key: cord-0761264-8p0undjd authors: El-Sayed, Amr; Abdel-Daim, Mohamed M.; Kamel, Mohamed title: Causes of respiratory failure in COVID-19 patients date: 2021-05-05 journal: Environ Sci Pollut Res Int DOI: 10.1007/s11356-021-14200-1 sha: c93266c07c03f1a9150570ca818075a00c23ff62 doc_id: 761264 cord_uid: 8p0undjd nan 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. 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 , gastrointestinal 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 ). 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 ). 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 ; (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 ); (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 or via the trans-synaptic route (olfactory bulb) (Brann et al. 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) . 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. Availability of data and materials Not applicable. Author contribution AE and MK: manuscript writing and revision. MMA conducted manuscript moderation and revision. Conflict of interest The authors declare no competing interests. Molecular basis of pathogenesis of coronaviruses: a comparative genomics approach to planetary health to prevent zoonotic outbreaks in the 21st century Computing the effects of SARS-CoV-2 on respiration regulatory mechanisms in COVID-19 The coronavirus disease 2019 (COVID-19) pandemic Sex differential in COVID-19 mortality varies markedly by age The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the Spike protein, allowing assembly of virus-like particles Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia SARS-CoV-2, early entry events Histopathological observations in COVID-19: a systematic review Deleterious effects of viral pneumonia on cardiovascular system Neurological associations of COVID-19 Association of Kawasaki disease and COVID-19 in children A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm Genetic susceptibility for COVID-19-associated sudden cardiac death in African Americans SARS-CoV-2 Overweight, obesity, and risk of hospitalization for COVID-19: a community-based cohort study of adults in the United Kingdom A recently explored aspect of the iceberg named COVID-19: multisystem inflammatory syndrome in children (MIS-C) Presence of hyaluronan in lung alveoli in severe Covid-19-an opening for new treatment options The cytokine storm and COVID-19 Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19 COVID-19: a global threat to the nervous system Whither COVID-19 vaccines? Pulmonary arterial thrombosis in COVID-19 with fatal outcome : results from a Environ Sci Pollut Res prospective, single-center, clinicopathologic case series The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Thyroid dysfunction in relation to immune profile, disease status, and outcome in 191 patients with COVID-19 The current status of COVID-19 vaccines. Front Genome Ed 2:10 Brainstem involvement and respiratory failure in COVID-19 COVID-19-associated acute hemorrhagic necrotizing encephalopathy: imaging features Advances in gene-based vaccine platforms to address the COVID-19 pandemic Cutaneous manifestations in COVID-19: report on 31 cases from five countries Viral pathogenesis of SARS-CoV-2 infection and male reproductive health A review of COVID-19 vaccines in development: 6 months into the pandemic Structural insight into the role of novel SARS-CoV-2 E protein: a potential target for vaccine development and other therapeutic strategies Coronavirus envelope protein: current knowledge Neurological involvement in SARS-CoV-2 infection: a clinical systematic review Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity A rare manifestation of indolent systemic mastocytosis and its management during the coronavirus disease 2019 pandemic; educational lessons from Syria Neurological infection with SARS-CoV-2 -the story so far COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis Structural features of coronavirus SARS-CoV-2 spike protein: targets for vaccination A rare presentation of renal papillary necrosis in a COVID-19-positive patient The structure of the membrane protein of SARS-CoV-2 resembles the sugar transporter semiSWEET Evaluating the impact of COVID-19 on male reproduction Vaccines for COVID-19 Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: a different phenotype of thrombotic disease? SARS-CoV-2: structure, biology, and structure-based therapeutics development COVID-19 as the leading cause of death in the United States Place and causes of acute cardiovascular mortality during the COVID-19 pandemic Nervous system involvement after infection with COVID-19 and other coronaviruses Coronavirus vaccine development: from SARS and MERS to COVID-19 Gastrointestinal and hepatic abnormalities in patients with confirmed COVID-19: a systematic review and meta-analysis Meta-analysis of chest CT features of patients with COVID-19 pneumonia Association of asthma and its genetic predisposition with the risk of severe COVID-19 Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations