Causes of respiratory failure in COVID-19 patients.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was reported in 2019 in Wuhan, China, causes the coronavirus disease (COVID-19) pandemic (Baloch et al. 2020). It has spanned nearly 108,026,145 million people around the world, with 2,369,067 million deaths by the day of 11 February 2021, and continues to increase. It restricted the travel for most of the global population over the past year. COVID-19 is now the top wellbeing, fiscal, and healthcare concern throughout the modern age.

With full genetic sequence details, SARS-CoV-2 can be identified as a member of the subgenus Sarbecovirus in the Coronaviridae family. It codes its RNA genome for 4 structural and 16 non-structural proteins (Fig. 1) (Asrani et al. 2020; Schoeman and Fielding 2019; Huang et al. 2020; Sarkar and Saha 2020). Structural proteins include spike (S), envelope (E), nucleocapsid (N), and membrane (M) proteins (Boson et al. 2020; Thomas 2020; Gupta 2020). The coronavirus protein S gives the surface appearance of the spike crown and is important to recognize host receptors, host repertoire, binding, viral tissue tropism, entry, fusion and activation of T cell responses, and antibody neutralization (Huang et al. 2020; Sternberg and Naujokat 2020; Chambers et al. 2020). The M protein is the basic type component of the surface of the virus, which delineates inflammatory responses and generates ribonucleoproteins. Although N protein facilitates its entrance and survival inside the host cells, the E protein increases its pathogenicity and acts as an ion channel (Huang et al. 2020; Sarkar and Saha 2020; Wang et al. 2020). SARS-CoV-2 adapts to a variety of hosts due to high mutation rates (Sarkar and Saha 2020; Huang et al. 2020) (13). Different forms of vaccines are being produced to defend against COVID-19. The vaccines included inactivated, DNA, mRNA, viral vector, saRNA, and protein subunits (DeFrancesco 2020; Lundstrom 2020; Pushparajah et al. 2021; Sanicas et al. 2020; Sarkar and Saha 2020; Tregoning et al. 2020). While some vaccines are already approved, others are still being developed or tested clinically (DeFrancesco 2020; Lundstrom 2020; Pushparajah et al. 2021; Sanicas et al. 2020; Sarkar and Saha 2020; Tregoning et al. 2020; Li et al. 2020b). Potency, safety, and purity are the main concerns in vaccine evaluation. Despite the available control measures, deaths are still ongoing. We highlighted here on the different factors triggering respiratory failure due to COVID-19 infecton as the main cause of death and the deteminants of its susceptibility in a population is also focused.

Fig. 1

Schematic structure of SARS-CoV-2

Factors determining COVID-19 susceptibility in the population

Since the emergence of SARS-CoV-2 in 2019, about 2,369,067 persons died until the date. Due to the high binding affinity of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2) receptors which are expressed by different tissues, SARS-CoV-2 has a broad tissue tropism and can attack various systems of the body. Therefore, infection with SARS-CoV-2 can result in wide range of clinical signs. The patients may demonstrate one or more of the following symptoms: respiratory manifestations (Zheng et al. 2020), gastro-intestinal symptoms and hepatic abnormalities (Zarifian et al. 2020), integumentary system and skin lesions (e.g., pityriasis rosea, exanthem, papules, vesicles, and urticaria) (Rodriguez-Cerdeira et al. 2021; Deshmukh et al. 2020), multisystem inflammatory syndrome and Kawasaki-like syndrome in children (Esmaeilzadeh et al. 2021; Haslak et al. 2020), nervous signs (Soltani et al. 2021; Ellul et al. 2020), severe immune response (storm of cytokines) (Hu et al. 2021), and cardiovascular manifestations (Israel et al. 2021) and may even infect the male reproductive system leading to testicular damage and reduction of male fertility (Roychoudhury et al. n.d.; Tian and Zhou 2021).

According to literature, SARS-CoV-2 can initiate clinical signs or complications in other organs in seldom cases, such as the induction of renal papillary necrosis (Tallai et al. 2021), thyroid dysfunction (Lui et al. 2021), or systemic mastocytosis (Slaibi et al. 2021). While some patients remain clinically asymptomatic, others must be hospitalized and even intubated. The individual susceptibility to COVID-19 in the population varies according to several factors. In other words, there are many risk factors which influence COVID-19 prevalence among individuals and among population. Within the same population, factors as age, sex, weight, and health status play a major role in the determination of disease severity (high-risk individuals: males, old age, overweight, history of chronic diseases as diabetes, cardiovascular diseases, or asthma). Similarly, other factors determine disease susceptibility among different populations including population density, percentage of youth in the population, traditional diet/gut microbiota, lifestyle, genetic factors including ethnic differences, and the share of Neanderthals DNA in the genome (Giudicessi et al. 2020; Shelton et al. 2020; Bhopal and Bhopal 2020; Nelson 2020; Woolf et al. 2021; Hamer et al. 2020).

Causes of respiratory failure in COVID-19 patients

As mentioned above, SARS-CoV-2 can infect several body systems and induce life-threatening clinical signs. Death can result from cardiovascular events (e.g., stroke and acute coronary syndrome), severe uncontrolled immune response (cytokine storm), damage of the brain stem, or respiratory failure (Wu et al. 2021; Solomon 2021).

Respiratory failure is one of the major causes of COVID-19 induced mortalities. However, the high mortality rate even among intubated ICU patients proves the multifactorial nature of the COVID-19 respiratory failure (Fig. 2) so that other therapeutic approaches must be developed including the use of hymecromone and cortisone (Hellman et al. 2020).

Fig. 2

Factors trigerring and causing respiratory failure in COVID-19 infected patients

Among these factors: (A) cardiovascular factors (Fig. 3): (1) production of bradykinin and inflammatory mediators, which increase the permeability of blood vessels, leads to the accumulation of fluids in air alveoli. The resulting pulmonary oedema interferes with gas exchange and results in hypoxaemia; (2) the accumulation of exudates/fluids in the lungs accompanied with inflammatory pulmonary oedema results additionally in pulmonary hypertension. The stagnation and slowing of the circulation exert an additional load/overload on right heart volume (Duan et al. 2020); (3) the interference with gas exchange and the resulting hypoxaemia creates a state of imbalance of oxidation and antioxidation system in the myocardium. This, in turn, provokes the accumulation of reactive oxygen species (ROS), destroys the cardiomyocyte cell membrane, and initiates the programmed cell death. The damaging effects of ROS in cardiomyocytes extend also to involve transport system of calcium ions. The resulting intracellular chaos includes the activation of sarcoplasmic reticulum Ca2+-ATPase accompanied with the reduction of intracellular Ca2+ level, the inactivation of Ca2+-ATPase in cardiomyocytes cell membrane, opening the receptors of melastain 2 cation channel, and enhancing Ca2+ loading ending with cardiomyocyte apoptosis (Duan et al. 2020); (4) increased production of hyaluronic acid which interacts with the fluids in the alveoli producing hydrogel (hyaluronan-based jelly) (Garvin et al. 2020; Hellman et al. 2020; van Dam et al. 2020), and (5) arterial and venous thrombosis of the pulmonary vessels which lead to pulmonary embolism and tissue ischemia. The thrombi in small pulmonary vessels are secondary to endothelial damage due to viral infection (harbor expressed ACE2 receptors) or due to alveolar damage and the deposition of alveolar fibrin (thromboinflammatory syndrome) (Lax et al. 2020; Wu et al. 2021). (B) Neurotropism of the brainstem which enhances viral invasion. The resulting permanent damage of the brainstem responsible for normal breathing can explain why some of the recovered patients from COVID-19 pneumonia remain in dependable on mechanical ventilation (Manganelli et al. 2020). The virus can invade the CNS via hematogenous and nervous routes. This occurs following damage of the BBB caused by the auto-immune response (Scoppettuolo et al. 2020), transportation of the virus with infected WBCs to the brain, or due to the direct interaction between viral S protein and ACE2 receptors (Wu et al. 2020) or via the trans-synaptic route (olfactory bulb) (Brann et al. 2020). The resulting damages include encephalopathy (no direct CNS invasion occurs) and encephalitis (induced by direct viral invasion to CNS) (Poyiadji et al. 2020; Koralnik and Tyler 2020). Additional nervous damage due to intracranial cytokine storms can complicate the situation (Poyiadji et al. 2020). (C) Direct viral invasion of the lung tissue is facilitated by the presence of ACE2 receptors in airway epithelium, lung parenchyma, and endothelial cells. Severe alveolar damage and consolidation of lung parenchyma were common findings of post-mortal studies where bilateral diffuse alveolar damage, fibrosis, oedema, proliferation of pneumocytes and fibroblasts, presence of pulmonary emboli, and infarctions were reported (Lax et al. 2020; Li et al. 2020a; Baig 2020). (D) Genetic factors: relatively high percentage of patients who developed severe COVID-19 pneumonia harbored rare genetic variants in at least 13 genes regulating the immune response and interferon production. They produced auto-reactive antibodies which attack their immune system rather than the invading virus (Bastard et al. 2020). In addition, a clear relationship between the severity of the disease, asthma, and a predisposing genetic factor was also established among COVID-19 patients (Zhu et al. 2020).

Fig. 3

Cardiovascular factors as a source of respiratory failure in COVID-19 infected patients

In conclusion, understanding the underlying factors trigerring RF is very pivotal for treating COVID-19 patients. Trial to re-use and repurpose already available drugs or developing novel drugs targetting these factors will enhance COVID-19 recovery and diminishing its effect. Cardiovascular factors, genetic factors, direct invasion of lung tissue, and permentnat damage of the brain stem are the main factors causing RF in COVID-19 infected patients. Factors affecting the susceptability to COVID-19 in a population should be taken into consideration in its control and preventative measures.