Pre-2019 Coronaviruses

Definition

Human coronaviruses are a frequent cause of respiratory illness. Seasonal human coronaviruses (CoV) 229E, OC43, NL63, and HKU1 generally cause mild, self-limited upper respiratory tract infections, including about 15 to 30% of all common colds ( Chapter 329 ). However, three newer, highly pathogenic coronaviruses have caused major public health challenges: severe acute respiratory syndrome coronavirus (SARS-CoV), which was first identified in 2003; Middle East respiratory syndrome (MERS-CoV), which was identified in 2012; and SARS-CoV-2, which was identified in 2020 and which has caused the coronavirus disease 2019 (COVID-19; Chapters 335 to 337 ) global pandemic.

The Pathogen

The family Coronaviridae is currently divided into four genera—alpha, beta, gamma, and delta coronaviruses ( Fig. 334-1 ). Human coronaviruses (HCoVs) are currently in two of these genera: alpha coronaviruses (229E and NL63), and beta coronaviruses (HKU1 and OC43). MERS-CoV, SARS-CoV, and SARS-CoV-2 are also beta coronaviruses but belong to different lineages than the common human coronaviruses.

Coronaviruses are single-stranded positive-sense RNA viruses that contain large genomes (27 to 32 kb) that can be replicated fully or can be replicated partially via subgenomic RNAs. The coronavirus genome encodes four main structural proteins: spike, membrane, nucleocapsid, and envelope; HKU1 and OC43 genomes also encode a hemagglutinin-esterase protein. Interspersed between the main structural proteins are several accessory proteins that vary among human coronaviruses and interact with the host immune response. Coronavirus genomes also encode a variety of nonstructural proteins that contribute to viral replication, proofreading, and modulation or evasion of the host response.

Epidemiology

Seasonal coronaviruses 229E, NL63, HKU1, and OC43 are found worldwide. Seroprevalence studies indicate that exposure is common in early childhood and that a majority of adults are seropositive for at least one seasonal coronavirus. Although these viruses have been known to cause infection at any time of the year, in most temperate regions of the northern hemisphere, infections occur primarily in December through March, with peaks in January and February. In a large prospective study in Norway of all hospitalized children aged 16 years or younger with respiratory tract infections, seasonal coronaviruses were present in 9% of patients. Among patients with a seasonal coronavirus, approximately two thirds had co-detection of another respiratory virus. Consistent with other studies, OC43 and NL63 were detected most frequently, with HKU1 and 229E detected much less frequently in the hospitalized patients. OC43 and NL63 infections had clear biennial peaks and alternated with HKU1, which circulated every second year when OC43 and NL63 detection rates were low. By comparison, coronavirus 229E appears to be sporadic. Consistent with these findings, another recent household study showed that the proportion of acute respiratory infections associated with coronaviruses varied from 8 to 16% during annual respiratory virus season, which generally occurs from October through April in the temperate Northern Hemisphere.

The incidence of symptomatic infection is highest in children below age 5 years for all seasonal coronaviruses except 229E, for which the incidence is relatively consistent across age groups. However, multiple studies indicate that all seasonal coronaviruses can infect individuals of all ages and that reinfection is common.

Seasonal coronaviruses are likely spread via direct contact with respiratory droplets, aerosols, or secretions ( Table 334-1 ). Viral shedding can frequently occur beyond 1 week in both symptomatic and asymptomatic adults and children, with viral detection typically persisting for a longer duration in children under age 5 years. Seasonal coronaviruses have a high attack rate within households; the proportion who become infected after exposure to an infected household member ranges from 7.2% for 229E to 12.6% for NL63. As a result, approximately 25% of all infections are likely acquired from an infected household contact. Children are the most frequently identified index case except for 229E, whereas adults ages 18 to 49 years comprise nearly half of the secondarily infected household contacts. Seasonal coronavirus outbreaks associated with significant morbidity have been described in babies in neonatal intensive care units and in adults in long-term care facilities.

Pathobiology

Similar to other human coronaviruses, seasonal coronaviruses are thought to have a zoonotic origin (see Table 334-1 ) and to attach to human cells via the receptor binding domain of the coronavirus spike protein. NL63 binds to angiotensin converting enzyme 2 (ACE-2), the same receptor as SARS-CoV and SARS-CoV-2. By comparison, 229E binds aminopeptidase N, whereas OC43 and HKU-1 bind 9-O-acetylated sialic acid. Although both ACE-2 and aminopeptidase N are present in a range of human tissues, host tropism of human coronaviruses is also determined by the presence of host proteases that cleave the S1 and S2 components of the spike protein, thereby permitting cell fusion and entry of viral RNA.

Seasonal coronaviruses predominantly infect cells of the upper respiratory tract. NL63, OC43, and HKU1 infect ciliary cells, whereas 229E preferentially infects nonciliary cells but can still depress ciliary function. The cytopathic effect of seasonal coronaviruses appears to be generally limited to the upper respiratory tract, although bronchiolitis, pneumonia, and acute lung injury also have been reported. The association of rare severe pulmonary disease with immunocompromise indicates the importance of the host immune response. Outside the respiratory tract, OC43 can infect neurons, and the virus has a mutation that likely enables cleavage by host cells in the nervous system. OC43 infection has been linked to neurologic syndromes including encephalitis.

Clinical Manifestations

Asymptomatic infections occur frequently. In human challenge studies, 72% of adults infected with 229E develop cold symptoms, with an incubation period of 2 to 5 days (median 3 days). The incubation period for the four seasonal coronaviruses is similar to other human coronaviruses (see Table 334-1 ) and has been estimated to be 3.2 days. Clinical manifestations of 229E, OC43, NL63, and HKU1 are generally mild and similar to those of other viral causes of the common cold ( Chapter 329 ). Rhinorrhea, sore throat, cough, wheezing, and fever are common presenting symptoms. In a multiyear prospective household study, about 10% of infections in adults and 20% of infections in children were associated with medical consultation, with about 30% of coronavirus detections associated with moderate illness and 10% with relatively severe illness, which was defined as wheezing, dyspnea, or seeking care for the illness. Such infections are more likely in children under age 5 years and in adults age 50 years or older, and are more likely to be caused by 229E virus infection compared with the other three seasonal coronaviruses. Overall, about 5% of all hospitalized adults with acute respiratory illnesses are associated with these coronaviruses in the pre-COVID era. Otitis media, gastroenteritis, an exacerbation of prior asthma, and pneumonia occur more frequently in individuals who are immunocompromised or have underlying medical conditions. Rare neurologic manifestations such as meningoencephalitis and seizures have been noted in children with seasonal coronavirus infections, including fatal encephalitis in immunocompromised infants infected with OC43.

Diagnosis

Given the lack of specific treatment, confirmatory diagnosis of these pathogens is generally of limited clinical utility. However, testing of nasopharyngeal samples with multipathogen respiratory viral panels using polymerase chain reaction (PCR) assays, often to exclude other pathogens such as SARS-CoV-2, is the best method for confirming the diagnosis.

Treatment