Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly became a worldwide pandemic in 2020, leading to widespread illness and death. As the understanding of the disease and its impact evolves, and as the disease proceeds to endemicity, it is crucial to review and summarize the current knowledge of clinical features, symptoms, risk factors, epidemiology, treatments, vaccines, and prevention strategies. This review provides a comprehensive clinical overview of the current understanding of COVID-19.

Whereas the clinical nature of the COVID-19 pandemic has evolved greatly following the roll-out of vaccines, updated vaccine boosters, and emergence and dominance of Omicron variants to a less morbid condition for many with dramatically lower hospital rates and virus-related deaths, moderate and severe acute disease is still observed with a mortality greater than influenza and other respiratory illnesses. The National Institutes of Health (NIH) classify five stages of COVID-19 based on severity (Figure 1) (1). These are asymptomatic or presymptomatic, mild, moderate, severe, and critical illnesses. The first stage, asymptomatic or presymptomatic, is when persons test positive for SARS-CoV-2 by a nucleic acid amplification test or antigen test but do not display clinical symptoms (1, 2). The mild illness stage is those patients without dyspnea or lower respiratory radiological findings but with other symptoms such as fever, cough, pharyngitis, malaise, cephalgia, nausea, or emesis. Those in the classification of moderate illness are persons with clinical symptoms, radiological findings of disease in the lower respiratory tract, and oxygen saturation > 94%. The severe illness stage is those with tachypnea at a respiratory frequency > 30 breaths/min, or lung infiltrates >50%, oxygen saturation < 94%, and partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <300 mmHg. Critical illness is the most severe stage and includes patients who develop acute respiratory distress syndrome (ARDS) or display acute respiratory failure with septic shock or multiple organ dysfunction (1, 2). ARDS is a form of respiratory failure that requires clinical and radiological findings. ARDS progression is evaluated by decreasing PaO2/FiO2 levels from mild (200–300 mmHg) to moderate (100–200 mmHg) to severe (<100 mmHg).

ARDS (Figure 2A) is the hallmark of COVID-19 and accompanies a histological pattern known as diffuse alveolar damage (DAD). DAD includes edema, death of pneumocytes, thrombosis, capillary congestion, and hyaline membrane formation. The dead and dying pneumocytes will release cytokines and chemokines to recruit immune cells and cause inflammation (Figure 2B). Ultimately, the inflammatory response will damage microvascular endothelial cells, further causing leaky vessels. Hyaline membrane formation diminishes oxygen exchange, resulting from coagulation dysregulation and fibrotic signaling. Also, hyaline membranes will result in fibrin thrombi, depleting platelets and generating clots. Clotting further increases inflammation and is exacerbated by interleukin (IL)-6 production. The death of the lung epithelium and endothelium will result from viral replication, coagulation, and hypoxia and is the underlying pathology of pneumonia in SARS-CoV-2 infection (3, 4).

Symptomatic clinical presentations include dyspnea, fever, cough, pharyngitis, nausea, anorexia, anosmia, dysgeusia, cephalgia, malaise, myalgia, and diarrhea. Dyspnea, fever, and cough are the most common presentations in 70% of cases, followed by myalgia (36%) and cephalgia (34%) (2). SARS-CoV-2 infection, especially with pre-Omicron variants, can target the brain, eyes, nose, lungs, vasculature, liver, kidneys, and intestines. Approximately 23% of persons infected with SARS-CoV-2 will progress to severe COVID-19, with 5.6% of infected persons dying pre-Omicron and before widespread vaccination (5). Progression to more severe disease has become rare with the Omicron variants in those without risk factors. Symptoms relating to the gastrointestinal system, such as nausea and emesis, are associated with severe COVID-19 with pre-Omicron strains, as are symptoms of the respiratory system, such as angina and dyspnea (5). Finally, end-organ failure and pneumonia are associated with mortality (5).

Moving on to risk factors, risk factors for COVID-19 can be classified into environmental, viral, and host. Environmental factors include human crowding, occupational exposure, poor ventilation, and animal contact. On the other hand, viral risk factors are associated with the rapid evolution of SARS-CoV-2 throughout the pandemic and include transmissibility, evasive mutations, and viral loads associated with a particular variant (6).

Shifting our focus to host risk factors, most of which were identified prior to most persons experiencing vaccination or at least one infection, the primary host risk factors for COVID-19 in non-vaccinated individuals are old age, male sex, racial and ethnic minorities, diabetes mellitus, immunocompromised state, obesity, hypertension, lung disease, cardiovascular disease, cancer, pregnancy. For instance, advanced age is associated with COVID-19, intensive care unit (ICU) admission and mortality (6–11). This can be explained by the fact that age is associated with more comorbidities, weaker immune response, and septic shock complications that correlate with mortality (9, 12, 13). Moreover, males are more likely to acquire, be admitted to the ICU, and die from COVID-19 than females (5, 6, 8, 9). The underlying reasons for this sex difference include estrogen’s effect on solubilizing ACE2, levels of ACE2 and TMPRSS2, hormonal differences in the inflammatory response, health behaviors, personal concerns, social alarm, and responsible attitudes (6, 8, 9, 14, 15). Racial and ethnic minorities are also at higher risk for COVID-19 hospitalization and death. The reasons for this may include barriers to healthcare access, transportation, lack of insurance, and hesitancy about COVID-19 treatments (16). Other risk factors include diabetes mellitus, a known inflammatory disease shown to have immune system consequences (17). People with diabetes mellitus are at a higher risk for COVID-19, are less responsive to treatments, are more frequently admitted to the ICU, and are at higher risk of mortality (5–10, 13). An independent risk for people with diabetes mellitus is poorly controlled and elevated glucose (13, 18). Elevated glucose levels are also associated with increased ACE2 expression (9, 17, 18) and higher viral titers (19), as SARS-CoV-2 hijacks host cell metabolism (20, 21). Additionally, cardiovascular disease is a risk factor for COVID-19 due to the expression of ACE2 on cardiac myocytes and vascular fibroblasts (6, 7). Statin and aspirin use in diabetes and cardiovascular disease should be continued in those already taking them. Still, it should not otherwise be initiated during COVID-19 (22). Furthermore, immunodeficiency or immunosuppression increases the risk of severe disease and mortality in COVID-19 (23). Next, obesity in persons under 50 years of age increases the risk of hospitalization with COVID-19. Notably, obesity lengthened the stay of COVID-19 patients in hospitals (7, 9). As for hypertension, it causes a higher risk of acquiring COVID-19 and dying from the disease. Hypertension is related to the renin-angiotensin-aldosterone axis regulating blood pressure, (9, 24, 25), and a component of that axis is ACE2, the protein that SARS-CoV-2 binds to for entry. As many with hypertension take medications that decrease blood pressure, they will also be increasing ACE2 expression (6). However, the increase in mortality of hypertensives is related to the condition itself, and antihypertensives reduce the mortality in COVID-19 in those already on antihypertensive; thus, those on ACE inhibitors are often advised to continue to use them (22, 26). Lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and pulmonary embolism are also risk factors for COVID-19 (9). Malignancy increases the risk of COVID-19, as it is associated with a weakened immune response, particularly when associated with chemotherapy (6). Pregnant women are more susceptible to COVID-19 infection than are non-pregnant women (9). Lastly, other host risk factors include malnutrition, autoimmunity, neurological disease, chronic kidney disease, smoking, and liver disease (6, 9–11).

The SARS-CoV-2 virus first emerged in Wuhan, Hubei Province, China, on December 12, 2019 (27, 28). Upon its emergence, the Hubei Provincial Hospital notified the Chinese public health authorities that many unexplained pneumonia cases emerged from the Huanan market (29). Subsequently, the first report to the World Health Organization (WHO) of the outbreak of SARS-CoV-2 (then known as 2019-nCoV) was on December 31, 2019 (29–31). In a matter of weeks, by January 18, 2020, 2019-nCoV had spread to the United States, with the first reported case in Washington State (31, 32). Rapidly escalating, by February 12, 2020, more than 44,730 cases had been reported in China (28). Recognizing the severity, on March 11, 2020, the WHO declared the COVID-19 pandemic (30, 31, 33), and the White House announced on March 31, 2020, that 100,000–240,000 U.S. deaths were expected (31, 34). The Centers for Disease Control and Prevention (CDC) recommended facial masking guidelines in early April to curb the spread (31). In a further effort to contain the virus, 43 states of the United States had issued stay-at-home orders by April 24, 2020 (35). Despite these and other efforts, by November 30, 2020, SARS-CoV-2 had spread worldwide, infecting more than 62 million persons. Although vaccines gave hope to an end to the pandemic in early 2021, tragically, by early November 2021, there were more than 250 million confirmed cases and 5 million deaths worldwide. As of August 2024, that number had grown to 775 million cases and 7 million deaths worldwide, with over 103 million cases and 1.2 million deaths in the US (36, 37).

The natural history of COVID-19 (Figures 3A–C), determined pre-Omicron, begins with exposure to SARS-CoV-2 (38–42). Upon exposure, the mean incubation period—the point of exposure to the onset of clinical signs—is between 5.8 and 6.9 days, ranging from 2.33 to 17.6 days. The range may vary due to age and infectious dose, and Omicron and other evolving strains will alter these metrics (38, 41, 43). As the infection develops, the latent period for SARS-CoV-2, the time between infection and infectiousness, is between 5.5 and 6.0 days (41, 44). Infectiousness and transmission start before symptom onset and peak at symptom onset (39). The intrinsic generation time—the interval between the infection dates of an infector and its secondary cases in a fully susceptible population—averages 6.84 days for the Omicron variant (45). The serial interval—the time between the onset of symptoms between successive cases—is between 4.8 to 6.8 days, with a mean of 5.8 days. During the infection, viral RNA load peaks near symptom onset or an average of 2 to 4 days post-infection and then gradually wanes, with infectiousness averaging 9.8 days post-symptom onset (38, 42). Interestingly, this waning corresponds with the approximate limit of detection of SARS-CoV-2 by viral RNA of 21 days (39). Immunocompromised persons, however, shed for much longer, with one study showing shedding for 151 days post-initial infection, during which time the virus evolved intra-host (46). IgG and IgM seroconversion occurs ~13 days following symptom onset (47). Some patients who cannot limit the infection to a mild illness will progress to severe disease. Severe disease can progressively be classified into the pulmonary phase and hyperinflammatory phase. The pulmonary phase of the disease happens an average of 5 days after symptom onset and is characterized by pneumonia and lung infiltrates (42). Unfortunately, some will further progress to the hyperinflammatory phase, characterized by ARDS discussed above (42). Ultimately, hospital discharge or death occurs at a mean of 18.1 days (15.1–21) from symptom onset (40). Tissue seeding is a concept that has come to light with the advent of Long COVID (48, 49). Tissue seeding likely begins during the initial viral infection and can be detected in organs throughout the body for weeks to years (49, 50). Major gaps in our knowledge of tissue seeding are currently being addressed. The viruses’ continued evolution and widespread vaccination will likely continue to alter these epidemiological characteristics.

The interventions in this pandemic are continuously evolving and involve vaccines and treatments, including small-molecule drugs, convalescent plasma, and monoclonal antibodies (summarized in Table 1 and Figure 2) (51, 52). As of 2024, the three recommended treatments for non-hospitalized COVID-19 in the United States are ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir, and molnupiravir (53, 54). In contrast, for patients requiring hospitalization, nine treatments are presently in use depending on disease severity and therapeutic indications: remdesivir, dexamethasone, baricitinib, heparin, tofacitinib, tocilizumab, sarilumab, infliximab, and abatacept (54, 55). The European Medicines Agency refused marketing authorization for molnupiravir due to a lack of clinical benefit (56, 57). This decision followed the PANORAMIC study, which showed that molnupiravir did not reduce hospitalizations and death in a vaccinated population of high-risk adults during the omicron variant time period—and may contribute to further viral evolution (58).

SARS-CoV-2 is transmitted by asymptomatic, pre-symptomatic, and symptomatically infected individuals (148). The transmission of SARS-CoV-2 proceeds from susceptible individuals to exposed individuals; exposed individuals can either remain asymptomatic and recover or become presymptomatic and infected. The infection then results in either recovery or mortality (Figure 5A) (148). Pre-symptomatic persons transmit 40–60% of new infections, and asymptomatic persons transmit <10% (148). This presymptomatic transmission is demonstrated by the median time between infection and symptom onset being 5.7–7 days (43, 94, 149). Furthermore, between 17.9 and 33.3% of patients infected with SARS-CoV-2 will remain asymptomatic (2). Otherwise, high transmission occurs ~2.5 days before symptom onset (148), which means that people who have not sought medical care or a diagnostic test can still transmit the virus. So much so that even vaccinated persons can shed and transmit the virus, which has been particularly prevalent with variants (113, 150–153). SARS-CoV-2 has a variable reproductive number (R0) from 0.52–5.08 that changes with new variant strains (154–156). The secondary attack rate was 16.6% in late 2020 but escalated to 19.4% with the Delta VOC and 25.1% with the Omicron VOC (157, 158). The case fatality rate began at 3.71% in March 2020 but decreased to 1.13% by July 2022 and is higher in areas with a low vaccination rate (155, 159).

Containment strategies were also implemented, including government-issued stay-at-home orders and travel restrictions. The pandemic defense was centered around overlapping responses that generate multiple layers of protection—known as the Swiss cheese model (Figure 5B) (160). This comprehensive model relies upon personal and communal measures to prevent the spread and transmission of the virus. Individual defense measures include physical distancing, staying at home, hygiene, etiquette, mask-wearing, contact avoidance, and limiting time in crowds. In parallel, communal measures include rapid testing, tracing, air filtration, government messaging, financial assistance, mandatory quarantining, and vaccines. Together, these responses served as the pandemic defense and public policy response for nearly two and a half years until the CDC lifted restrictions on masks in early 2022 (161).

The rapid spread of COVID-19 worldwide has vastly changed hospitals and treatments since the pandemic began in late 2019. This dynamic included many drugs and treatments once in use that have since been revoked due to ineffectiveness and a fluid dynamic facilitated by the evolving variants of SARS-CoV-2. This review aims to provide a complete summary of the present status of COVID-19. This collection signifies historical and present status in a constantly changing and active field.

The subjects covered herein must be continually reassessed and reflected upon as further evidence emerges globally. Reassessing and reflecting on these topics can improve pandemic response plans, refine treatment plans, and develop a more robust vaccine policy. To maintain the highest level of care, current treatments need to be monitored for maintained effectiveness, and treatment successes of other countries should be explored. To exemplify this, understanding how patients react during hospitalization can point to the success of hypnotics as used in China (12). By evaluating the current pandemic response plans, we can allow for response implementation sooner in future COVID-19 waves or other pandemics. Such a response will include masking, distancing, stay-at-home orders, and other components of the Swiss-cheese model. To develop a more robust vaccine policy and design future SARS-CoV-2 vaccines, we must continually monitor the viral evolution and incorporate the viral changes into our vaccines to maintain effectiveness and identify the correlates of protection necessary for an appropriate and long-lasting response. This vaccine evaluation should include evaluating multiple SARS-CoV-2 proteins in the vaccines and adjuvants that can produce the response needed for long-term protection and identifying algorithms for determining the emergence of variants such as flu vaccines (97). The persistent evaluation of these aspects facilitates optimal control and preparedness for COVID-19 and other potential pandemics.