The coronavirus disease 2019 (COVID-19) pandemic has caused a sudden and significant increase in hospitalizations for respiratory syndrome with multiorgan disease. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a large, enveloped, positive-sense single-stranded RNA virus and belongs to the same Coronaviridae family with other viruses like SARS and Middle East respiratory syndrome. The SARS-CoV-2 contains a surface glycoprotein also called spike proteins or S protein that studs the viral envelope and is responsible for the tropism it displays as they bind only with specific receptors on the cell surfaces of target organisms. Such receptors include angiotensin-converting enzyme 2 (ACE2) in the respiratory epithelium and other organs such as the arteries, heart, kidney, and intestines. ACE2 is an enzyme attached to the cell surface of the endothelium and functions to lower blood pressure by catalyzing the conversion of angiotensin II (a vasoconstrictor) into angiotensin 1-7 (a vasodilator). Besides for SARS-CoV-2, ACE2 is also the main entry point into cells for some other coronaviruses, including HCoV-NL63 and SARS-CoV-1. The binding of the spike S1 protein to the ACE2 results in endocytosis and translocation of both the virus and the enzyme into endosomes inside cells. SARS-CoV-2 infection may be asymptomatic in some individual or it may cause a wide spectrum of symptoms, such as mild symptoms of upper respiratory tract infection to life-threatening sepsis.
Coronaviruses are found in humans and other mammals, such as dogs, cats, chicken, cattle, pigs, and birds. Coronaviruses cause respiratory, vascular, heart, kidney, gastrointestinal, and neurological diseases. SARS-CoV-2 is the third coronavirus that has caused severe disease in humans to spread globally in the past 2 decades.1 Through genetic recombination and variation, coronaviruses can adapt to and infect new hosts. Bats are thought to be a natural reservoir for SARS-CoV-2, but it has been suggested that humans became infected with SARS-CoV-2 via an intermediate host, such as the pangolin.2
Incubation
Most viral infections have an incubation period. COVID-19, for example, has a median incubation period of 5 days. During this time, they live in the upper respiratory system, like the nose and throat, before they move further down into the lungs. An infected individual would not experience symptoms but would still be contagious to others. During this incubation period, the virus begins to replicate inside the epithelial cells in the lining of the nose, throat, and larynx. Once the virus moves to the lungs and starts to replicate inside the lung cells, symptoms appear as the immune system starts to react to the viral invasion.
Infection
Once the virus has entered into the lungs and begins its replication in the epithelial cells of the airways, which is usually 2-14 days after the exposure to the SARS-CoV-2 virus, the immune system releases a plethora of inflammatory cytokines and chemokines to initiate and drive the immune response. At this point, the infected individual would have symptoms such as fever, fatigue, dry cough, swollen lymph nodes, and body aches which are similar to flu symptoms.
Immune overdrive can cause a cytokine storm which injures the host cells. The cytokine storm involves high levels of proinflammatory cytokines such as IL-6, IL-10, and tumor necrosis factors (TNF-α) being released as part of a well-conserved innate immune response. IL-6 is a key mediator in the purported cytokine storm. Acute respiratory distress syndrome (ARDS) can occur as a result of the cytokine storm. In severe and very ill cases, the lungs fill with fluid, pus, and cellular debris which prevents the transfer of oxygen to the blood and their system eventually fails.
During the SARS epidemic caused by SARS-CoV-1, the cytokine storm was described to associate with adverse outcomes. In the COVID-19 pandemic, the cytokine storm has also been viewed as one of the common causes of mortality. However, several case studies in COVID-19 has reported that the plasma cytokines levels are elevated above the normal range, but are a lot lower than that in previous cohorts of patients with ARDS. The median IL-6 levels in patients with the hyperinflammatory ARDS are 10- to 200-fold higher than levels in patients with severe COVID-19.5
Postmortem reports of patients with COVID-19 revealed that the unfavorable clinical outcomes in COVID-19 are caused by a severe systemic vascular injury which is not seen in the hyperinflammatory ARDS from influenza. Alveolar capillary microthrombi in patients with COVID-19 were 9 times as prevalent as in patients with influenza. The injury to the microcapillary of the alveoli in the lungs as well as other organs can trigger the blood coagulation process and the microcapillaries become filled with blood clots which block blood circulation.6
Research results have found that such catastrophic microvascular injuries are mediated by intense activation of the complement system. The complement system is an important component of the innate immune system that is crucial for defense from microbial infections and clearance of immune complexes and injured cells. The complement system consists of over 30 different small proteins that circulate in the blood as inactive precursors which can be recruited and brought into action by several triggers. When stimulated by one of several triggers, such as antigen-antibodies complex, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this complement activation is the stimulation of phagocytes to clear foreign and damaged material and activation of the cell-killing membrane attack complex which causes the cell to swell and burst. In normal conditions, complement activation is tightly controlled to avoid injury to autologous tissues. When the complement activation is out of control, it drives a severe inflammatory response causing severe injury in numerous organs.7
In some individuals who are infected by SARS-CoV-2, the activation of the complement system induced by the virus becomes unrestrained which causes inflammation, endothelial cell injuries, thrombus formation, and intravascular coagulation. Microcirculation blockage in the lung can lead to decreased oxygen intake and will have a more serious consequence if they are not being treated promptly at this point.
When the epithelia of the vascular system are severely damaged, it triggers blood clot formation which, along with the cellular debris that falls off from the lining, can block the body’s circulation in other organs. Patients can develop severe circulatory problems such as deep venous thrombosis and thrombotic arterial complications resulting in serious conditions such as limb ischemia with symptoms of severe body pains like being punctured by a needle, ischemic stroke, or myocardial infarction in critically ill patients.4 The development of viral sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, may further contribute to multiorgan failure and death.
The outcome of COVID-19 has a wide spectrum of symptoms ranging from asymptomatic, mild response with symptoms just like the regular flu, to terminally ill. Researchers have tried to identify the cause of the difference and have found that the mild form of COVID-19 have healthy levels of circulating T cells including CD4 and CD8.8 These T cells are SARS-CoV-2-specific and are induced by the viral infection. However, the circulating T cell levels in all severe patients with COVID-19 are lower than healthy volunteers.8
Both T and B cells against SARS-CoV-2 are detected in the blood around one week after the onset of COVID-19 symptoms.9 CD4+ T cells are responsible for initiating immune responses and prime both CD8+ T cells and B cells. CD8+ T cells are the body’s antiviral assassins and are responsible for directly attacking and killing virus-infected cells with more precision than macrophages. Neutralizing antibody responses begin to develop by week 2, and most patients develop neutralizing antibodies by week 3.9 Although potent antibodies to SARS-CoV-2 have been found in people recovered from COVID-19, most people who recovered from COVID-19 had low levels of antibodies in their blood.9 Research has found that T cells have played a crucial role in fighting the SARS-CoV-2. In a research study which examined the T cell counts, T cell exhaustion markers and serum cytokine levels from 522 patients with COVID-19 and 40 healthy controls showed that in COVID-19 patients requiring Intensive Care Unit (ICU) care the number of total T cells, CD4+, and CD8+ T cells were dramatically reduced, while the serum IL-6, IL-10, and TNF-α concentration were significantly increased with a significantly higher levels of the T cell exhausted markers such as PD-1 and Tim-3.10 Total T cell counts were negatively correlated with patient survival.10 Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages.10 While patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts.10
Patients with SARS-CoV mainly use cellular immunity to control the infection. A healthy level of T cells is responsible for a good outcome for the COVID-19 patients while T cell exhaustion and reduced functionality predicted severe disease. Patients who recovered from SARS-CoV infection developed coronavirus-specific memory T cells, which were found up to 2 years after recovery. The researchers also found that a subset of healthy, unexposed people also had some of these T cells that react to the virus, perhaps due to previous exposures to other coronaviruses that cause symptoms of the common cold. So far, a lot of emphases has been put on antibodies. These important findings have raised questions on whether antibodies or T cells are more important for protection from the virus.
Complications
About 1 in 6 individuals will have further complications in the lung, heart, and kidneys. These organs have high amounts of ACE2, the receptor of the SARS-CoV2, that enable the coronavirus to attach to them, invade, replicate, and damage the tissues.11 This is due to the large cytokine storm that occurs as a defense system by the host as well as the blood clot formulation due to the damage of the epithelial cells from hyperactivation of the complement system.11 Large amounts of cytokines in the blood can damage and kill tissues in the lungs, heart, and kidneys.
Acute respiratory failure and acute respiratory distress syndrome (ARDS) can occur in the lungs which triggers severe lung inflammation and causes pneumonia. Blood clots in one of the artery branches can prevent blood from going to certain segments of the lung while the blood clots in the capillary-level vessels can prevent the transfer of oxygen to the blood. In severe and very ill COVID-19 patients, the lungs fill with fluid, pus, and cellular debris and their respiratory system eventually fails.
Most patients recovered completely with some residual cough and shortness of breath. But a certain population has excessive lung damage and some of them end up with fibrosis of the lung. Post-COVID fibrosis is defined as irreversible lung damage and can result in severe functional limitations with symptoms such as cough, shortness of breath, and need for oxygen. The cause of post-COVID fibrosis is severe lung inflammation caused by the viral infection.
Studies have found that some individuals develop acute cardiac injury following infection of COVID-19. Though a good portion of these patients already had underlying health issues involving the heart, like heart disease or high blood pressure, many otherwise healthy patients have also developed heart problems, including blood vessel injuries, blood clots, arrhythmia, strokes, and heart attacks.
Although the exact cause is not known yet, a few factors include the widespread inflammation the infection causes, the possibility that the virus directly infects and injures the cardiovascular system, and the overall stress the infection puts on preexisting heart conditions. On top of those potential factors, the large cytokine storm can directly damage the heart and cause myocarditis with heart muscle cell necrosis.
Some people suffering from severe cases of COVID-19 are showing signs of kidney damage, even those who had no underlying kidney problems before they were infected with the coronavirus. Early reports say that up to 30% of patients hospitalized with COVID-19 in China and New York developed moderate or severe kidney injury. Reports from doctors in New York are saying the percentage could be higher. Signs of kidney problems in patients with COVID-19 include high levels of protein in the urine and abnormal blood work. The tiny clots can clog the smallest blood vessels in the kidney and impair its function. In research that followed 701 COVID-19 patients that were hospitalized, 44% had proteinuria, and about 27% had hematuria on admission. After adjustment for age, sex, disease severity, and leukocyte count, patients with elevated baseline serum creatinine or elevated baseline proteinuria had a 2- and 5-fold higher risk of in-hospital death, respectively, than COVID-19 patients with normal kidney parameters.
In summary, the unfavorable clinical outcome in some individuals with SARS-CoV2 infections are caused by multiple factors which include a cytokine storm that causes ARDS, unstrained complement activation which causes epithelial damage and blood clot formation, and low circulating T cell levels which renders a decreased immunity to the viral infection.
