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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 63
| Issue : 6 | Page : 245-249 |
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Interplay of COVID-19 and physiological dysfunctions
Yu-Hsiu Chang1, Chih-Heng Huang1, Po-Shiuan Hsieh2
1 Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan
2 Department of Physiology and Biophysics, National Defense Medical Center; Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan
| Date of Submission | 02-Nov-2020 |
| Date of Decision | 09-Nov-2020 |
| Date of Acceptance | 10-Nov-2020 |
| Date of Web Publication | 09-Dec-2020 |
Correspondence Address:
Prof. Po-Shiuan Hsieh
Department of Physiology and Biophysics, National Defense Medical Center, No. 161, Section 6, Min-Chuan East Road, Taipei 114
Taiwan
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/CJP.CJP_91_20
The outbreak of the global coronavirus disease 2019 (COVID-19) pandemic continues to impact the socioeconomic fabric and the general well-being of numerous populations and communities around the world. As cases continue to rise exponentially, gaining a better understanding of the pathophysiology and the associated clinical implications of SARS-CoV-2, the causative agent of COVID-19, becomes increasingly necessary. In this article, we delineate the role of COVID-19 in physiological and immunological dysfunction. Specifically, we highlight the various possible mechanisms and effects of SARS-CoV-2 infections on major organ systems as well as their contribution toward multiorgan system failure. By analyzing studies and statistics regarding various comorbidities in COVID-19 patients, we make inferences on the linkage between COVID-19, immune injury, multiorgan system damage, and disease progression.
Keywords: COVID-19, SARS-CoV-2, Physiological dysfunction
How to cite this article:
Chang YH, Huang CH, Hsieh PS. Interplay of COVID-19 and physiological dysfunctions. Chin J Physiol 2020;63:245-9 |
| Introduction | |  |
Coronavirus disease 2019 (COVID-19), caused by the recently discovered coronavirus SARS-CoV-2, has been announced by the World Health Organization as an infectious disease pandemic. COVID-19 results in a respiratory infection characterized by mild-to-severe symptoms such as dry cough, fever, and difficulty breathing, which can appear up to about 14 days after exposure to the virus. Besides respiratory infection, COVID-19 patients also suffer from the symptoms and signs of other organ system disorders in areas such as the gastrointestinal, neurological, and cardiovascular systems. This review highlights the underlying mechanism of SARS-CoV-2 on organ system damage, and delineates the effects of the virus on main human organ systems. Through an analysis of the relationship between COVID-19 and major organ systems, we outline the pathophysiology of SARS-CoV-2, particularly the interaction between the virus and the corresponding pro-inflammatory immune injury.[1],[2]
In addition, by stressing that the incidence of hypertension, cardio-cerebrovascular diseases, and diabetes in patients with COVID-19 is about 2–3 folds higher in intensive care unit (ICU)/severe cases than that in non-ICU counterparts, we characterize the role of dysfunctional immune response in disease progression.[3] In this way, it is also implicated that there is a close linkage between the abnormalities of physiological functions and COVID-19. These aspects further emphasize the need for multidisciplinary assessment and treatment as well as a deeper analysis of the interaction between COVID-19 and various major organ systems.
| Effects of Coronavirus Disease 2019 on Main Human Organ Systems | | |
Coronavirus disease 2019 and the respiratory system
COVID-19 largely targets airway epithelial cells, vascular endothelial cells, and macrophages in the lungs, all of which express angiotensin-converting enzyme-2 (ACE2). As shown in [Table 1], by reducing ACE2 expression and function in the lungs, viral infection may correspond to acute respiratory distress syndrome (ARDS) and enhanced inflammation and vascular permeability in lung airways. The functional implications of this peculiar ARDS pathogenesis include a progressive worsening of ventilation/perfusion imbalances and a loss of hypoxic vasoconstriction reflexes, as well as a marked component of microvascular pulmonary thrombosis, as suggested by lactate dehydrogenase and D-dimer elevations.[9] In severe cases of COVID-19, ARDS is largely characterized by difficulty breathing and low blood oxygen levels. As a result, some patients may succumb to secondary bacterial and fungal infections, potentially exacerbating multiorgan system damage.
Coronavirus disease 2019 and the cardiovascular system
SARS-CoV-2 infection is triggered by the binding of the spike S protein of the CoV to ACE2, a membrane-bound aminopeptidase that plays a critical role in the cardiovascular and immune systems and is highly expressed in the heart and lungs.[10] ACE2 is critical to heart function, the development of hypertension, and diabetes mellitus. Host cell infection by SARS-CoV-2 leads to COVID-19-related pneumonia and causes acute myocardial injury and chronic damage to the cardiovascular system, as shown in [Table 1] and [Figure 1], although the specific mechanism of myocardial damage is uncertain. Accordingly, SARS-CoV-2 has recently been reported to infect human induced pluripotent stem cell-derived cardiac cells and further support novel cytopathic features in the hearts of COVID-19 patients.[11] Thereby, patients with underlying cardiovascular disease (CVD) and SARS-CoV-2 infection may have an adverse prognosis. | Figure 1: Impact of coronavirus disease 2019 on organ systems including lung, heart, gut, and nervous system and metabolism.
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Meanwhile, multiple studies suggest that 20%–40% of hospitalized/severe cases involve a form of myocardial injury such as cardiac chest pain, fulminant heart failure, cardiac arrhythmias, and cardiac death.[12] ACE2 has been identified as a functional receptor for three CoVs including HCoV-NL63, SARS-CoV, and SARS-CoV-2; therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19.[13]
| Coronavirus Disease 2019 and Metabolism | | |
Obesity and coronavirus disease 2019
Obesity is a chronic inflammatory disease that is a crucial contributor to the onset of metabolic syndrome and type 2 diabetes mellitus (T2DM). Individuals in obese condition could possess modified innate and adaptive immune responses, making the body more vulnerable to infections and also less responsive to vaccinations.[14]
Obesity-related complications such as T2DM, hypertension, and CVD could also represent an additional risk factor for escalated morbidities and mortality rate of COVID-19 in obesity. Furthermore, for diabetic patients with COVID-19, the following four risk factors could increase the risk of poor outcomes: susceptibility to hyperglycemia, inadequate glycemic control, lack of contact with health-care professionals, and inappropriate discontinuation of an angiotensin receptor blocker or an ACE inhibitor. These detrimental factors could individually or synergistically lead to the worst prognosis in patients with T2DM and COVID-19.[15] However, there is currently limited scientific evidence regarding the pathophysiological mechanisms linking obesity and COVID-19.
| Coronavirus Disease 2019 and the Nervous System | | |
Although CoV is one of the major respiratory viruses, it is also capable of spreading viruses from the respiratory tract to the central nervous system (CNS).
CoV infections have been reported to be associated with neurological manifestations such as febrile seizures, convulsions, change in mental status, encephalomyelitis, and encephalitis.[16],[17] In addition, the neurotropic and neuro-invasive capabilities of CoVs have also been described in humans. These neurotropic and neuro-invasive capabilities not only allow the virus to achieve latency and avoid host immune response but also manifest neurological implications that can complicate the disease associated to its infection, as shown in [Table 1] and [Figure 1]. For instance, CoV through nasal infection could enter the CNS through the olfactory bulb, causing inflammation and demyelination.[16] Moreover, a growing number of COVID-19 patients report a sudden loss of smell or taste. The ACE2 receptor is also widely expressed on the epithelial cells of the mucosa of the oral cavity. Therefore, it is likely that anosmia and dysgeusia might be observed in patients with COVID-19.[18],[19],[20]
| Coronavirus Disease 2019 and the Digestive System | | |
The viral receptor for SARS-CoV-2, ACE2, is also highly expressed in gastrointestinal epithelial cells, such as the absorptive enterocytes of the stomach, small intestine, and colon. While a majority of COVID-19 patients exhibit fever and typical respiratory illness symptoms, some patients also report gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain,[21] as illustrated in [Table 1] and [Figure 1]. In conjunction, studies have identified SARS-CoV-2 RNA in stool specimens of infected patients. Based on an analysis of single-cell co-expression pattern of key proteins in the viral entry process, the digestive system has been speculated to be a potential route for COVID-19.[22] This suggests that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract. Furthermore, this research holds important implications to the disease transmission, management, and infection control of SARS-CoV-2.[23]
| Coronavirus Disease 2019 and Gut Microbiota | | |
Gut microbiota plays a significant role in the human immune system because of its protective, trophic, and metabolic functions. Due to the vital cross-talk between the lungs and gut microbiota, or the bidirectional gut–lung axis, when inflammation occurs in the lung, it can affect the gut microbiota as well.[24] In fact, several studies on the gut–lung axis suggest that respiratory infections are associated with a change in the composition of gut microbiota or gut dysbiosis.[25] Moreover, gut dysbiosis is another critical factor that would potentially increase the risk of developing severe forms of COVID-19 in obese individuals. Obesity is associated with a blunted composition of gut microbiota that results in a decrease or lack of regulation of the immune system and protection from infection. Maintaining homeostasis in gut microbiome, a critical factor of the optimal immune system, would potentially contribute to circumventing an array of excessive, pro-inflammatory immune reactions that would exacerbate multiorgan failure. In this way, gut microbiota is not only a vital component of the immune system but also has a major influence on disease progression such as the magnification of clinical complications such as ARDS or pneumonia in a viral disease like COVID-19.[26] Moreover, gut microbiome has a role in attenuating the damage consequent to infection. In fact, some protocols for the treatment of COVID-19 include the use of probiotics to maintain the balance of intestinal microecology and therefore indirectly strengthen the immune system.[27],[28]
| Mechanisms of SARS-CoV-2 Infections on Organ System Damage | | |
Angiotensin-converting enzyme 2
SARS-CoV-2 enters target cells through the cell surface receptor ACE2, a cardio-cerebral vascular protection factor that exists in a variety of organs. ACE2 is present in nervous and skeletal systems, arterial and venous endothelial cells, arterial smooth muscle cells, the surface of lung epithelial cells, and in enterocytes of the small intestine. As a crucial component of the renin–angiotensin system (RAS), a reduction in ACE2 function due to SARS-CoV infection could result in dysfunction of the RAS, further impacting the regulation of blood pressure and anti-atherosclerosis mechanisms.[29] Moreover, ACE2 protects against organ damage as well as diabetes, hypertension, and CVD. Consequently, as an important target for various CoVs and influenza viruses, the active replication and release of SARS-CoV-2 causes direct cellular damage and release of pro-inflammatory alarmins from dying cells.[30],[31]
Immune injury
In addition to this direct effect, viral particles may elicit innate immune responses of the host through different mechanisms, including the activation of alveolar macrophages and the complement cascade through the lectin pathway. These locally formed immune complexes may contribute to further activating the complement system and boosting the inflammatory response, as suggested by the recent finding of a large number of activated plasma cells in the bronchoalveolar lavage of a patient with severe COVID-19 pneumonia.[32]
The activation of the complement cascade not only directly causes endothelial damage but also recruits leukocytes via C3a and C5a formation, which is responsible for a massive local release of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and IL-8 and interferon-γ.[33] Within this massive host immune response, lymphocytes, resident macrophages, monocytes, and neutrophils exert their potent pro-inflammatory functions, causing additional severe collateral tissue injury, massive vascular endothelial and alveolar epithelial cell damage, and microvascular thrombosis.[34],[35] The progression of endothelial damage with microvascular thrombosis can spread locally in the lung and potentially extend the systemic inflammatory reaction to the microvascular bed of the kidneys, brain, and other vital organs.[36] In this way, the resulting cytokine storm and uncontrolled inflammation would not only inflict multiorgan damage but also influence disease progression and severity. However, although cytokine profiles in the peripheral blood of patients with COVID-19 have been reported, there is still some controversy and uncertainty about the expression levels of cytokines in the progression of COVID-19. For example, IL-1β concentrations were undetectable (<5 pg/mL) in nearly all the patients with either severe or moderate COVID-19.[37] There are no differences of IL-1β, IL-8, and tumor necrosis factor-alpha in COVID-19 patients with different severity of illness.[38]
On the other hand, a systematic review and meta-analysis shows the association of lymphocyte count on admission and the severity of COVID-19. It indicates that lymphopenia on admission was associated with poor outcome in patients with COVID-19.[39] It is suggested that in chronic state of SARS-CoV-2 infection, natural killer cells and T cells might become exhausted, which leads to lymphopenia.[40] Thereby, low level of lymphocytes is positively correlated with the disease severity of COVID-19 patients.
| Others | | |
Neuropilin 1 (NRP1) has been reported to be a potential mediator of SARS-CoV-2 infection. A pathological analysis of human COVID-19 autopsies revealed that SARS-CoV-2-infected cells including olfactory neuronal cells facing the nasal cavity exhibited the positive stain for NRP1.[41] A study presented a detailed in silico analysis of the expression of NRP1 in the human brain, highlighting the potential role of NRP1 as an additional SARS-CoV-2 infection mediator in the CNS via NRP1-expressing cells. It is also implicated that NRP1 may be involved in the pathogenesis of COVID-19-induced neurologic disorders.[42]
| Conclusion | | |
This review has some limitations related to the lack of scientific evidence regarding COVID-19 produced thus far due to the recent onset and rapid spread of the pandemic. However, it presents an accessible summary of the epidemiological evidence and possible pathophysiological mechanisms regarding physiological dysfunction and COVID-19. Further studies of the mechanism and consequences of COVID-19 are necessary, including retrospective studies on a larger sample of the population, autopsy studies, and especially randomized clinical trials. These studies would provide important implications to which individuals are most at risk of becoming infected or developing complications. In addition, a better understanding of the long-term consequences on patients' health as well as the casual mechanisms of which it is possible to intervene with prophylactic and therapeutic measures is imperative to recognize the interplay of COVID-19 and physiological dysfunction.
Acknowledgment
The authors would also like to thank Tia Hsieh for assistance in the preparation of the manuscript.
Financial support and sponsorship
We thank the Ministry of Science and Technology (MOST 109-200327-B-016-002-) for their support.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1]
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