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.