of lymphocytes in patients. Both helper T cells and suppressor T cells in COVID-19 patients tend to be below normal levels and lower level of helper T cells in the severe group. The percentage of naive helper T cells increased, and memory helper T cells decreased in severe cases. Thus, enhancing the immunity of the patient might strengthen the fight against novel coronavirus. 
Vitamin C (ascorbic acid) is a water-soluble vitamin that has beneficial effects in patients with severe and critical illnesses. It is an antioxidant and free radical scavenger that has anti-inflammatory properties, influences cellular immunity and vascular integrity. Humans require more vitamin C in states of oxidative stress, vitamin C supplementation has been evaluated in numerous disease states, including serious infections and sepsis. Because serious COVID-19 may cause sepsis and acute respiratory distress syndrome (ARDS), the potential role of high doses of vitamin C in ameliorating inflammation and vascular injury in patients with COVID-19 is being studied.
Antiviral drugs are proven effective and should probably be considered for SARS-CoV-2 treatment.
Favipiravir is an antiviral medication that was initially developed to treat influenza in Japan. In February 2020, post the outbreak of Novel Coronavirus (COVID-19), Favipiravir was studied in China and several other countries as an experimental treatment of COVID-19.
Favipiravir is a broad-spectrum oral antiviral drug that selectively inhibits RNA-dependent RNA polymerase (RdRp) and the viral replication phase of SARS-CoV-2. "The drug has demonstrated positive outcomes, including a reduction in the duration of COVID-19 and improved lung conditions for the patients". 
Ulinastatin (UTI), is a serine protease inhibitor with anti-inflammatory properties. It inhibits cytokine storm, which is a severe immune reaction wherein the body releases too many cytokines into the blood too quickly.
Results from trials have shown that Ulinastatin improved oxygenation index, shortened duration of mechanical ventilation and decreased mortality and ICU stay compared to standard therapies in Covid-19 patients.
As the pathogenesis of COVID-19 is not yet well understood and associations between clinical status and viral clearance, radiological or immunological evaluations are unclear, the use of clinical outcomes should be encouraged. Rapid identification of such therapies is thus essential, but challenging. Repurposing of existing antiviral and immunomodulating drugs is an important strategy, because the safety profile of these drugs is well known. We may expect that in the next few weeks carefully performed trials will be reported that will guide doctors around the world to give the best care (both in terms of reducing viral replication and mitigating hyper-inflammation) to COVID-19 patients.