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The graphical abstract from Li et al. 2020, showing general features of SARS-CoV-2, current knowledge of molecular immune pathogenesis, and diagnosis methods of COVID-19 based on present understanding of SARS-CoV and MERS-CoV viral infections

COVID-19 has presented numerous societal challenges, from supply line interruptions and economic sagging to overwhelmed healthcare systems and civil disorder. However, these are largely the social, economic, and political ripple effects of a disease that has brought with it a set of inherent attributes that make it more difficult to manage in human populations than say the flu.

However, COVID-19 is not the flu, and it is indeed worse in its effects than the flu, contrary to many people's perceptions. Yes, COVID-19 and the flu have some symptom overlap. Yes, COVID-19 and the flu have some transmission type overlap. But from there it diverges. COVID-19 and SARS-CoV-2 is different in that it is more prone to be transmitted to others during the presymptomatic phase. And the body of evidence has grown since early on in the pandemic that SARS-CoV-2 is transmittable predominately via an airborne route, though transmission from contaminated surfaced or physical intimacy are also believed possible. Hospitalization rates are higher, perhaps up to 10 times higher than the flu, and hospital stays are longer with COVID-19. People are dying more often from COVID-19 too, up to 10 times more often than people stricken with the flu. And while flu vaccines are largely the norm around the world, and COVID-19 vaccines are gradually becoming more available, those who willing choose to not get the vaccine have a massively higher chance of dying from COVID-19 (as of August 2021, more than 99 percent of all deaths from COVID-19 are found with the unvaccinated, compared to some 80% of children who die from the flu while unvaccinated).

Other aspects of the disease that make it difficult to manage include:

• Median incubation period: According to research published in Annals of Internal Medicine, the median (i.e., the central tendency, which is less skewed than average) incubation period is 5.1 days (Note that as new variants arrive, incubation times my change; the delta variant is thought to have an incubation period of four days, for example.), with 97.5% of symptomatic carriers showing symptoms within 11.5 days. The authors found this to be compatible with U.S. government recommendations of monitored 14-day self-quarantines if individuals were at risk of exposure. However, many people continue to not take mask-wearing—and vaccination—seriously, and thus unmasked presymptomatic (and asymptomatic) carriers are thus largely more prone to spreading the virus. This has become even more precarious with the highly contagious delta variant, which can be spread even by the vaccinated, highlighting that "measures such as masks and hand hygiene which can reduce transmission are important for everyone, regardless of vaccination status."

• Presymptomatic and asymptomatic virus shedding: As mentioned in the previous point, carriers can be contagious during the presymptomatic phase of the disease, even while remaining symptom-free. (The latest comprehensive research, from August 2021, appears to indicate that 35.1 percent of infected people may go without any recognizable symptoms after infection occurs.) This contagion is a result of what's called viral shedding, when the virus moves from cell to cell following successful reproduction. When the virus is in this state, it can be actively found in a carrier's body fluids, excrement, and other sources. Depending on the virus, the virus can then be introduced to another person via those sources. In the case of COVID-19, the core route of transmission appears to be through the air via aerosolized and other forms of water droplets, though saliva and other bodily constituents pose a transmission hazard due to shedding (see previous bulletpoint). Early in the pandemic, uncertainty about transmission routes of viral shedding, along with mixed messages early on about masks and their effectiveness for COVID-19, caused problems. Today we know that masks and social distancing—when appropriate—are an even stronger necessity to limit community transmission of the disease from presymptomatic and asymptomatic individuals, even for those who are vaccinated.

• Understanding of high viral loads and infectious doses: Respiratory diseases such as influenza, SARS, and MERS see a correlation between the infectious dose amount and the severity of disease symptoms, meaning the higher the infectious dose, the worse the symptoms. Similarly, viral load—a quantification of viral genomic fragments—also tends to correlate with clinical symptoms. However, even with the breakthroughs in COVID research since the start of the pandemic, we are still in the investigative stages of definitively determining if that similarly holds true to COVID-19. Research early on indicated, for example, there is little difference between the viral load of those with mild or no COVID-19 symptoms and those with more severe symptoms. However, Pujadas et al. suggested a link between high viral load and overall mortality rate. Research later in 2020 has suggested more of a positive correlation between severity of symptoms and viral load, as has a July 2021 study published in Science. However, more research must be performed to better understand how the viral load infectious dose plays a role in transmission. Given the continued unknowns in this realm, wearing masks and getting vaccinate help minimize exposure and remain the best defense against the worst outcomes of the disease.

• Cardiovascular issues: Coronaviruses and their accompanying respiratory infections are known to complicate issues of the cardiovascular system, which in turn may "increase the incidence and severity" of infectious diseases such as SARS and COVID-19. While the exact cardiac effect COVID-19 has on patients is still unknown, suspicion is those with "hypertension, diabetes, and diagnosed cardiovascular disease" may be more prone to having cardiovascular complications from the disease. Current thinking is SARS-CoV-2 either attacks heart tissues, causing myocardial dysfunction, or inevitably causes heart failure through a "cytokine storm,", an overproduction of signaling molecules that promote inflammation by white blood cells (leukocytes). What's scary is that like the 1918 Spanish flu, SARS, and other epidemics, some otherwise healthy patients' immune responses are entirely overreactive, leading to acute respiratory distress syndrome (ARDS) or heart failure. Additionally, as the disease has progressed, medical professionals have noted two additional cardiovascular issues. First, an atypical amount of blood clotting has shown up in some infected patients, which may be related to overreactive immune systems, autoantibodies, and underlying health conditions. Second, what is being called pediatric multisystem inflammatory syndrome (PMIS) or multisystem inflammatory syndrome in children (MIS-C) has shown up in children after the infection has passed, characterized by inflamed blood vessels and toxic shock syndrome. While research is ongoing to determine whether these seemingly hyperactive cardiovascular responses are directly linked to the virus or if virus-independent immunopathology is responsible, these uncertainties only emphasize the level of difficulty of properly treating COVID-19.

• Other systemic and bodily issues: As the pandemic has progressed, researchers have discovered SARS-CoV-2 appears to negatively impact other organs and systems in the human body, including the renal system, digestive system, endocrine system, neurological system, and even the reproductive system. Another bodily issue that appears to remain for a subset of post-recovery COVID-19 patients is fatigue. The University of Minnesota's Center for Infectious Disease Research and Policy reports on an observational study published in PLOS One' that showed more than half of people who recovered from their COVID-19 infection still dealt with the lingering effects of fatigue at a median of 10 weeks after recovery. The study reports no link between the persistent fatigue and severity of symptoms, need for hospitalization, concentration of laboratory biomarkers, and age. These systemic and body issues have added further complication to an already complicated disease, making extended treatment planning difficult. The long-term affects of these and other organ system injuries remains to be fully understood.

• Mental health concerns: The mental health toll of the pandemic is becoming increasingly apparent as it wears on. A June 2020 CDC survey of 5,412 U.S. adults (regardless of infection status) "found that 40.9% of respondents reported 'at least one adverse mental or behavioral health condition,' including depression, anxiety, posttraumatic stress, and substance abuse, with rates that were three to four times the rates one year earlier." More than 10 percent of respondents also indicated they had seriously considered suicide in a time period thirty days prior to responding. From an inability to grieve communally with loved ones, to income loss, increased anxiety, and long periods of social isolation, these increasing numbers are not surprising, particularly in light of research on previous pandemics. Without proper treatment, these conditions may worsen into prolonged grief disorder, only exasperating a growing mental health crisis. Further, at least one study suggests that those who contract COVID-19 may be at a greater risk of developing some sort of mental illness within 90 days, including anxiety, depression, and insomnia. This effect may be worse for those who already have a history of mental health illness. Mitigating the effects of these mental health concerns will require further study, greater funding, expanded screening, and improved focus on community methods of dealing with tragedy and loss.