The most common and frequent infections in humans are respiratory virus infections. Some classical respiratory viruses (e.g., rhinoviruses) enter the body through the respiratory tract, replicating and causing disease only in cells of the respiratory epithelium. Other, more systemic viruses (e.g., measles virus and severe acute respiratory syndrome [SARS] coronavirus) spread via the bloodstream and cause systemic disease; however, they also may enter through and cause disease in the respiratory tract. Although infections with systemic viruses often induce lifelong immunity against disease, respiratory viruses that do not cause viremia usually can reinfect the same host many times throughout life. Reinfection with the same virus is common because of incomplete or waning immunity after natural infection. Hundreds of different viruses cause infection of the respiratory tract, and within each virus type there can be a nearly unlimited diversity of field strains that vary antigenically, geographically, and over time (e.g., antigenically drifting influenza viruses). Specific antiviral treatment options are limited, and only a few licensed vaccines are available. For further discussion of common respiratory virus infections, see Chap. 31 and syndrome-specific chapters.
Common viral respiratory infections can be categorized in several ways, including by site of anatomic involvement, disease syndrome, or etiologic agent.
ANATOMIC SITES IN THE HUMAN RESPIRATORY TRACT
The type of respiratory disease that develops during virus infection is dictated to a large degree by the cell types and tissue organization in the respiratory tract. The vocal cords mark the transition between the upper and lower respiratory tracts. The upper respiratory tract is a complex anatomic system with interconnected structures, including the sinuses, middle-ear spaces, Eustachian tubes, conjunctiva, nasopharynx, oropharynx, and larynx. The tonsils and the adenoids are large collections of lymphoid tissue in the pharynx that participate in immunity but also are susceptible to infections. The lower respiratory tract structures include the trachea, bronchi, bronchioles, alveolar spaces, and lung tissue, including epithelial cells and blood vessels. The epithelial cell types that line the respiratory tract are varied in morphology and function, and their susceptibility to different virus infections varies. The principal types of cells in the major airways are ciliated or nonciliated epithelial cells, goblet cells, and Clara cells. Smooth-muscle cells form major tissue structures around the epithelial structures of the large airways of the lower respiratory tract down to the level of the bronchioles, and these cells are reactive to intrinsic and extrinsic signals, including viral infection or exposure to allergens or pollutants. The pathologic process of wheezing is driven by smooth-muscle contraction and obstruction of airways caused by mucous accumulation and epithelial sloughing in the lumen. Reactive airways causing wheezing are most often due to constriction of lumen size at the level of the bronchioles (which have the narrowest lumen diameter of the airways). The lung does not have smooth-muscle or ciliated cells, but instead possesses pneumocytes of types I and II. Pneumonia (Chap. 121) is an infection of the pneumocytes in the lung tissue and the alveolar spaces. The alveolar spaces also contain cells of the monocyte lineage, such as macrophages, which patrol the air spaces.
Since different respiratory viruses tend to have a predilection for replication in differing cells or regions of the respiratory tract, it is possible for the well-trained clinician with epidemiologic information to understand the most likely associations of viruses with clinical syndromes. The clinical diagnoses for virus infections in the upper respiratory tract are rhinitis or the common cold, sinusitis, otitis media, conjunctivitis, pharyngitis, tonsillitis, and laryngitis. In reality, some upper respiratory tract infections affect more than one upper respiratory tract anatomic site during a single infection, such as the classical pattern of pharyngoconjunctival fever during adenovirus infection. Lower respiratory tract syndromes also can be associated easily with anatomic region, including tracheitis, bronchitis, bronchiolitis, pneumonia, and exacerbations of reactive airway disease or asthma. Bronchiolitis is a disease condition characterized by trapping of air in the lungs with difficulty in expiration (i.e., wheezing); it is caused by inflammation or infection of the bronchioles, the smallest and most highly resistant airways. Again, mixed syndromes occur, such as laryngotracheitis, usually termed croup. Croup, a disease condition characterized by difficulty in inspiration associated with a barky cough, is caused by inflammation or infection of the larynx, trachea, and bronchi. When respiratory symptoms occur in the context of a respiratory viral illness with significant systemic signs, infection with particular agents can be suspected (e.g., influenza, measles, SARS, or hantavirus pulmonary syndrome [HPS]), with exposure history taken into account.
RESPIRATORY VIRUSES CAUSING DISEASE IN IMMUNOCOMPETENT HOSTS
Children have more frequent respiratory virus infections than adults; thus it was natural that many early discoveries about the viral causes of respiratory infections came from pediatric studies. The principal causes of acute viral respiratory infections were determined in large epidemiologic studies in the 1960s and 1970s, when cell culture of infectious agents became available. More recently, studies of viral epidemiology have been conducted in adults, especially in special populations such as the elderly, nursing home residents, and immunocompromised individuals. Rapid antigen detection tests (based on immunoassays for detection of viral proteins) became available for respiratory syncytial virus (RSV) and influenza virus in the 1980s. With the availability of sensitive and specific molecular tests, such as reverse transcription combined with the polymerase chain reaction (RT-PCR), studies in the past two decades have greatly increased the extent to which we understand the causes of viral respiratory infections. Multiplex panels of RT-PCR tests capable of detecting a dozen or more viruses are commonly available for clinical testing of respiratory secretions. These sensitive tests have been especially helpful in studies of infection in adults, who often shed much lower concentrations of virus in secretions than do children. Influenza viruses, RSV, and human metapneumovirus (hMPV) are the most common causes of serious lower respiratory tract disease in otherwise healthy subjects; parainfluenza viruses (PIVs) and adenoviruses also cause substantial disease. Rhinoviruses (the most common cause of the common cold syndrome) have been increasingly associated with lower respiratory tract syndromes. Rhinovirus infection is so common, even in asymptomatic individuals, that it has been hard to establish clear figures for the role of rhinovirus in lower respiratory disease. Generally, about two-thirds of cases of respiratory illness in a research setting can be associated with a specific viral agent. Besides the viruses mentioned above (and discussed below), a number of additional viruses identified with molecular tools have been associated with respiratory illness. Still, it is fair to say that our diagnostic tools remain suboptimal since a specific infectious agent is not identified in approximately one-third of clinical respiratory illnesses in large surveillance studies. It is likely that in most of these cases pathogens are not detected because of the very low titers of virus in patient samples at the time of clinical presentation, which may occur after the period of peak virus shedding. It is also possible that novel agents are yet to be identified. As emerging tools for microbiome and “virome” studies (with sequencing of all nucleic acids in a sample) are applied in these settings in coming years, new agents and new associations with disease will probably be discovered.
RESPIRATORY VIRUSES CAUSING DISEASE IN IMMUNOCOMPROMISED HOSTS
Special populations of patients are susceptible not only to the conventional respiratory viruses discussed above but also to agents causing symptoms during reactivation of latent viruses or new infections with opportunistic agents. Most prominently, reactivating latent viruses, such as herpes simplex virus (HSV) and cytomegalovirus (CMV) and adenoviruses, cause disease in immunocompromised humans. Patients at most risk are those with hematopoietic stem cell or solid organ transplantation, leukopenia caused by chemotherapy, or advanced HIV-AIDS. In immunosuppressed patients with pneumonia, CMV is the virus recovered most frequently during deep respiratory tract diagnostic procedures such as bronchoalveolar lavage. These patients also are highly susceptible to more frequent and more severe disease caused by common respiratory viruses, including RSV, hMPV, PIVs, influenza viruses, rhinoviruses, and adenoviruses. Conventional acute respiratory viruses can cause chronic and sometimes fatal infections in these populations. Nosocomial transmission of respiratory viruses occurs in hematopoietic stem cell transplantation units, and the frequency of transmission can be high, with entire units affected.
SPECIFIC VIRAL CAUSES OF RESPIRATORY DISEASE
Orthomyxoviridae: Influenza Viruses
Influenza virus infection and influenza syndrome usually are associated with fever, myalgias, fatigue, sore throat, headache, and cough (See also Chap. 195). Influenza causes severe and even fatal pneumonia, particularly in elderly patients, nursing home residents, immunocompromised persons, and very young children. Influenza pneumonia has an unusually high rate of complication by bacterial superinfection, with staphylococcal and streptococcal bacterial pneumonia occurring in as many as 10% of cases in some clinical series.
Influenza is a single-stranded, segmented, negative-sense, RNA genome virus of the family Orthomyxoviridae. There are three (sero)types of influenza viruses: A, B, and C. Influenza A and C viruses infect multiple species, while influenza B virus infects humans almost exclusively. Type A viruses appear to be the most virulent for humans and most commonly cause severe disease manifestations, although type B viruses cause substantial morbidity. On the basis of antibody response, influenza A viruses can be subdivided into 18 different hemagglutinin (H) surface protein subtypes and 11 neuraminidase (N) surface protein subtypes. The subtypes that have caused major pandemics in humans are H1N1, which caused the 1918 pandemic; H2N2, which caused the 1957 pandemic; H3N2, which caused the 1968 pandemic; and H1N1pdm2009, which caused the 2009 pandemic. Currently, type A subtypes H1N1 and H3N2 and type B viruses cause annual seasonal epidemics.
Major pandemics caused by new influenza viruses are always possible. Many highly pathogenic influenza viruses circulate in aquatic birds. Occasionally, avian viruses infect humans directly after close contact with infected wild birds or poultry. Co-housing of pigs (which have both avian and human influenza virus receptors) with poultry may increase the risk of reassortment of human and animal or bird viruses; reassortment can make the zoonotic viruses more fit for replication in humans. Several outbreaks of avian influenza have occurred in limited numbers of humans to date, and there is the risk of a worldwide pandemic with avian influenza viruses if a strain acquires the potential to spread efficiently from human to human. H5N1 influenza virus infection of humans, predominantly by direct chicken-to-human transmission, occurred during an epizootic in Hong Kong’s poultry population in 1997. The disease affected many types of wild and domestic birds and caused a high rate of systemic disease and death in infected humans. This virus, carried in the gastrointestinal tract of wild birds, has spread throughout Asia and beyond and continues to evolve antigenically. Avian H7N7 and H7N9 viruses also have caused zoonotic outbreaks. A significant outbreak of H7N9 virus infection began in China in March 2013, with high mortality, and seasonal outbreaks that have subsequently occurred nearly yearly threaten to cause a pandemic. H1N2 virus is endemic in pigs and affects humans with close contact. An H3N2 variant virus that differs antigenically from seasonal human viruses is endemic in pigs and occasionally infects children who have close contact with pigs in the United States. Rare human cases caused by H6, H7, H9, and H10 viruses have been reported. Type B influenza viruses co-circulate in humans during seasonal epidemics. Type B viruses mutate less frequently than type A viruses, and there is only one influenza B subtype. The slower evolution of type B viruses is probably linked to the fact that they are almost exclusively human pathogens. There is some antigenic diversity in these strains, however, and two major lineages have been designated B/Shanghai-like and B/Fujian-like strains.
RESPIRATORY SYNCYTIAL VIRUS
RSV is a single-stranded, negative-sense, nonsegmented, RNA genome virus of the genus Pneumovirus in the family Paramyxoviridae. Infection is ubiquitous, affecting most humans in the first several years of life and causing reinfections throughout life. RSV is among the most transmissible viruses of humans. Disease epidemics occur yearly, typically between October or November and March in temperate regions. RSV is one of the most common viral causes of severe lower respiratory tract illness in the elderly and in children; it is among the most important causes of hospitalization of elderly and infant patients throughout the world. There is only one serotype of RSV, but antigenic variability does occur in circulating field strains. In immune serum reciprocal cross-neutralization studies, the two antigenic subgroups, A and B, appear to be ~25% antigenically related; this relatedness may partially explain the susceptibility of humans to reinfection, which is very common and can be caused by viruses of the same subgroup or even the same strain. However, reinfection in otherwise healthy adults usually is associated with mild disease confined to the upper respiratory tract. Severe lower respiratory tract disease is common in the elderly, especially in frail institutionalized elderly populations. Immunocompromised patients of any age also are at risk of severe or prolonged disease, especially recipients of hematopoietic stem cell transplants. Wheezing is common with primary infection in children (bronchiolitis), and there is a strong association of RSV infection early in life and subsequent asthma, although it is unclear whether severe childhood RSV causes asthma or is the first manifestation of reactive airway disease. RSV causes exacerbations of asthma and is associated with acute exacerbations of chronic obstructive pulmonary disease (COPD), also referred to as acute exacerbations of chronic bronchitis (AECB).
HUMAN PARAINFLUENZA VIRUSES
The human PIVs are a group of four distinct serotypes (designated 1–4) of single-stranded, negative-sense RNA viruses belonging to the family Paramyxoviridae. PIV3 most commonly causes severe disease, and repeated infection is common throughout life, although secondary infections often are mild or asymptomatic. Primary infections in children manifest as laryngotracheitis (croup), while subsequent infections typically are limited to the upper respiratory tract. PIVs are detected with sensitive RT-PCR tests or, more classically, by cell culture with immunofluorescent microscopy or hemadsorption in reference laboratories.
hMPV was discovered only in 2001 but probably has always been present in human populations. Infection occurs first in early childhood, and reinfections are common throughout life. This virus is similar in many respects to RSV. It belongs to the family Paramyxoviridae and is a member of the genus Pneumovirus. It causes both upper and lower respiratory disease. It appears to be somewhat less virulent than RSV, causing about half as much severe lower respiratory tract disease, probably because it does not possess the nonstructural genes that RSV expresses in infected cells to abrogate the effect of host innate immune effectors like interferons. The clinical features of lower respiratory tract infections caused by hMPV are similar to those of such infections caused by other paramyxoviruses, most often including cough, coryza, and wheezing. Like RSV, hMPV plays an important role in exacerbations of asthma or COPD and causes pneumonia or wheezing in frail and institutionalized elderly individuals and immunocompromised patients.
Measles virus is also a paramyxovirus but of the genus Morbillivirus (See also Chap. 200). This virus causes a systemic infection known as rubeola but also can manifest with respiratory symptoms. Measles virus probably is the most contagious respiratory virus infection of humans: it is transmitted efficiently not only by direct contact with infected persons or fomites (like other respiratory viruses) but also by small-particle aerosols. Measles virus infection is preventable by vaccination but is so infectious that cases are inevitable—even in the United States—whenever vaccination rates fall below 90–95% in a population. The virus causes systemic illness, sometimes including severe pneumonia, when primary infection occurs in an unvaccinated adult or an immunocompromised person of any age. Therefore, vigilance in maintaining high vaccination rates is critical. With primary infection, the illness in children is typically milder; however, mortality rates in lower-resource countries are high, especially among persons with underlying risk factors, including malnutrition.
Symptoms of measles include ≥3 days of high fever and a classical set of upper and lower respiratory tract symptoms sometimes termed “the 3 Cs”: cough, coryza, and conjunctivitis. Unlike most respiratory viruses, measles virus circulates in the bloodstream and thus causes disseminated infection with systemic manifestations. Usually, a characteristic diffuse maculopapular rash appears within days of fever onset. Koplik’s spots (see Fig. A1-2)—typical mucosal lesions in the mouth that appear briefly—are considered diagnostic of measles infection in the setting of the typical rash and fever.
A wide variety of picornaviruses cause respiratory disease, including non-polio enteroviruses, rhinoviruses, and parechoviruses (Chap. 199). The designations of these viruses can be confusing: the enterovirus, rhinovirus, and parechovirus species names were changed (with the approval of the International Committee on Taxonomy of Viruses in February 2013) to remove references to host species names. These changes are summarized in Table 194-1. The genus Enterovirus consists of 13 species, including enteroviruses A through D and rhinoviruses A through C. The genus Parechovirus contains two species, one of which—Parechovirus A—encompasses 19 types: human parechovirus (HPeV) 1 through 19. These viruses exhibit seasonal patterns that differ from those of most other acute respiratory viruses. Rhinovirus infections occur year-round. Enterovirus infections occur most commonly in the summer months in temperate areas.
TABLE 194-1Enterovirus, Rhinovirus, and Parechovirus Species Name Changes Made in Order to Remove References to Host Species Names and Approved by the International Committee on Taxonomy of Viruses in February 2013 ||Download (.pdf) TABLE 194-1 Enterovirus, Rhinovirus, and Parechovirus Species Name Changes Made in Order to Remove References to Host Species Names and Approved by the International Committee on Taxonomy of Viruses in February 2013
|Genus ||Current Species Name ||Former Species Name |
|Enterovirus (now 13 species) ||Enterovirus A: consists of 25 serotypes, including coxsackieviruses and some non-polio enteroviruses that cause respiratory disease ||Human enterovirus A |
| ||Enterovirus B: consists of 63 serotypes, including some coxsackieviruses, echoviruses, and non-polio enteroviruses ||Human enterovirus B |
| ||Enterovirus C: consists of 23 serotypes, including the polioviruses ||Human enterovirus C |
| ||Enterovirus D: consists of 5 serotypes and includes enterovirus D68 ||Human enterovirus D |
| ||Rhinoviruses A–C ||Human rhinoviruses A–C |
|Parechovirus (2 species) ||Parechovirus A: consists of 19 types (1–19). Human parechoviruses (HPeVs) 1 and 2 are common human pathogens. ||HPeV-1 and HPeV-2 were formerly classified in the genus Enterovirus as echoviruses 22 and 23, respectively. |
Rhinoviruses have single-stranded, positive-sense RNA genomes. Rhinoviruses A through C represent species in the Enterovirus genus of the family Picornaviridae. Rhinoviruses are the most common viral infective agents in humans and the most frequent cause of the common cold. Field isolates of rhinovirus are exceptionally diverse; they can be classified by serotyping into more than 100 serotypes or alternatively by genotyping into a large number of genotypes that cause cold symptoms. At the time of writing in 2017, the species Rhinovirus A contained 80 types, Rhinovirus B had 32 types, and Rhinovirus C had 55 types. The viral particles are icosahedral in structure and are non-enveloped. Rhinoviruses are responsible for at least half of all cases of the common cold. Rhinovirus-induced common colds may be complicated in children by otitis media and in adults by sinusitis. Most adults, in fact, have radiographic evidence of sinusitis during the common cold, which resolves without therapy. Therefore, the primary disease is probably best termed rhinosinusitis. Rhinovirus infection is associated with exacerbations of reactive airway disease in children and asthma in adults. It is not clear whether rhinovirus is restricted to the upper respiratory tract and only indirectly induces inflammatory responses that affect the lower respiratory tract or whether the viruses spread to the lower respiratory tract. In the past, it was thought that these viruses did not often replicate or cause disease in the lower respiratory tract. However, recent studies have discerned strong epidemiologic associations of rhinoviruses with wheezing and asthma exacerbations, including episodes severe enough to require hospitalization. Rhinoviruses likely can infect the lower airways to some degree, inducing a local inflammatory response. Another possibility is that significant local infection of the upper respiratory tract may induce regional elaboration of mediators that causes lower airway disease. The association of rhinovirus infection with lower respiratory tract illness is difficult to study because diagnosis by cell culture is not sensitive. RT-PCR diagnostic tests are difficult to interpret because they are often positive for prolonged periods and even asymptomatic individuals may have a positive test. Comprehensive serologic studies to confirm infection are difficult because of the large number of serotypes. Nevertheless, most experts believe rhinoviruses are a common cause of serious lower respiratory tract illness.
Non-polio enteroviruses are common and distributed worldwide. Although infection often is asymptomatic, these viruses cause outbreaks of clinical respiratory disease, sometimes with fatal consequences. The species Enterovirus A consists of 25 serotypes, including coxsackieviruses and some non-polio enteroviruses that cause respiratory disease. Coxsackieviruses cause oral lesions and often are associated in children with hand-foot-and-mouth disease. The pharyngitis associated with this infection characteristically manifests with herpangina, a clinical syndrome of ulcers or small vesicles on the palate that often involves the tonsillar fossa and is associated with fever, difficulty swallowing, and throat pain. Outbreaks commonly occur in young children during the summer. Enterovirus A71 also causes large outbreaks of hand-foot-and-mouth disease, especially in Asia, sometimes leading to neurologic complications and even death. The species Enterovirus B consists of 63 serotypes, including the echoviruses (echo being an acronym for enteric cytopathic human orphan, which may be an archaic notion since most echoviruses are associated with human diseases, most commonly in children). Echoviruses can be isolated from many children with upper respiratory tract infections during the summer months. Echovirus 11 has been associated with laryngotracheitis or croup. Epidemiologic studies also have associated echoviruses with epidemic pleurodynia, an acute illness characterized by sharp chest pain and fever. The species Enterovirus C consists of 23 serotypes, including the polioviruses. The species Enterovirus D consists of five serotypes, including enterovirus D68, which has been associated with wheezing and some severe syndromes in children.
The genus Parechovirus comprises two species, one of which is Parechovirus A. The most common member of the genus Parechovirus, human parechovirus 1, is a frequent human pathogen. The genus also includes the closely related human parechovirus 2. Human parechoviruses usually cause mild respiratory or gastrointestinal illness. Most infections occur in young children. The seroprevalence of parechoviruses 1 and 2 is high among adults.
Viruses of the family Adenoviridae infect both humans and animals. As their designation indicates, adenoviruses were first isolated in human lymphoid tissues from surgically removed adenoids. In fact, some serotypes establish persistent asymptomatic infections in tonsil and adenoid tissues, and virus shedding can occur for months or years. These double-stranded DNA viruses are <100 nm in diameter and have non-enveloped icosahedral morphology. The large double-stranded DNA genome is linear and nonsegmented. The seven major human adenovirus species (designated A through G) fall into 57 immunologically distinct serotypes. Human respiratory tract infections are caused mainly by the B and C species. Adenovirus infections can occur throughout the year. Many serotypes cause sporadic outbreaks, while others appear to be endemic in particular locations. Respiratory illnesses include mild disease such as the common cold and lower respiratory tract illnesses including croup, bronchiolitis, and pneumonia. Conjunctivitis is associated with infection by the B and D species. A particular constellation of symptoms referred to as pharyngoconjunctival fever is frequently associated with acute adenovirus infection. In contrast, gastroenteritis has been associated most frequently with serotypes 40 and 41 virus of species F. Immunocompromised patients are highly susceptible to severe disease during infection with respiratory adenoviruses. The syndrome of acute respiratory disease (ARD), especially common in stressful or crowded living conditions, was first recognized among military recruits during World War II and has continued to be a problem when vaccination has been suspended temporarily because of lapses in vaccine supply. ARD is most often associated with adenovirus types 4 and 7.
Members of the genus Coronavirus also contribute to respiratory illness, including severe disease. Dozens of coronaviruses affect animals. In the twentieth century, only two representative strains of human coronaviruses were known to cause disease: 229E (HCoV-229E) and OC43 (HCoV-OC43). An outbreak of infection with SARS-associated coronavirus (SARS-CoV) showed that animal coronaviruses have the potential to cross from other species to humans, with devastating effects. The one major epidemic to date (November 2002 through July 2003) encompassed more than 8000 cases, with mortality rates approaching 10%. SARS-CoV causes a systemic illness with a respiratory route of entry. SARS is a unique form of viral pneumonia. In contrast to most other viral pneumonias, SARS lacks upper respiratory symptoms, although cough and dyspnea occur in most patients. Typically, patients present with a nonspecific illness manifesting as fever, myalgia, malaise, and chills or rigors; watery diarrhea may occur as well. Investigators have reported the identification of a fourth human coronavirus, HCoV-NL63. Evidence is emerging that this new group 1 coronavirus is a common respiratory pathogen of humans, causing both upper and lower respiratory tract illness. HCoV-HKU1 was first described in January 2005 after its detection in a patient with pneumonia. Several cases of respiratory illness have been associated with this virus, but its infrequent identification suggests that this putative group 2 coronavirus has caused a low incidence of illness to date. The Middle East respiratory syndrome coronavirus (MERS-CoV), first isolated in 2012, causes severe disease in humans, with 35% mortality. MERS-CoV is a zoonotic virus (transmitted between animals and people). The virus may have emerged from bats in the Middle East. Studies have shown that humans are infected through direct or indirect contact with infected dromedary camels.
Several herpesviruses cause upper respiratory infections, especially infection of the oral cavity. Herpes simplex pharyngitis is associated with characteristic clinical findings, such as acute ulcerative stomatitis and ulcerative pharyngitis. HSV types 1 and 2—also called human herpesvirus (HHV) 1 and 2, respectively—both cause oral lesions (Chap. 187), although >90% of oral infections are caused by HSV-1. Primary oral disease can be severe, especially in young children, who sometimes are admitted for rehydration therapy as a result of poor oral intake. A significant proportion of individuals suffer recurrences of symptomatic disease consisting of vesicles on the lips. Epstein-Barr virus (EBV) mononucleosis syndrome (Chap. 189) is often marked by acute or subacute exudative pharyngitis; in some cases, tonsillar swelling in EBV pharyngitis is so severe that airway occlusion appears imminent. Most of the viruses in the family Herpesviridae—including CMV (Chap. 190); EBV; varicella-zoster virus (VZV; Chap. 188); and HHV-6, -7, and -8 (Chap. 190)—can cause severe disease in immunocompromised patients, especially hematopoietic stem cell transplant recipients.
Parvoviridae: Human Bocavirus
A new virus was recently identified in respiratory samples from children with lower respiratory tract disease in Sweden. Sequence analysis of the genome revealed that the virus is highly related to canine minute virus and bovine parvovirus and is a member of the genus Bocavirus (subfamily Parvovirinae, family Parvoviridae). This virus, tentatively named human bocavirus (HBoV), has been identified as the sole agent in a limited number of respiratory samples from children hospitalized with respiratory tract disease. Whether the virus causes or is merely associated with disease remains controversial.
Pharyngitis occurs with primary HIV infection and may be associated with mucosal erosions and lymphadenopathy.
Polyomaviruses are small, double-stranded, DNA-genome, non-enveloped icosahedral viruses that may be oncogenic. Two major polyomaviruses, JC and BK viruses, are known to infect humans. Of adults in the United States, ≥80% are seropositive for these viruses. JC virus can infect the respiratory system, kidneys, or brain. BK virus infection causes a mild respiratory infection or pneumonia and can involve the kidneys of immunosuppressed transplant recipients.
Age (along with the associated factor of prior exposure history) is a major determinant of risk for symptomatic disease during respiratory virus infection. Primary infection with most of the acute respiratory viruses often is more severe than secondary infection. Indeed, reinfection with most of these viruses occurs throughout life, but primary infection is much more likely to be associated with severe lower respiratory tract disease, while secondary infection typically is asymptomatic or associated with upper respiratory tract symptoms only. As these infections are ubiquitous, most primary infections (and thus many of the severe cases) occur during the first few years of life. Later, exposure to young children (in populations such as parents of young children and daycare workers) is a risk factor for frequent reinfection. Despite a lifetime of previous exposures, the risk of severe disease increases with age in the elderly, probably because of immune senescence and general medical decline.
Infections with most of the conventional respiratory viruses (e.g., influenza virus, RSV, and hMPV) occur in winter. Typically, there is one dominant virus sweeping through a local community at any one time, a pattern that suggests some population-level interference with transmission. However, outbreaks can be closely spaced, and co-circulation of different viruses or antigenically diverse strains of one virus does occur. In the United States, some regional differences in seasonality have been noted; for example, RSV often appears in Florida and other southeastern states first. Seasons are, of course, reversed in the Northern and Southern hemispheres, so that winter epidemics occur roughly from November to March in the United States but from April to August in Australia; therefore, “winter” epidemics are almost always occurring somewhere in the world. Seasonal variances differ in the tropics, where acute respiratory viral infections are more common in the rainy season.
Infection with these viruses is nearly universal, but disease expression varies among individuals infected with identical viruses. Therefore, investigators have sought to identify risk factors for severe disease. Most single risk factors identified have a moderate effect on the incidence of severe disease, but an accumulation of factors is associated with high risk. Underlying lung disease is a major factor, especially diseases associated with the need for chronic oxygen supplementation. COPD is one of the most profound risk factors. Other severe underlying medical conditions, especially cardiovascular disease, also enhance risk. Smoking (or exposure to wood smoke), low socioeconomic status, and male gender all contribute to a minor increase in the risk of lower respiratory tract illness. Close exposure to infected people is a major factor. For instance, living in close quarters (e.g., housing for military trainees, college dormitories, or nursing homes) puts groups of individuals at risk for rapid outbreaks. The U.S. military has instituted an adenovirus vaccination program to prevent severe or fatal adenovirus respiratory infections that can occur during outbreaks when new recruits are brought together. A breakdown in isolation and hand-washing compliance procedures can lead to cycles of nosocomial transmission of infection in hospital inpatient wards and intensive care units. In assessments of severe lower respiratory tract illness, a history of travel to an area with unusual agents should be considered carefully (e.g., exposure to avian influenza outbreaks in Asia, exposure to MERS-CoV in the Middle East).
Respiratory viruses are transmitted by two principal modes: fomites or large-particle aerosols of respiratory droplets spread directly from person to person by coughing or sneezing. Fomite transmission occurs indirectly when infected respiratory droplets are deposited on the hands or on inanimate objects and surfaces, with subsequent transfer of secretions to a susceptible person’s nose or conjunctiva. Most respiratory viruses do not spread by small-particle aerosols across rooms or down halls, although measles virus and VZV do spread in this manner. Therefore, contact and droplet precautions are sufficient to prevent transmission in most settings; hand washing is especially critical in health care settings during the winter.
APPROACH TO THE PATIENT Common Viral Respiratory Infections
The principal interventions that make a difference in the care of patients with acute respiratory virus infections are supportive, and these factors should be managed meticulously. Hypoxia is managed with supplemental oxygen and respiratory failure with mechanical ventilation. Because the tachypnea and fever that often accompany pneumonia and wheezing frequently result in dehydration, fluid management is important. The astute clinician can narrow the etiologic possibilities on the basis of epidemiologic knowledge; information about viruses circulating in the community (widely available from local reference laboratories, county and state health departments, and the U.S. Centers for Disease Control and Prevention [CDC]); and the patient’s exposure history, age, and immunologic status, including vaccination status. Proper use of rapid diagnostic tests is important. When diagnostic tests are applied only to samples from individuals at high risk of exposure to an infectious agent in the appropriate season, the positive predictive value of the test is increased. A central medical decision is whether or not to use a specific antibacterial or antiviral agent to treat a respiratory infection. Antibiotics do not improve the outcome of uncomplicated respiratory virus infections in otherwise healthy subjects. Some viral infections, especially influenza, can be complicated by secondary bacterial infection. There are only a limited number of licensed antiviral drugs, which should be used when a specific viral etiology is determined. Antiviral treatment generally is effective only when administered early in the course of illness.
The common cold is characterized by nasal congestion, sneezing, rhinorrhea, cough, and sore throat. Laryngitis is accompanied by hoarseness or dysphonia. Acute bronchitis is characterized by a dry or productive cough of <3 weeks’ duration (most prevalent in winter) in the absence of signs and symptoms of pneumonia and of evidence of pneumonia on chest radiography and is primarily caused by viruses. Bacteria play a more prominent role in chronic bronchitis. Bronchiolitis is an acute illness with wheezing and evidence of upper respiratory infection, most commonly seen in the winter in infants and young children. The typical clinical manifestations of acute pneumonia include cough, sputum production, dyspnea, and chest pain. More systemic signs and symptoms also occur in pneumonia, including fever, fatigue, sweats, headache, myalgia, and occasionally nausea, abdominal pain, and diarrhea.
The clinical diagnosis of a respiratory syndrome and the anatomic location of infection is based on history, physical examination, and radiography. A specific viral etiology can be determined by specific diagnostic tests. The gold standard for diagnosing a respiratory viral infection is virus isolation, performed by inoculation of cell cultures with fresh secretions and use of multiple cell types in a reference laboratory staffed by experienced technologists. Direct or indirect fluorescent antibody detection can be used to visualize virus-infected cells in nasal secretions. Rapid antigen-based diagnostic tests are used to detect influenza virus or RSV proteins in nasopharyngeal secretions. The most sensitive tests typically are RT-PCR molecular diagnostic tests that amplify and detect the presence of viral genomic RNA or DNA in respiratory secretions. Multiplex panels assaying a sample for a dozen or more common respiratory viruses are available. These tests must be used and interpreted carefully because of their extreme sensitivity. If care is not taken, it is relatively easy to contaminate a PCR test in the laboratory with small amounts of DNA from a previous reaction. In addition, because a viral genome can sometimes persist in nasal secretions for weeks after an infection resolves, a positive test may indicate a recently resolved rather than a currently acute infection. Despite these limitations, PCR tests generally are considered the most sensitive and specific tests available. Chest radiographs should be obtained for all patients with suspected pneumonia.
TREATMENT Common Viral Respiratory Infections NFLUENZA
A number of drugs are licensed in the United States for the treatment or prophylaxis of influenza (See also Chap. 195). Neuraminidase inhibitors act on both influenza A and B viruses by serving as transition-state analogs of the viral neuraminidase that is needed to release newly budded virion progeny from the surface of infected cells. The cell surface normally is coated heavily with the viral receptor sialic acid. Oseltamivir is administered orally and is effective for the prevention or treatment of uncomplicated influenza in otherwise healthy adults. Observational studies indicate that oseltamivir also may be beneficial during serious illness. The drug is generally well tolerated, with primarily gastrointestinal toxicity. Zanamivir, a powder that is administered through oral inhalation, exhibits effectiveness similar to that of oseltamivir. Moreover, zanamivir is active against some influenza virus strains that are resistant to oseltamivir. Inhalation of zanamivir powder may cause bronchospasm in patients with COPD or asthma. Peramivir is a newer drug that is administered intravenously as a single 600-mg dose. It is efficacious in acute, uncomplicated influenza and is approved for treatment of individuals who cannot take oral or inhaled medications. Its efficacy in severe influenza requiring hospitalization has not yet been demonstrated. Laninamivir is a new drug that is approved in Japan for prophylaxis and treatment of influenza. It is a polymeric zanamivir conjugate that is delivered by oral inhalation, and it exhibits greater potency and longer retention times than conventional zanamivir. The adamantanes amantadine and rimantidine have been used for the treatment of influenza A infection. These drugs interfere with the ion channel activity caused by the M2 protein of influenza A viruses, which is needed for viral particle uncoating after endocytosis. These agents were commonly used in the past, but widespread resistance has been found in many currently circulating influenza A viruses. Therefore, the adamantanes should not be used unless isolate sensitivity is demonstrated, and, in many influenza seasons, the CDC advises against their use. When they are used, they are administered orally and display efficacy against uncomplicated influenza A caused by susceptible strains. The effectiveness of these drugs in serious illness has not been established. Toxicity with rimantadine generally manifests as gastrointestinal intolerance. Toxicity with amantadine is primarily associated with central nervous system symptoms. RSV INFECTION
Ribavirin is a nucleoside antimetabolite prodrug whose activation by kinases in the cell results in a 5′-triphosphate nucleotide form that inhibits RNA replication. The drug was licensed in an aerosol formula in the United States in 1986 for treatment of children with severe RSV-induced lower respiratory tract infection. The efficacy of aerosolized ribavirin therapy remains uncertain despite a number of clinical trials. Most centers use it infrequently, if ever, in otherwise healthy infants with severe RSV disease. Intravenous ribavirin has been used for adenovirus, hantavirus, measles virus, PIV, and influenza virus infections, although a good risk/benefit profile has not been clearly established for any of these uses. OTHER VIRAL TARGETS
Pleconaril, an oral drug with good bioavailability for treatment of infections caused by picornaviruses, has been tested for treatment of rhinovirus infection. This drug acts by binding to a hydrophobic pocket in the VP1 protein and stabilizing the protein capsid, preventing release of viral RNA into the cell. Pleconaril reduces mucus secretions and other symptoms and is being further examined for this indication. Acyclovir and related compounds are guanine-analog antiviral drugs used in the treatment of herpesvirus infections. HSV stomatitis in immunocompromised patients is treated with famciclovir or valacyclovir, and immunocompetent patients with severe oral disease compromising oral intake are sometimes treated with these agents. These compounds have also been used prophylactically to prevent the recurrence of outbreaks, with mixed results. Intravenous acyclovir is effective against HSV or VZV pneumonia in immunocompromised patients. Ganciclovir, given together with human immunoglobulin, may reduce the mortality rates associated with CMV pneumonia in hematopoietic stem cell transplant recipients and has been used as monotherapy in other patient groups. Cidofovir is a nucleotide analog with activity against a large number of viruses, including adenoviruses. Intravenous cidofovir has been effective in the management of severe adenoviral infection in immunocompromised patients but may cause serious nephrotoxicity.
Co-infections with two or more viruses can occur because of the overlap in the winter season of these viruses in temperate areas. In general, in careful studies using cell culture techniques for virus isolation, two or more viruses were isolated from respiratory secretions of otherwise healthy adults with acute respiratory illness in ~5–10% of cases. There is little evidence that more severe disease occurs during co-infections. The incidence of positive results in two molecular diagnostic tests (generally RT-PCR for these RNA viruses) is expected to be higher than that of culture because, as discussed above, molecular tests can remain positive for an extended period after shedding of infectious virus has ended.
Numerous vaccines against influenza viruses have been licensed. In the United States, trivalent and quadrivalent inactivated intramuscular vaccines (covering H3N2, H1N1, and one or two B antigens) and a live attenuated trivalent vaccine for intranasal administration are available, although in 2017 the CDC stopped recommending the latter vaccine. Vaccines are effective when the vaccine strains chosen for inclusion are highly related antigenically to the epidemic strain, but occasional antigenic mismatches cause negligible efficacy of a vaccine component. Antigenic drift caused by point mutations in the H and N molecules leads to antigenic divergence, requiring the production of new vaccines each year. The segmented influenza genome allows reassortment of two viruses during co-infection of one individual or animal; sometimes the consequence is a major antigenic shift resulting in a pandemic. On average, pandemics occur every 20–30 years. There is current concern about the potential for an H5N1 or H7N9 pandemic, and experimental vaccines are being tested for these viruses.
Vaccines were developed for adenovirus serotypes 4 and 7 and were approved for prevention of epidemic respiratory illness among military recruits. Essentially, these vaccines consisted of unmodified viruses given by the enteric route in capsules instead of by the respiratory route—the natural route of infection leading to disease. Inoculation by the altered route resulted in an immunizing asymptomatic infection. Most U.S. military recruits are vaccinated against adenovirus, and epidemic disease recurs in the absence of vaccination.
Live attenuated and subunit vaccine candidates against RSV are under development and are being tested in clinical trials. Subunit RSV vaccines are being tested for maternal immunization and in the elderly. There are no licensed vaccines against rhinoviruses; as there is little or no cross-protection between serotypes, it will be challenging to develop a vaccine covering >100 serotypes. Efforts to develop coronavirus vaccines are in the preclinical stage.
PASSIVE PROTECTION WITH IMMUNOTHERAPY
Palivizumab, a humanized mouse monoclonal antibody to the F protein of RSV, is licensed for prevention of RSV hospitalization in high-risk infants, in half or more of whom it is effective. Experimental treatment of both immunocompetent and immunocompromised RSV-infected individuals has been reported, but the efficacy of this approach has not been established. Next-generation antibodies with higher potency and an extended half-life of ~90 days are being tested.
ISOLATION PROCEDURES, PERSONAL PROTECTIVE EQUIPMENT, AND HAND WASHING
Most respiratory viruses are spread by direct contact—i.e., body-surface to body-surface contact and physical transfer of microorganisms between a susceptible person and an infected person. Poor hand hygiene is probably the most common cause of contact transmission of viruses, which occurs often in family, school, and workplace settings. Transmission between health care workers and patients also takes place when hand-washing compliance is low. Fomites (objects or substances capable of carrying infectious organisms), including instruments, stethoscopes, and other objects in medical environments, can contribute to transmission. Airborne transmission can occur but is probably not the dominant mode of transmission for most respiratory viruses. Particle size affects the epidemiology of airborne pathogens. The composition and size distribution of the generated particles affect the duration of suspension of the infectious agents in the air, the distance across which they can be transported, the interval during which the virus remains infectious, and the site of deposition in the airway of a susceptible host. Direct exposure to large-particle aerosols (e.g., exposure at close range—up to 3 ft—to a cough or sneeze) causes some transmission. Particles of small size can remain suspended in the air for long periods; for instance, particles of ~1 μm can remain suspended for hours. However, in general, only a few respiratory viruses are thought to be transmitted by small-particle aerosols. Protection from transmission in health care environments can be achieved by proper implementation of and adherence to established procedures for the appropriate level of precaution.
Standard and Contact Precautions
Standard precautions, the basic level of infection control that is used in the care of all patients at all times, reduces the risk of transmission of viruses from respiratory tract secretions and mucous membranes. Contact precautions, the second level, require a single room for the patient when possible and the use of additional personal protective equipment, including the wearing of clean, nonsterile gloves when touching a patient or coming into contact with secretions. Fluid-resistant nonsterile gowns are used to protect skin and clothing during activities where contact with secretions is anticipated, and providers should wear each gown for the care of only one patient. A face mask is used when there is potential for direct contact with respiratory secretions. Eye protection (goggles or face shields) is worn in anticipation of potential splashing of respiratory secretions. Good hand hygiene should always follow any patient contact, including washing for 20 seconds with soap and warm water or cleaning with an alcohol-based hand rub. Providers should attempt to avoid the contamination of clothing and the transfer of microorganisms to other patients, surfaces, or environments.
Large-particle droplets are generated during sneezing and coughing and during the performance of some medical procedures, such as airway suctioning in critical care units or bronchoscopy. Such droplets may contain viruses, but their range is usually limited to about 3 ft. Transmission of large-particle droplets occurs when they are deposited on the nasal mucosa or conjunctivae. To prevent transmission in these settings, providers should implement droplet precautions. They should wear a face mask, such as a surgical mask, for close contact (within 3 ft of the patient). Patients also should wear a face mask when exiting the examination room and should avoid coming into close contact with other patients.
Airborne transmission occurs through the dissemination of airborne droplet nuclei (particles of ≤5 μm) or evaporated droplets containing viruses that can remain suspended in the air for long periods. Certain viruses that are carried by the airborne route can be inhaled by a susceptible host in the same room or over a long distance from the source patient, depending on environmental factors such as temperature and ventilation. Viruses transmitted by this route are SARS-CoV, measles virus, and VZV. Patients with these infections should be managed with personal respiratory protection and special ventilation and air handling. Providers should wear an N95 respirator selected with fit-testing, which must be repeated annually. Powered air-purifying respirators (PAPRs) are used in some cases. The patient should be housed in an airborne-infection isolation room—a negative-pressure room that has a minimum of six air exchanges per hour and exhausts through high-efficiency particulate air (HEPA) filtration or directly to the outside.
These emerging paramyxoviruses, which are grouped in their own new genus (Henipavirus), may not be respiratory pathogens in a conventional sense, but they probably infect humans by the respiratory route. Nipah virus is a newly recognized zoonotic virus, named after the location in Malaysia where it was first identified in 1999. It has caused disease in humans who have had contact with infectious animals. Hendra virus (formerly called equine morbillivirus) is another closely related zoonotic paramyxovirus and was first isolated in Australia in 1994. The viruses have caused only a few localized outbreaks, but their wide host range and ability to cause high mortality raise concerns for the future. The natural host of these viruses is thought to be a certain species of fruit bat present in Australia and the Pacific. Pigs may be an intermediate host for transmission to humans in Nipah infection and horses in Hendra infection. Although the mode of transmission from animals to humans is not defined, inoculation of infected materials onto the respiratory tract probably plays a role. The clinical presentation usually appears to be an influenza-like syndrome that progresses to encephalitis, includes respiratory illness, and causes death in about half of identified cases.
Intermittent outbreaks of hantavirus infection occur in South America and cause a severe lung infection: HPS. In addition, more than 400 cases of HPS have been reported in the United States. The disease was first recognized during an outbreak in 1993. About one-third of recognized cases end in death. The Four Corners outbreak (at the intersection of the northwestern corner of New Mexico, the northeastern corner of Arizona, the southeastern corner of Utah, and the southwestern corner of Colorado) is well known; however, cases now have been reported in a total of 32 states. Patients with HPS usually present with an influenza-like illness, including fever. Findings on physical examination are nonspecific, often consisting only of fever and elevated respiratory and heart rates. In addition to respiratory symptoms, abdominal pain is common. Diagnosis is often delayed until illness becomes severe, at which point intubation and mechanical ventilation may be required for respiratory support.
Viruses are the leading causes of acute lower respiratory tract infection in most populations. Influenza virus and RSV are the most common pathogens; hMPV, PIV3, and rhinoviruses account for most other acute viral respiratory infections. Infection in otherwise healthy adults generally leads to partial immunity to these pathogens, with protection against severe lower respiratory disease. However, reinfection, with upper respiratory tract illness, is common throughout life. Special populations such as immunocompromised patients, institutionalized frail elderly patients, and patients with COPD are at highest risk for severe disease.
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