As noted in the previous chapter (Chapter 2: Transmission of SARS-CoV-2), SARS-CoV-2 is transmitted through respiratory particles and the virus is believed to first infect the epithelium of the respiratory
tract. Larger particles laden with the virus (droplets) infect the upper respiratory tract, while smaller particles laden with the virus (aerosols) can infect the lower respiratory tract. Moreover, the virus can also infect the epithelium of the intestines.¹

COVID-19 develops following SARS-CoV-2 infection. The median incubation period for COVID-19 is estimated to be 5.1 days and 97.5% of individuals who develop symptoms do so within 11.5 days of infection.² For individuals infected with the Delta variant, the median incubation period is estimated to be only 4 days, as the virus is believed to replicate far more rapidly than ancestral strains.³ The Chinese Center for Disease Control and Prevention examined 44,500 confirmed infections and found that 81% of individuals experienced mild or asymptomatic cases, 14% of individuals developed severe disease, 5% of patients became critical, and 2.3% of all cases resulted in a fatality.⁴ All fatalities in this study occurred in critical cases.

Since that study’s publication, fatality rates have dropped considerably as health care workers have learned how to better treat COVID-19. A retrospective study that relied on a national surveillance database in England and included approximately 21,000 critical care patients with COVID-19 found that survival rates in intensive care units improved from 58% in late March 2020 to 80% by June 2020.⁵ As of this writing, the fatality rate is believed to be in the vicinity of 0.9% to 1.0%.⁶

As discussed in Chapter 1 (particularly Viruses), SARS-CoV-2 attaches to angiotensin-converting enzyme 2 (ACE2) receptors with its spike protein once it has been primed and cleaved by transmembrane protease serine (TMPRSS) and/or furin, which is a ubiquitous membrane protein.⁷ Both ACE2 receptors and TMPRSS are coexpressed in the epithelia of the respiratory tract and alveolar cells, GI tract, and many other locations throughout the body, including major organs like the heart and kidneys.⁸ Infection of the GI tract can lead to symptoms of GI pain, nausea, diarrhea, and vomiting, while infection in the respiratory tract give rise to symptoms such as congestion, sore throat, and cough. ACE2 receptors are also expressed in the olfactory neuroepithelium, the infection of which may result in abnormalities in sense of smell and taste without nasal inflammation.⁹ There is also evidence to suggest that SARS-CoV-2 can bind to neuropilin-1 (NRP1) receptors, which are also expressed in olfactory neuroepithelium and olfactory neurons, as well as in lung tissue, and may increase SARS-CoV-2 infectivity.¹⁰ Several variants, particularly the Delta variant, have mutated in such a way that allows them to more easily invade host cells and bind to ACE2 receptors.¹¹

In mild infections (approximately 81% of all cases), patients experience either no symptoms or symptoms comparable to mild cases of the flu. In the vast majority of mild cases, particularly in younger individuals, symptoms can be managed and treated without the need for hospitalization. Symptoms include taste and smell disturbances, malaise, myalgia, headache, dry cough, and fever. Symptoms may also include enteric symptoms like diarrhea, abdominal pain, nausea, and vomiting. Most patients recover within one to 2 weeks, though some may develop post-acute sequelae of SARS-CoV-2 (PASC), which is more popularly known as long COVID (see Chapter 4: Neuropsychiatric Symptoms and Postacute Sequelae of SARS-CoV-2—The Long Haulers).

In approximately 19% of cases, the infection spreads deeper into the lower respiratory tract, affecting bilateral lobes of the lung and causing pneumonia, which typically occurs over the course of about 10 days.¹² More importantly, the histopathologic findings have determined the predominant lung pathology to be diffuse alveolar damage (DAD) characterized by hyaline membrane formation.¹³ These phenomena are known as ground-glass opacities, since the infected areas of the lungs may look hazy or shadowy when seen on a computed tomography (CT) scan (see Figure 3.1).

As the infection spreads and the pneumonia becomes more severe, the resultant lung parenchymal damage and pulmonary fibrosis, patients may experience decreased oxygen saturation and low blood oxygen levels (hypoxia). In rare cases, some patients’ oxygen levels may fall dangerously low even if they do not feel particularly ill (a condition is known as silent hypoxia), though most patients experience shortness of breath (dyspnea) when in a hypoxic state. Silent hypoxia has been described as especially dangerous for patients because their condition may deteriorate significantly before seeking medical care and lead to poor prognosis.¹⁴ Patients who are experiencing hypoxia and pneumonia may need supplemental oxygen or even require ventilator support. It is worth noting that hypoxia is associated with blood clot risk and is one of several factors contributing to the increased risk of ischemic stroke in COVID-19 patients, even in those who are otherwise healthy.¹⁵ An overactive cytokine response is yet another factor that can contribute to coagulopathy and other complications. It has also been theorized that a persistent enteric infection may worsen viremia and further exacerbate cytokine response.¹⁶

In 5% of cases, aberrant host immune response results in a surge of proinflammatory cytokines, thereby leading to severe complications, particularly pulmonary edema and ARDS, which may result in respiratory failure and death.¹⁷ Patients with severe and critical COVID-19 symptoms have tested positive for elevated levels of myriad cytokines (see Table 3.1), and elevated cytokine levels can also sometimes cause mucus hypersecretion, thereby leading to the formation of mucus plugs. As the name suggests, these plug up airways and make it difficult for patients to breathe.⁸

Damage caused by the inflammatory response is not restricted to the lungs. In severe cases, the acute inflammatory response ultimately affects other organs and can lead to MODS, sepsis, and death.¹⁹ A combination of hypoxia, cytokine storm, and infection of heart tissue (ACE2 is highly expressed in cardiomyocytes) may lead to myocardial injury, which appears to be associated with a worse prognosis, especially in those with preexisting heart conditions.¹⁹ Cardiac injury via myocyte necrosis, predominantly in the left ventricle, has also been reported.²⁰

Acute kidney injury (AKI) (also known as acute renal failure [ARF]) occurs in up to half of those hospitalized with COVID-19 and is even more common among those who are admitted to intensive care units.²¹ COVID-19 patients with kidney injury are reportedly five times more likely to suffer in-hospital mortality when compared with patients without AKI.¹⁹ While renal failure has not been publicized as a major feature of SARS-CoV-2, the risk of severe kidney damage is well documented in other coronaviruses, particularly Middle Eastern respiratory syndrome (MERS).²² Of note,
ACE2 receptors are expressed in kidney tissue and may suffer direct damage from infection, though computed tomography have also found renal abnormalities suggestive of inflammation and edema, but so far the exact mechanism remains unclear.²³ As a result of the kidney failure, some patients may require routine dialysis even after the initial infection has passed.¹⁹

Severity of infection has been associated with liver damage and increased levels of liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). Temporary liver damage has been reported in even mild infections and patients with preexisting liver comorbidities may have a heightened risk of complications. ACE2 receptors
are also expressed in liver tissue suggesting that direct infection may be responsible for damage, though it is also possible that a combination of hypoxia and inflammatory responses may play a role in COVID-19-induced liver injury.²⁴

As noted above, COVID-19 can trigger abnormal coagulation leading to microthrombi in tissues and cause ischemia.¹⁸ Elevated levels of D-dimer, a breakdown product of fibrin, have been frequently reported in severe and critical cases, while D-dimer levels remain relatively static in individuals who experience mild symptoms. Consequently, D-dimer has been proposed as a biomarker to evaluate the prognosis of patients.²⁵ Prolonged prothrombin time has also been reported in severe cases of COVID-19 and may serve as a biomarker, as well.²⁶

D-dimer levels may remain elevated for months following initial infection. This phenomenon is believed to be more common in patients who required hospital admission and are older than 50 years, but a small study found that 4 months after initial infection 29% of patients with elevated D-dimer levels had managed symptoms without the need for hospitalization. Of note, other coagulation and inflammation markers had largely returned to normal levels in convalescent patients, which suggests that symptoms of long COVID may be associated with pulmonary microvascular immunothrombosis.²⁷

It is difficult to provide accurate estimates for the symptomology of COVID-19. Many individuals may only develop minor symptoms and assume that they are not infected with the novel coronavirus. Similarly, many people who believe that they are infected with COVID-19 may only seek medical help if their symptoms become severe enough for them to realize that they may have more than just the flu. Consequently, the rate of occurrence of individual symptoms may be skewed. Estimates about the frequency of symptoms that are common among individuals with mild infections and uncommon among those with more severe infections may be far too low. Conversely, estimates about the frequency of symptoms that are common among individuals with severe infections and uncommon among those with less severe infections may be far too high. From an epidemiological perspective this is an important point, but unfortunately, there is no remedy for this issue at the present time.

That said, the symptoms of COVID-19 that are most frequently reported include fever, dry cough, dyspnea, fatigue, sore throat, congestion, and myalgia (see Table 3.2).¹⁷ What has been surprising
and one of the many reasons why COVID-19 is considered to be such a diagnostic chameleon is that no single sign or symptom has been universally reported across all positive cases at presentation or even during hospitalization. A report of over 370,000 confirmed COVID-19 cases compiled by the US Centers for Disease Control and Prevention (CDC) found that only 50% of patients reported a cough and that 43% had a fever.²⁸ The reported percentages of other symptoms were even lower:

Meta-analyses from multiple countries have met with similar issues. A systematic review of 24,410 adults across nine countries found that fever was reported by 78% of patients, 57% experienced a cough, and that 31% reported fatigue.²⁹ Meanwhile, a global meta-analysis involving 67 studies and 8302 patients found that the most common symptoms were:

To reiterate the point made at the beginning of this section, disparities in datasets makes it extremely difficult to access accurate estimates of symptomology for COVID-19.

Another curious phenomenon, one that has been observed since the first months of the pandemic, is that different symptoms appear with greater frequency in different populations. For example, in early 2020, rates of olfactory dysfunction ranged from 5.14% to 98.33% depending on the study and were found to be much more common in North America and Europe than in East Asia.³¹ It is unclear if this was due to oversight while recording patient symptoms at the earlier stages of the outbreak or if there was another reason as to why these symptoms were so infrequently reported—it could possibly be due to genetic or environmental factors. Similarly, enteric symptoms appear to have been less common during the initial outbreak than they were after the virus spread to other parts of the world. A meta-analysis involving 4243 patients from six countries found that prevalence of GI symptoms was 16.2% in studies that were based in Hubei and 18.6% for all studies from outside of the province.³² Once again the reasons are unclear.

It is also possible that certain symptom constellations may be more common in some variants than others. For example, some medical workers have observed that patients who have been infected with the Delta variant tend to report symptoms that have more in common with a bout of severe flu—headache, sore throat, runny nose, fever—and seem to less frequently report symptoms associated with ancestral strains of the virus, such as anosmia, gustatory dysfunction, cough, etc.³³ At present, this should be considered anecdotal until a peer-reviewed study has examined disparities in symptoms between variants.