At the end of 2019, China reported a global outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was temporarily named 2019-nCoV. It is part of the coronavirus family, which includes common viruses like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The virus rapidly spread throughout China, followed by a global pandemic, and was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. COVID-19 spreads quickly through droplets and aerosols that deposit virus into the upper respiratory tract, lungs, and respiratory system.
Most infected individuals with the virus experience mild-to-moderate respiratory illness and recover without special treatment. However, some require intensive medical care. Individuals over the age of 65 years and those with underlying medical conditions like cardiovascular disease, diabetes, chronic respiratory diseases, or cancer are more likely to develop severe symptoms. To curb the pandemic, countries implemented nonpharmaceutical measures such as masking, physical distancing, lockdowns, and travel restrictions. However, these measures adversely affected the health and well-being of populations, even as SARS-CoV-2 viral spread was being limited. Thus, the pandemic resulted in substantial social and economic loss and showed the vulnerability of human beings to emerging zoonotic diseases. In this chapter, we provide information regarding the virus epidemiology, transmission, impact of public health response, and organization challenges. We also discuss the lessons learned to address future pandemics.

As of 2023, there were seven known pathogenic coronaviruses that have made the presumed zoonotic leap from bats to mammals to humans. Prior to 2003, four coronaviruses were well-known causes of common colds in children and adults; mouse hepatitis virus had served as a lab model for demyelinating diseases, suggesting that all coronaviruses would not be benign.^{1, 2 and 3} In early 2003, the SARS-CoV-1 virus emerged from Guangdong Province in China, first to Hong Kong, and resulted in the 2003-2004 global pandemic of SARS that caused recognized disease in at least 8,098 persons in 29 countries and killed at least 774 persons (estimated 9.6% case fatality).⁴ Many cases were nosocomial when sick patients presented for healthcare, inadvertently infecting healthcare workers (HCWs), other patients, and visitors. A less common and more lethal corona virus is caused by the Middle East Respiratory Syndrome (MERS) virus, with 2,601 laboratory-confirmed cases and 935 deaths reported (estimated 35.9% case fatality) from April 2012 to November 2022, nearly all in the Arabian Peninsula.⁵ In 2015, a Korean business traveler was infected in Saudi Arabia and triggered a multimonth transmission cycle in South Korea.⁶ The emergence of COVID-19 should not have been a surprise, given the SARS and MERS experiences; over 200 bat coronaviruses have been characterized and humans have been infected by multiple coronavirus types in the past^{7, 8, 9, 10 and 11} (Figure 1.1). It is nearly certain that additional bat coronaviruses will emerge and infect mammals and humans in the future.^{12, 13 and 14}

First recognized in December 2019 in Wuhan, Hubei Province, in central China and named COVID-19 by the WHO, the cause of the respiratory syndrome was SARS-CoV-2 whose sequence was published by Chinese investigators online just a few weeks after recognition of the syndrome.^{15, 16, 17 and 18} The lethal emergence of COVID-19 occurred in Wuhan, a city of 11 to 12 million population, and spread rapidly to Europe and the rest of the world. Details of the clinical syndrome are provided in Section 4.

Two hypotheses as to the origin of human infection in Wuhan are extant. First is the zoonotic hypothesis, consistent with our understanding of the bat origin of coronaviruses, thought to spread to vertebrate animals and then transmitted to humans. SARS-CoV-1 (the cause of the SARS pandemic of 2003-2004) may have emerged from the exotic food “wet market” that brings unusually wild animals to the dinner tables of Chinese consumers seeking specialty dishes. Civet cats, specifically the masked palm civet, were the likely responsible intermediary at that time.^19,20 SARS-CoV-2 is expected to have emerged in this fashion, presumably through nasal/respiratory inoculation during the preparation and consumption of a different mammal, perhaps a pangolin. The epicenter of the local outbreak was the Huanan Seafood Wholesale Market, which also sold other animals and was closed promptly by regional officials.^{21, 22, 23 and 24} Ironically, this prompt closure made it more challenging to sample animals to find a putative source; the pangolin has been implicated based on phylogenic similarities of bat and pangolin viruses to SARS-CoV-2^{25, 26 and 27} (Figure 1.2). The second hypothesis is that the virus was a laboratory contaminant inadvertently brought out by a lab worker on their way home from the Wuhan Institute of Virology, where


coronaviruses were studied. Given the novel nature of the emerging virus and a lack of evidence for either lab contamination or its release from the lab, the “One Health” zoonotic origin is favored.^28,29 The government of China has been lauded for its scientific advocacy to request and release the viral sequence so quickly (early January 2020). However, it was criticized for lack of transparency during the viral emergence in December 2019.

SARS-CoV-2 was well adapted for human transmission. Shortly after introduction of SARS-CoV-2 into humans, the global pandemic spread via travel. From its December 2019 emergence and recognition in Wuhan, it emerged in other Asian nations, Europe, North America, Africa, Australia, and Oceania just weeks thereafter^{30, 31, 32, 33 and 34} (Figure 1.3). The first recognized case in Africa was in Egypt and the cases were tied directly to a January 2020 business travel to Wuhan with a return to Cairo introducing the virus to Africa.³² Once introduced, autochthonous respiratory transmission was efficient and resulted in at least 766 million confirmed cases of COVID-19, including 6.93 million deaths reported to the WHO as of mid-May 2023.³⁵

The apparently worst affected nation is the United States, but reports are distorted by the degree of testing and case detection, national surveillance systems, and available treatments. Nonetheless, about 104 million cases and 1.12 million deaths in the United States through mid-May 2023 illustrate the massive burden on the U.S. healthcare system alongside humanitarian burden of so many deaths³⁶ (Figure 1.4). Now SARS-CoV-2 is endemic globally and will likely cycle seasonally as do other respiratory viruses in temperate climate regions.

Respiratory routes of transmission are dominant for SARS-CoV-2. Although droplets were implicated early in the pandemic, as with tuberculosis, it is now apparent that smaller aerosols are also an infectious route, as with influenza. However, the substantial heterogeneity of respiratory viral load from one infected person to another may be more important than the academic discussion of droplet versus aerosol transmission.³⁷ When droplets were thought to be dominant, the argument for physical distancing was supported, given that proximity to an infected person might have been thought a dominant risk factor, as with tuberculosis risk on an airplane or train when proximate persons to an infectious person are at greatest risk.³⁸ However, current thinking is that aerosols are substantial contributors and physical distancing may not be as protective as once thought.³⁹

Other sources of infection can be fomites and surfaces that harbor respiratory secretions that are breathed, coughed, or sneezed such that droplets and aerosols might settle down onto the surface.⁴⁰ Environmental assessments suggest multiday viability on surfaces, depending upon the type of surface (eg, paper, cardboard, stainless steel, plastic, composites), but the proportion of cases attributable to surface to nose/face transmission is likely small compared to respiratory transmission.^{41, 42, 43 and 44} Similarly, viable virus is found in feces and sewage, but fecal-oral transmission frequency is likely exceedingly rare.⁴⁵ Saliva and sputum can be sources of transmission, as with kissing, coughing, and sneezing. Sexual transmission and perinatal transmission during vaginal delivery are postulated, but not well documented; the presence of SARS-CoV-2 in semen and vaginal fluid has been documented, but not consistently.^{46, 47 and 48} This respiratory virus is likely spread through respiratory and saliva routes, with other routes of transmission likely to be rare.

Identifying suspected or confirmed COVID-19 cases enables effective public health modeling, interventions, evaluation of programs, and prevention of transmission.^{49, 50, 51, 52 and 53} Models depend upon sound epidemiologic and clinical data to estimate their parameters. The advent of widespread home testing,



however, suggests that innovative approaches are needed, including a focus on hospitalization and death surveillance (“tip of the iceberg”), sentinel and laboratory approaches, and modeled incidence estimates.^{54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 and 68} Surveys and targeted studies will also illuminate in ways that routine case surveillance no longer can; surveillance and surveys in nursing homes are examples.^{69, 70, 71, 72, 73, 74, 75 and 76}

COVID-19 pandemic surveillance encompasses monitoring the transmission of the infection and its most severe consequences (ie, hospitalization, death, long COVID) to identify the trends, patterns of risk and progression, and for the most efficient implementation of preventive and control measures.⁷⁷ Surveillance is one of the cornerstones for controlling the COVID-19 pandemic, identifying high-incidence or high-risk settings, and mitigating with intensive control measures, as with targeted vaccine campaigns in priority populations.^{78, 79, 80, 81, 82, 83, 84, 85, 86, 87 and 88} Testing and surveillance can enable control measures like mask use to be set aside in low-incidence settings or resumed when respiratory virus season results in SARS-CoV-2 surges.^79,81 Early in the pandemic, the WHO sought to strengthen COVID-19 pandemic surveillance systems, and urged countries to detect, assess, report, and respond to public health emergencies of international concern (PHEIC) and to enhance clear communication and collaboration between government leaders across borders and public health agencies.^89,90 The core surveillance objectives for the COVID-19 pandemic included (a) early warning for changes in epidemiologic patterns, (b) monitoring trends in morbidity and mortality, (c) monitoring disease burden on healthcare systems and capacity, and (d) incorporating strategic and geographically representative genomic surveillance.^{91, 92, 93 and 94}

Timely and accurate data of the disease burden because of the COVID-19 pandemic are needed to inform decisions about preventive and control measures, such as masking and vaccine boosting. Comparative surveillance and disease control experiences help learn from the experiences of past and others, both internationally and within countries, though this is impeded by systems of epidemiologic intelligence that are not robust enough to guide and inform public health action. Indirect effects on mortality through healthcare utilization pathways, including health services running at limited capacity, unmet demand for healthcare services other than COVID-19 infection, and nonreporting of cases, are some challenges limiting analysis and interpretation of the data.^{56,95, 96, 97, 98, 99, 100, 101, 102, 103 and 104} To better capture outcomes and mortality because of COVID-19, there is a need to build and maintain a robust and real-time epidemic surveillance infrastructure to help plan and implement strategies, monitor the pandemic’s progress, and offer policymakers insights to prevent and manage the infection.^{105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 and 117}

Excellent work has been done in the mathematical modeling of transmission, though data for parameter estimations have familiar limitations. The emergence of new viral variants, changing dynamics of susceptibility with immune protection from infection or immunization, different dynamics in varying venues and populations, and a host of estimated parameters whose values change with emerging knowledge require revisions of public health models as new information occurs. Validation of models is sometimes possible through new surveillance and survey data. Typical models estimate the susceptible population (S), the number of infected (I), the basic reproductive number (R0) suggesting the number of S who will be infected by exposure to a single I, the mean infection period (D), and the size of the population (N).¹¹⁸ To estimate the incidence in a defined population N, many approaches use case surveillance data, hospitalization data, mortality data, the proportion of positive specimen tests, sludge positivity, and surveys.^{119, 120, 121, 122 and 123} There are also a host of simulation estimation strategies based on inferences of parameters and the states of the subjects (S, I, proportion of I who are infectious to others, age profile of the population, and others). The scenarios are complex as different periods have included factors that affect R0 transmission risks, including infectiousness of different variants (Omicron > delta > beta > ancestral alpha variant); fidelity in prevention measures such as mask use, vaccine type, and coverage, including booster doses; and background characteristics such as temperate versus tropical climate and season of the year.

Current mathematical models now cope with endemic dynamics as much as epidemic ones. Seasonality in temperate climate zones likely tracks with other respiratory viruses to which the population has partial immunity (through cross-reacting antibodies, and through vaccine coverage that is incomplete [influenza or SARS-CoV-2] or has been unavailable [respiratory syncytial virus (RSV) or rhinoviruses]). Strategies for effective responses are studied intensively but model-based planning is limited by parameter uncertainties.

Mortality rates have not been easy to measure for COVID-19; theoretically, this would be the number of deaths per total population per time interval, perhaps by estimating confirmed
COVID-19-related deaths from excess mortality rates in a defined period.^55,56 This is complicated by measurement challenges of direct effects of COVID-19 (death from respiratory disease, for example) versus indirect effects (death from delayed medical care because of overwhelmed hospital services, for example). Case fatality risk (CFR; or a case fatality rate if assessed over a defined time) derives from denominators of tested persons, typically omitting persons with mild disease who may not come to medical attention and those without symptoms who were never tested from the denominator.^124,125 CFRs will differ based on population characteristics as with early 2020 CFR estimates of 2.3% in China and 7.2% in Italy, indeed reflecting the relatively more significant proportion of elderly afflicted in Italy.¹²⁶ Health systems metrics such as delayed time to care, the influence of comorbidities, or the quality of healthcare can be measured with CFR, but actual mortality risks are overestimated.¹²⁷

Surveys can help estimate the infection fatality risk (IFR; also can be a rate over a defined time), namely the risk of death among those symptomatically or asymptomatically infected, which is arguably more meaningful to considerations of societal risks.¹²⁵ An IFR will be lower than the CFR for respiratory viruses because the CFR includes persons tested in the denominator, with symptomatic persons overrepresented, whereas IFR seeks to include both symptomatic and asymptomatic persons in the denominator, that is, a population-level denominator estimate from surveys. These denominators enable better estimates of the actual infections, including those mild enough to have never resulted in testing. With home-based COVID-19 antigen testing now the norm, epidemiologists will need to estimate IFR to assess the lethality of a given variant, only obtainable through surveys and models.

Fundamental elements of the illness are reminiscent of influenza and other common respiratory viruses. In estimating the disease’s incubation period, investigators have suggested that this may vary by viral variant. From the ancestral (or alpha) variant, a pooled mean incubation period (time from exposure to onset of symptoms) from multiple studies was 6.5 days.¹²⁸ During peak delta variant transmission, a mean 4.3-day incubation period was suggested, with these comparators between 6,374 persons with alpha, 528 beta/gamma, and 651 delta viral infections:

Other investigators estimated a median of 3 to 4 days incubation during high levels of Omicron variant transmission.^130,131

As with influenza, the latent period (the time between inoculation and infectiousness of the host) for SARS-CoV-2 will be shorter than the incubation period (time to symptoms) such that infected persons are infectious before they are symptomatic. A Chinese study provided mean estimates of the incubation period of 3.8 days (95% credible interval: 3.5, 4.1) and latent period mean of 3.1 days (2.8, 3.5).¹³²

Clinical parameters include illness onset to hospital admission, onset to death, and time of hospital admission to discharge or death. These parameters are all highly variable based on the baseline health status of the infected person (age, underlying diabetes, or other chronic condition), the variant, the vaccination status, and the clinical care provided before and during hospitalization. Once infected, the estimate of the infectious period helps drive guidance on optimal isolation periods for infected persons or quarantine periods for exposed persons. For SARS-CoV-2 antigen or polymerase chain reaction (PCR)-positive persons, the Centers for Disease Control and Prevention (CDC) recommends staying at home or otherwise isolated for at least 5 days and isolating from others in the environment during this time, including fastidious mask use whenever crossing shared spaces.¹³³ As for persons who do not test positive for COVID-19 but have encountered an infected person, the CDC has defined “exposed” to be more than 15 minutes at a distance of fewer than 2 m/6 feet and recommended calculating from day 0 as the day of the last exposure to someone with COVID-19 and day 1 as the first full day after the previous direction. Precautions to be taken for 10 days are to wear a high-quality mask or respirator whenever around others indoors and take extra precautions if proximate to persons especially vulnerable to COVID-19 complications. If there are no symptoms (eg, fever of 100.4 °F
or greater; cough; shortness of breath; or other COVID-19 symptoms like a loss of smell or taste), then a test is recommended on day 6, that is, at least 5 full days after the last exposure, with the continuance of precautions through day 10.¹³⁴ In circumstances where herd immunity is extant and transmission rates are low, isolation of the infected individual is still needed, but quarantine of exposed persons may not be of substantial utility.

Surveillance and reporting have been spotty around the globe given the nonspecific nature of COVID-19 symptoms, test kit shortages, especially in 2020 and early 2021, and overwhelmed public health programs, leading to alternative approaches to surveillance.^{135, 136 and 137} Case definitions depend upon the availability of lab confirmation of infection or patient clinical profile and probability of SARS-CoV-2 origin; widespread testing makes diagnosis more straightforward.¹³⁸ Sorting “deaths from” versus “deaths with” has been fraught with interpretation challenges; some investigators have looked at deaths over baseline to indicate the probably overall COVID-19 mortality effect, both direct and indirect, from delayed care because of COVID-19 medical care restrictions.^{103,104,139, 140, 141, 142, 143, 144 and 145} Active surveillance of less severe cases has been deemphasized in the United States and elsewhere.^49,146 Whether electronic contact tracing has a viable future, using dongles, smartphones, or other digital devices to identify exposures, is not known.^{147, 148, 149, 150, 151, 152, 153, 154 and 155}

COVID-19 can affect anyone of any age, and the infection can cause symptoms ranging from mild to severe. Severe illness is seen in older persons far more frequently, unlike influenza that also affects infants and pregnant women more severely.^156,157 During the COVID-19 pandemic, even high-income nations failed to protect the most vulnerable persons in a timely fashion with consequent high mortality rates, particularly in the elderly.¹⁵⁸ Social determinants of disease were more prevalent among lower income persons (who typically had to go to work outside the home during lockdowns), racial/ethnic minorities, the elderly, immigrants/refugees, persons with housing instability, in nursing homes, disabled, underinsured, incarcerated, and persons with diabetes and other immunosuppressive medical conditions. Vulnerable groups that were disproportionately affected by COVID-19 might be divided into four categories:

Elderly: Older age has, perhaps, the most important impact on the burden of diseases. For instance, the older age distribution of patients who become severely ill is a notable difference between COVID-19 and such diseases as influenza (young children and the elderly), measles (young children), and RSV (young children, with rising adult incidence in recent years). Although hospitalization rates for influenza are often highest in the 0- to 4-year age group in comparison to other age groups, mortality rates tend to be higher in the elderly.²⁰⁵ In contrast, hospitalization rates, IFRs, and mortality rates in people infected with SARS-CoV-2 increase steeply with age, and fatal outcomes are overwhelmingly more common in people older than 50 years.²⁰⁶ Greater risk of severe COVID-19 disease with increasing age is like what was seen with SARS and MERS.²⁰⁷ Elderly patients (ie, age 65 and older) are most susceptible to developing severe COVID-19 infection, with increased need for ICU admission, ventilation, and hospitalization.²⁰⁸ Multiple age-related comorbidities including heart and lung disease, diabetes, physiologic changes of aging, lower immunity levels, and excess production of type 2 cytokines could lead to prolonged proinflammatory immune responses,²⁰⁹ which are some of the contributing factors to adverse health outcomes among the elderly. A systematic review found patients with age 50 years and more were associated with a 15.4-fold significantly increased mortality risk as opposed to patients with age below 50 years.²¹⁰

Pregnant women: Pregnancy does not appear to increase susceptibility to COVID-19 but may worsen its clinical course when compared to nonpregnant women.^{211, 212 and 213} Pregnant people (women and trans men) with COVID-19 infection are at higher risk for ICU admission,²¹⁴ ventilation use,²¹⁴ need for extracorporeal membrane oxygenation, and maternal death than nonpregnant people with COVID-19 infection.²¹¹ Further, pregnancy is associated with higher odds of preeclampsia.²¹⁵ Future investigations for consistent evidence of vertical transmission of the virus from mother to fetus²¹² and fetal outcomes²¹⁴ are needed.

Children: COVID-19-related severe complications in children were reported toward the end of April 2020 in the UK, United States, and other European countries.²¹⁶ In this new presentation of COVID-19 infection, “multisystem inflammatory syndrome in children (MIS-C)” or pediatric inflammatory multisystem syndrome emerged in a subset of children. This infrequent condition in children usually occurs 2 to 6 weeks after a child is infected with COVID-19 and can occur, rarely, in asymptomatic children.^217,218 These children were hospitalized with coronary artery aneurysms, cardiac dysfunction, fever, gastrointestinal symptoms, and dermatologic or mucocutaneous symptoms or Kawasaki disease–like clinical manifestations temporally associated with severe acute COVID-19 infection.^{216,218, 219 and 220} Neonates born to mothers with COVID-19 infection during pregnancy have presented with a multisystem inflammatory syndrome with raised inflammatory markers and multiorgan involvement, described as a multisystem inflammatory syndrome in neonates (MIS-N).^216,221 Available data suggest that MIS-C incidence is higher among racial and ethnic minority populations, including Black, Hispanic/Latino/Latina, and Asian or Pacific Islander persons, and may vary by sex (small male excess) and geography (though reporting bias must be considered)^218,222; it is described in adolescents and adults, but less frequently compared with children aged 5 years or younger^219,220,223 and may occur more frequently in patients who are obese.²²⁴ The age group with a higher mortality rate during the COVID-19 pandemic was the elderly, which was a significant risk factor for COVID-19 mortality.²²⁵ In addition, recent studies suggest that neonates,^180,226 premature infants,¹⁸⁰ and children with comorbidities¹⁸⁰ have a higher risk of severe COVID-19 infection than other children.²²⁷ Given school and social disruptions, a high prevalence of mental health problems was witnessed among children and adolescents throughout the COVID-19 pandemic.^228,229

Pandemic control for person-to-person respiratory disease transmission has relied on key tools to reduce the likelihood of transmission from an infected individual to a susceptible person. COVID-19 also relied on these same measures.^{230, 231 and 232}