CHAPTER 95: COMMON VIRAL RESPIRATORY INFECTIONS

Acute viral respiratory illnesses are among the most common of human diseases, accounting for one-half or more of all acute illnesses. The incidence of acute respiratory disease in the United States is 3–5.6 cases per person per year. The rates are highest among children <1 year old (6.1–8.3 cases per year) and remain high until age 6, when a progressive decrease begins. Adults have 3–4 cases per person per year. Morbidity from acute respiratory illnesses accounts for 30–50% of time lost from work by adults and for 60–80% of time lost from school by children. The use of antibacterial agents to treat viral respiratory infections represents a major source of abuse of that category of drugs.

It has been estimated that two-thirds to three-fourths of cases of acute respiratory illness are caused by viruses. More than 200 antigenically distinct viruses from 10 genera have been reported to cause acute respiratory illness, and it is likely that additional agents will be described in the future. The vast majority of these viral infections involve the upper respiratory tract, but lower respiratory tract disease can also develop, particularly in younger age groups, in the elderly, and in certain epidemiologic settings.

The illnesses caused by respiratory viruses traditionally have been divided into multiple distinct syndromes, such as the “common cold,” pharyngitis, croup (laryngotracheobronchitis), tracheitis, bronchiolitis, bronchitis, and pneumonia. Each of these general categories of illness has a certain epidemiologic and clinical profile; for example, croup occurs exclusively in very young children and has a characteristic clinical course. Some types of respiratory illness are more likely to be associated with certain viruses (e.g., the common cold with rhinoviruses), whereas others occupy characteristic epidemiologic niches (e.g., adenovirus infections in military recruits). The syndromes most commonly associated with infections with the major respiratory virus groups are summarized in Table 95-1. Most respiratory viruses clearly have the potential to cause more than one type of respiratory illness, and features of several types of illness may be found in the same patient. Moreover, the clinical illnesses induced by these viruses are rarely sufficiently distinctive to permit an etiologic diagnosis on clinical grounds alone, although the epidemiologic setting increases the likelihood that one group of viruses rather than another is involved. In general, laboratory methods must be relied on to establish a specific viral diagnosis.

This chapter reviews viral infections caused by six of the major groups of respiratory viruses: rhinoviruses, coronaviruses, respiratory syncytial viruses, metapneumoviruses, parainfluenza viruses, and adenoviruses. The extraordinary outbreaks of lower respiratory tract disease associated with coronaviruses (severe acute respiratory syndrome [SARS] in 2002–2003 and Middle East respiratory syndrome [MERS] in 2012–2013) are also discussed. Influenza viruses, which are a major cause of death as well as morbidity, are reviewed in Chap. 96. Herpesviruses, which occasionally cause pharyngitis and which also cause lower respiratory tract disease in immunosuppressed patients, are reviewed in Chap. 88. Enteroviruses, which account for occasional respiratory illnesses during the summer months, are reviewed in Chap. 101.

ETIOLOGIC AGENT

Rhinoviruses are members of the Picornaviridae family—small (15- to 30-nm) nonenveloped viruses that contain a single-stranded RNA genome. Human rhinoviruses were first classified by immunologic serotype and are now divided into three genetic species: HRV-A, HRV-B, and HRV-C. The 102 serotypes described initially are encompassed by HRV-A and HRV-B species, whereas HRV-C encompasses more than 60 previously unrecognized serotypes. In contrast to other members of the picornavirus family, such as enteroviruses, rhinoviruses are acid-labile and are almost completely inactivated at pH ≤3. HRV-A and HRV-B species grow preferentially at 33°–34°C (the temperature of the human nasal passages) rather than at 37°C (the temperature of the lower respiratory tract), whereas HRV-C viruses replicate well at either temperature. Of the 101 initially recognized serotypes of rhinovirus, 88 use intercellular adhesion molecule 1 (ICAM-1) as a cellular receptor and constitute the “major” receptor group, 12 use the low-density lipoprotein receptor (LDLR) and constitute the “minor” receptor group, and 1 uses decay-accelerating factor.

EPIDEMIOLOGY

Rhinovirus infections are worldwide in distribution. They are a prominent cause of the common cold and have been detected in up to 50% of common cold–like illnesses by tissue culture and polymerase chain reaction (PCR) techniques. Overall rates of rhinovirus infection are higher among infants and young children and decrease with increasing age. Rhinovirus infections occur throughout the year, with seasonal peaks in early fall and spring in temperate climates. These infections are most often introduced into families by preschool or grade-school children <6 years old. Of initial illnesses in family settings, 25–70% are followed by secondary cases, with the highest attack rates among the youngest siblings at home. Attack rates also increase with family size.

Rhinoviruses appear to spread through direct contact with infected secretions, usually respiratory droplets. In some studies of volunteers, transmission was most efficient by hand-to-hand contact, with subsequent self-inoculation of the conjunctival or nasal mucosa. Other studies demonstrated transmission by large- or small-particle aerosol. Virus can be recovered from plastic surfaces inoculated 1–3 h previously; this observation suggests that environmental surfaces contribute to transmission. In studies of married couples in which neither partner had detectable serum antibody, transmission was associated with prolonged contact (≥122 h) during a 7-day period. Transmission was infrequent unless (1) virus was recoverable from the donor’s hands and nasal mucosa, (2) at least 1000 TCID₅₀ (50% tissue culture infectious dose) of virus was present in nasal washes from the donor, and (3) the donor was at least moderately symptomatic with the “cold.” Despite anecdotal observations, exposure to cold temperatures, fatigue, and sleep deprivation have not been associated with increased rates of rhinovirus-induced illness in volunteers, although some studies have suggested that psychologically defined “stress” may contribute to development of symptoms.

By adulthood, nearly all individuals have neutralizing antibodies to multiple rhinovirus serotypes, although the prevalence of antibody to any one serotype varies widely. Multiple serotypes circulate simultaneously, and generally no single serotype or group of serotypes has been more prevalent than the others.

PATHOGENESIS

Rhinoviruses infect cells through attachment to specific cellular receptors; as mentioned above, most serotypes attach to ICAM-1, while a few use LDLR. Relatively limited information is available on the histopathology and pathogenesis of acute rhinovirus infections in humans. Examination of biopsy specimens obtained during experimentally induced and naturally occurring illness indicates that the nasal mucosa is edematous, is often hyperemic, and—during acute illness—is covered by a mucoid discharge. There is a mild infiltrate with inflammatory cells, including neutrophils, lymphocytes, plasma cells, and eosinophils. Mucus-secreting glands in the submucosa appear hyperactive; the nasal turbinates are engorged, a condition that may lead to obstruction of nearby openings of sinus cavities. Several mediators—e.g., bradykinin; lysylbradykinin; prostaglandins; histamine; interleukins 1β, 6, and 8; interferon γ–induced protein 10; and tumor necrosis factor α—have been linked to the development of signs and symptoms in rhinovirus-induced colds.

The incubation period for rhinovirus illness is short, generally 1–2 days. Virus shedding coincides with the onset of illness or may begin shortly before symptoms develop. The mechanisms of immunity to rhinovirus infection are not well worked out. In some studies, the presence of homotypic antibody has been associated with significantly reduced rates of subsequent infection and illness, but data conflict regarding the relative importance of serum and local antibody in protection from rhinovirus infection.

CLINICAL MANIFESTATIONS

The most common clinical manifestations of rhinovirus infections are those of the common cold. Illness usually begins with rhinorrhea and sneezing accompanied by nasal congestion. The throat is frequently sore, and in some cases sore throat is the initial complaint. Systemic signs and symptoms, such as malaise and headache, are mild or absent, and fever is unusual in adults but may occur in up to one-third of children. Illness generally lasts for 4–9 days and resolves spontaneously without sequelae. In children, bronchitis, bronchiolitis, and bronchopneumonia have been reported; nevertheless, it appears that rhinoviruses are not major causes of lower respiratory tract disease in children. Rhinoviruses may cause exacerbations of asthma and chronic pulmonary disease in adults. The vast majority of rhinovirus infections resolve without sequelae, but complications related to obstruction of the eustachian tubes or sinus ostia, including otitis media or acute sinusitis, can develop. In immunosuppressed patients, particularly bone marrow transplant recipients, severe and even fatal pneumonias have been associated with rhinovirus infections.

DIAGNOSIS

Although rhinoviruses are the most frequently recognized cause of the common cold, similar illnesses are caused by a variety of other viruses, and a specific viral etiologic diagnosis cannot be made on clinical grounds alone. Rather, rhinovirus infection is diagnosed by isolation of the virus from nasal washes or nasal secretions in tissue culture. In practice, this procedure is rarely undertaken because of the benign, self-limited nature of the illness. In most settings, detection of rhinovirus RNA is more sensitive and easier by PCR than by tissue culture. Accordingly, PCR has generally become the standard for detection of rhinoviruses in clinical specimens. Given the many serotypes of rhinovirus, diagnosis by serum antibody tests is currently impractical. Likewise, common laboratory tests, such as white blood cell count and erythrocyte sedimentation rate, are not helpful.

TREATMENT

PREVENTION

Intranasal application of interferon sprays has been effective in the prophylaxis of rhinovirus infections but is also associated with local irritation of the nasal mucosa. Studies of prevention of rhinovirus infection by blocking of ICAM-1 or by binding of drug (pleconaril) to parts of the viral capsid have yielded mixed results. Experimental vaccines to certain rhinovirus serotypes have been generated, but their usefulness is questionable because of the myriad serotypes involved and the uncertainty about mechanisms of immunity. Thorough hand washing, environmental decontamination, and protection against autoinoculation may help to reduce rates of transmission of infection.

ETIOLOGIC AGENT

Coronaviruses are pleomorphic, single-stranded RNA viruses that measure 100–160 nm in diameter. The name derives from the crownlike appearance produced by the club-shaped projections that stud the viral envelope. Coronaviruses infect a wide variety of animal species and have been divided into four genera. Coronaviruses that infect humans (HCoVs) fall into two genera: Alphacoronavirus and Betacoronavirus. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are betacoronaviruses.

In general, human coronaviruses have been difficult to cultivate in vitro, and some strains grow only in human tracheal organ cultures rather than in tissue culture. SARS-CoV and MERS-CoV are exceptions whose ready growth in African green monkey kidney (Vero E6) cells greatly facilitates their study.

EPIDEMIOLOGY

Human coronavirus infections are present throughout the world. Seroprevalence studies of strains HCoV-229E and HCoV-OC43 have demonstrated that serum antibodies are acquired early in life and increase in prevalence with advancing age, so that >80% of adult populations have antibodies detectable by enzyme-linked immunosorbent assay (ELISA). Overall, coronaviruses account for 10–35% of common colds, depending on the season. Coronavirus infections appear to be particularly prevalent in late fall, winter, and early spring—times when rhinovirus infections are less common.

An extraordinary outbreak of the coronavirus-associated illness known as SARS occurred in 2002–2003. The outbreak apparently began in southern China and eventually resulted in 8096 recognized cases in 28 countries in Asia, Europe, and North and South America; ~90% of cases occurred in China and Hong Kong. The natural reservoir of SARS-CoV appeared to be the horseshoe bat, and the outbreak may have originated from human contact with infected semidomesticated animals such as the palm civet. In most cases, however, the infection was transmitted from human to human. Case–fatality rates varied among outbreaks, with an overall figure of ~9.5%. The disease appeared to be somewhat milder in cases in the United States and was clearly less severe among children. The outbreak ceased in 2003; 17 cases were detected in 2004, mostly in laboratory-associated settings, and no cases have been reported subsequently.

The mechanisms of transmission of SARS are incompletely understood. Clusters of cases suggest that spread may occur via both large- and small-droplet aerosols and perhaps via the fecal–oral route as well. The outbreak of illness in a large apartment complex in Hong Kong suggested that environmental sources, such as sewage or water, may also play a role in transmission. Some ill individuals (“super-spreaders”) appeared to be hyperinfectious and were capable of transmitting infection to 10–40 contacts, although most infections resulted in spread either to no one or to three or fewer individuals.

Since it began in June 2012, another extraordinary outbreak of serious respiratory illness, MERS, has been linked with a coronavirus (MERS-CoV). Through May 2014, a total of 536 cases and 145 deaths (27%) have been reported. All cases have been associated with contact or travel to six countries in or near the Arabian Peninsula: Jordan, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. Cases have also been reported in France, Italy, Tunisia, Germany, Spain, and the United Kingdom. Person-to-person transmission has been documented, but sustained spread in communities has not. The source of MERS-CoV has not been established, but it is suspected that bats may be the animal reservoir and that camels serve as an intermediate host.

PATHOGENESIS

Coronaviruses that cause the common cold (e.g., strains HCoV-229E and HCoV-OC43) infect ciliated epithelial cells in the nasopharynx via the aminopeptidase N receptor (group 1) or a sialic acid receptor (group 2). Viral replication leads to damage of ciliated cells and induction of chemokines and interleukins, with consequent common-cold symptoms similar to those induced by rhinoviruses.

SARS-CoV infects cells of the respiratory tract via the angiotensin-converting enzyme 2 receptor. The result is a systemic illness in which virus is also found in the bloodstream, in the urine, and (for up to 2 months) in the stool. Virus persists in the respiratory tract for 2–3 weeks, and titers peak ~10 days after the onset of systemic illness. Pulmonary pathology consists of hyaline membrane formation, desquamation of pneumocytes in alveolar spaces, and an interstitial infiltrate made up of lymphocytes and mononuclear cells. Giant cells are frequently seen, and coronavirus particles have been detected in type II pneumocytes. Elevated levels of proinflammatory cytokines and chemokines have been detected in sera from patients with SARS.

Because MERS-CoV was so recently detected, little is known at present about its pathogenesis. However, it may well be similar to that of SARS-CoV.

CLINICAL MANIFESTATIONS

After an incubation period that generally lasts 2–7 days (range, 1–14 days), SARS usually begins as a systemic illness marked by the onset of fever, which is often accompanied by malaise, headache, and myalgias and is followed in 1–2 days by a nonproductive cough and dyspnea. Approximately 25% of patients have diarrhea. Chest x-rays can show a variety of infiltrates, including patchy areas of consolidation—most frequently in peripheral and lower lung fields—or interstitial infiltrates, which can progress to diffuse involvement. In severe cases, respiratory function may worsen during the second week of illness and progress to frank adult respiratory distress syndrome accompanied by multiorgan dysfunction. Risk factors for severe disease include an age of >50 years and comorbidities such as cardiovascular disease, diabetes, and hepatitis. Illness in pregnant women may be particularly severe, but SARS-CoV infection appears to be milder in children than in adults.

Information regarding the clinical manifestations of MERS-CoV is limited. The case–fatality rate has been high in the initial cases, but this may represent an ascertainment bias, and it is clear that mild cases occur as well. The median incubation period has been estimated to be 5.2 days, and a secondary case was estimated to have an incubation period of 9–12 days. Cases have been reported that begin with cough and fever and progress to acute respiratory distress and respiratory failure within a week. Other cases have manifested as mild upper respiratory symptoms only. Renal failure has been noted, and DPP-4, the host cell receptor for MERS-CoV, is expressed at high levels in the kidney; these findings suggest that direct viral infection of the kidney may lead to renal dysfunction. Diarrhea and vomiting are also common in MERS, and pericarditis has been reported.

The clinical features of common colds caused by human coronaviruses are similar to those of illness caused by rhinoviruses. In studies of volunteers, the mean incubation period of colds induced by corona-viruses (3 days) is somewhat longer than that of illness caused by rhinoviruses, and the duration of illness is somewhat shorter (mean, 6–7 days). In some studies, the amount of nasal discharge was greater in colds induced by coronaviruses than in those induced by rhinoviruses. Coronaviruses other than SARS-CoV have been recovered occasionally from infants with pneumonia and from military recruits with lower respiratory tract disease and have been associated with worsening of chronic bronchitis. Two novel coronaviruses, HCoV-NL63 and HCoV-HKU1, have been isolated from patients hospitalized with acute respiratory illness. Their overall role as causes of human respiratory disease remains to be determined.

LABORATORY FINDINGS AND DIAGNOSIS

Laboratory abnormalities in SARS include lymphopenia, which is documented in ~50% of cases and which mostly affects CD4+ T cells but also involves CD8+ T cells and natural killer cells. Total white blood cell counts are normal or slightly low, and thrombocytopenia may develop as the illness progresses. Elevated serum levels of aminotransferases, creatine kinase, and lactate dehydrogenase have been reported.

A rapid diagnosis of SARS-CoV infection can be made by reverse-transcription PCR (RT-PCR) of respiratory tract samples and plasma early in the illness and of urine and stool later on. SARS-CoV can also be grown from respiratory tract samples by inoculation into Vero E6 tissue culture cells, in which a cytopathic effect is seen within days. RT-PCR appears to be more sensitive than tissue culture, but only around one-third of cases are positive by PCR at initial presentation. Serum antibodies can be detected by ELISA or immunofluorescence, and nearly all patients develop detectable serum antibodies within 28 days after the onset of illness.

Laboratory abnormalities in MERS-CoV infection include lymphopenia with or without neutropenia, thrombocytopenia, and elevated levels of lactate dehydrogenase. MERS-CoV can be isolated in tissue culture in Vero and LLC-MK2 cells, but PCR techniques are more sensitive and rapid and are the standard for laboratory diagnosis. Serologic tests using ELISA and immunofluorescence techniques have also been developed.

Laboratory diagnosis of coronavirus-induced colds is rarely required. Coronaviruses that cause those illnesses are frequently difficult to cultivate in vitro but can be detected in clinical samples by ELISA or immunofluorescence assays or by RT-PCR for viral RNA. These research procedures can be used to detect coronaviruses in unusual clinical settings.

TREATMENT

PREVENTION

The recognition of SARS led to a worldwide mobilization of public health resources to apply infection control practices to contain the disease. Case definitions were established, travel advisories were proposed, and quarantines were imposed in certain locales. As of this writing, no additional cases of SARS have been reported since 2004. However, it remains unknown whether the disappearance of cases is a result of control measures, whether it is part of a seasonal or otherwise unexplained epidemiologic pattern of SARS, or when or whether SARS might reemerge. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) maintain recommendations for surveillance and assessment of potential cases of SARS (www.cdc.gov/sars/). The frequent transmission of the disease to health care workers makes it mandatory that strict infection-control practices be employed by health care facilities to prevent airborne, droplet, and contact transmission from any suspected cases of SARS. Health care workers who enter areas in which patients with SARS may be present should don gowns, gloves, and eye and respiratory protective equipment (e.g., an N95 filtering facepiece respirator certified by the National Institute for Occupational Safety and Health).

Similarly, the WHO and the CDC have issued recommendations for identification, prevention, and control of MERS-CoV infections (www.cdc.gov/coronavirus/mers/index.html). Isolation precautions against airborne spread of infection should be instituted for patients hospitalized for suspected MERS, as described above for SARS.

Vaccines have been developed against several animal coronaviruses but not against known human coronaviruses. The emergence of SARS-CoV and MERS-CoV has stimulated interest in the development of vaccines against such agents.

ETIOLOGIC AGENT

Human respiratory syncytial virus (HRSV) is a member of the Paramyxoviridae family (genus Pneumovirus). It is an enveloped virus ~150–350 nm in diameter and is so named because its replication in vitro leads to the fusion of neighboring cells into large multinucleated syncytia. The single-stranded RNA genome codes for 11 virus-specific proteins. Viral RNA is contained in a helical nucleocapsid surrounded by a lipid envelope bearing two glycoproteins: the G protein, by which the virus attaches to cells, and the F (fusion) protein, which facilitates entry of the virus into the cell by fusing host and viral membranes. HRSV is considered to be of a single antigenic type, but two distinct subgroups (A and B) and multiple subtypes within each subgroup have now been described. Antigenic diversity is reflected by differences in the G protein, whereas the F protein is relatively conserved. Both antigenic groups can circulate simultaneously in outbreaks, although there are typically alternating patterns in which one subgroup predominates over 1- to 2-year periods.

EPIDEMIOLOGY

HRSV is a major respiratory pathogen of young children and the foremost cause of lower respiratory disease in infants. Infection with HRSV is seen throughout the world in annual epidemics that occur in late fall, winter, or spring and last up to 5 months. The virus is rarely encountered during the summer. Rates of illness are highest among infants 1–6 months of age, peaking at 2–3 months of age. The attack rates among susceptible infants and children are extraordinarily high, approaching 100% in settings such as day-care centers where large numbers of susceptible infants are present. By age 2, virtually all children will have been infected with HRSV. HRSV accounts for 20–25% of hospital admissions of young infants and children for pneumonia and for up to 75% of cases of bronchiolitis in this age group. It has been estimated that more than half of infants who are at risk will become infected during an HRSV epidemic.

In older children and adults, reinfection with HRSV is frequent, but disease is milder than in infancy. A common cold–like syndrome is the illness most commonly associated with HRSV infection in adults. It has been increasingly appreciated that severe lower respiratory tract disease with pneumonitis can occur in elderly (often institutionalized) adults, in individuals with cardiopulmonary disease, and in patients with immunocompromising disorders or treatment, including recipients of hematopoietic stem cell transplants (HSCTs) and solid-organ transplants (SOTs). HRSV is also an important nosocomial pathogen; during an outbreak, it can infect pediatric patients and up to 25–50% of the staff on pediatric wards. The spread of HRSV among families is efficient: up to 40% of siblings may become infected when the virus is introduced into the family setting.

HRSV is transmitted primarily by close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. Virus may also be spread by coarse aerosols produced by coughing or sneezing, but it is inefficiently spread by fine-particle aerosols. The incubation period is ~4–6 days, and virus shedding may last for ≥2 weeks in children and for shorter periods in adults. In immunosuppressed patients, shedding can continue for weeks.

PATHOGENESIS

Little is known about the histopathology of minor HRSV infection. Severe bronchiolitis or pneumonia is characterized by necrosis of the bronchiolar epithelium and a peribronchiolar infiltrate of lymphocytes and mononuclear cells. Interalveolar thickening and filling of alveolar spaces with fluid can also be found. The correlates of protective immunity to HRSV are incompletely understood. Because reinfection occurs frequently and is often associated with illness, the immunity that develops after single episodes of infection clearly is not complete or long-lasting. However, the cumulative effect of multiple reinfections is to temper subsequent disease and to provide some temporary measure of protection against infection. Studies of experimentally induced disease in healthy volunteers indicate that the presence of nasal IgA neutralizing antibody correlates more closely with protection than does the presence of serum antibody. Studies in infants, however, suggest that maternally acquired antibody provides some protection from lower respiratory tract disease, although illness can be severe even in infants who have moderate levels of maternally derived serum antibody. The relatively severe disease observed in immunosuppressed patients and experimental animal models indicates that cell-mediated immunity is an important mechanism of host defense against HRSV. Evidence suggests that major histocompatibility class I–restricted cytotoxic T cells may be particularly important in this regard.

CLINICAL MANIFESTATIONS

HRSV infection leads to a wide spectrum of respiratory illnesses. In infants, 25–40% of infections result in lower respiratory tract involvement, including pneumonia, bronchiolitis, and tracheobronchitis. In this age group, illness begins most frequently with rhinorrhea, low-grade fever, and mild systemic symptoms, often accompanied by cough and wheezing. Most patients recover gradually over 1–2 weeks. In more severe illness, tachypnea and dyspnea develop, and eventually frank hypoxia, cyanosis, and apnea can ensue. Physical examination may reveal diffuse wheezing, rhonchi, and rales. Chest radiography shows hyperexpansion, peribronchial thickening, and variable infiltrates ranging from diffuse interstitial infiltrates to segmental or lobar consolidation. Illness may be particularly severe in children born prematurely and in those with congenital cardiac disease, bronchopulmonary dysplasia, nephrotic syndrome, or immunosuppression. One study documented a 37% mortality rate among infants with HRSV pneumonia and congenital cardiac disease.

In adults, the most common symptoms of HRSV infection are those of the common cold, with rhinorrhea, sore throat, and cough. Illness is occasionally associated with moderate systemic symptoms such as malaise, headache, and fever. HRSV has also been reported to cause lower respiratory tract disease with fever in adults, including severe pneumonia in the elderly—particularly in nursing-home residents, among whom its impact can rival that of influenza. HRSV pneumonia can be a significant cause of morbidity and death among patients undergoing stem cell and solid organ transplantation, in whom case–fatality rates of 20–80% have been reported. Sinusitis, otitis media, and worsening of chronic obstructive and reactive airway disease have also been associated with HRSV infection.

LABORATORY FINDINGS AND DIAGNOSIS

The diagnosis of HRSV infection can be suspected on the basis of a suggestive epidemiologic setting—that is, severe illness among infants during an outbreak of HRSV in the community. Infections in older children and adults cannot be differentiated with certainty from those caused by other respiratory viruses. The specific diagnosis is established by detection of HRSV in respiratory secretions, such as sputum, throat swabs, or nasopharyngeal washes. Virus can be isolated in tissue culture, but this method has been largely supplanted by rapid viral diagnostic techniques consisting of immunofluorescence or ELISA of nasopharyngeal washes, aspirates, and (less satisfactorily) nasopharyngeal swabs. With specimens from children, these techniques have sensitivities and specificities of 80–95%; they are somewhat less sensitive with specimens from adults. RT-PCR detection techniques have shown even higher rates of sensitivity and specificity, particularly in adults. Serologic diagnosis may be made by comparison of acute- and convalescent-phase serum specimens by ELISA or by neutralization or complement-fixation tests. These tests may be useful in older children and adults but are less sensitive in children <4 months of age.

TREATMENT

PREVENTION

Monthly administration of RSVIg (no longer available) or palivizumab has been approved as prophylaxis against HRSV for children <2 years of age who have bronchopulmonary dysplasia or cyanotic heart disease or who were born prematurely. Considerable interest exists in the development of vaccines against HRSV. Inactivated whole-virus vaccines have been ineffective; in one study, they actually potentiated disease in infants. Other approaches include immunization with purified F and G surface glycoproteins of HRSV or generation of stable live attenuated virus vaccines. In settings where rates of transmission are high (e.g., pediatric wards), barrier methods for the protection of hands and conjunctivae may be useful in reducing the spread of virus.

ETIOLOGIC AGENT

Human metapneumovirus (HMPV) is a viral respiratory pathogen that has been assigned to the Paramyxoviridae family (genus Metapneumovirus). Its morphology and genomic organization are similar to those of avian metapneumoviruses, which are recognized respiratory pathogens of turkeys. HMPV particles may be spherical, filamentous, or pleomorphic in shape and measure 150–600 nm in diameter. Particles contain 15-nm projections from the surface that are similar in appearance to those of other Paramyxoviridae. The single-stranded RNA genome codes for nine proteins that, except for the absence of nonstructural proteins, generally correspond to those of HRSV. HMPV is of only one antigenic type; two closely related genotypes (A and B), four subgroups, and two sublineages have been described.

EPIDEMIOLOGY

HMPV infections are worldwide in distribution, are most frequent during the winter in temperate climates, and occur early in life, so that serum antibodies to the virus are present in 50% of children by age 2 and in nearly all children by age 5. HMPV infections have been detected in older age groups, including elderly adults, and in both immunocompetent and immunosuppressed hosts. This virus accounts for 1–5% of childhood upper respiratory tract infections and for 10–15% of respiratory tract illnesses requiring hospitalization of children. In addition, HMPV causes 2–4% of acute respiratory illnesses in ambulatory adults and elderly patients. HMPV has been detected in a few cases of SARS, but its role (if any) in these illnesses has not been established.

CLINICAL MANIFESTATIONS

The spectrum of clinical illnesses associated with HMPV is similar to that associated with HRSV and includes both upper and lower respiratory tract illnesses, such as bronchiolitis, croup, and pneumonia. Reinfection with HMPV is common among older children and adults and has manifestations ranging from subclinical infections to common cold syndromes and occasionally pneumonia, which is seen primarily in elderly patients and those with cardiopulmonary diseases. Serious HMPV infections occur in immunocompromised patients, including those with neoplasia, recipients of HSCTs, and children with HIV infection.

DIAGNOSIS

HMPV can be detected in nasal aspirates and respiratory secretions by immunofluorescence, by PCR (the most sensitive technique), or by growth in rhesus monkey kidney (LLC-MK2) tissue cultures. A serologic diagnosis can be made by ELISA, which uses HMPV-infected tissue culture lysates as sources of antigens.

TREATMENT

PREVENTION

Vaccines against HMPV are in the early stages of development.

ETIOLOGIC AGENT

Parainfluenza viruses belong to the Paramyxoviridae family (genera Respirovirus and Rubulavirus). They are 150–200 nm in diameter, are enveloped, and contain a single-stranded RNA genome. The envelope is studded with two glycoproteins: one possesses both hemagglutinin and neuraminidase activity, and the other contains fusion activity. The viral RNA genome is enclosed in a helical nucleocapsid and codes for six structural and several accessory proteins. All types of parainfluenza virus (1, 2, 3, 4A, and 4B) share certain antigens with other members of the Paramyxoviridae family, including mumps and Newcastle disease viruses.

EPIDEMIOLOGY

Parainfluenza viruses are distributed throughout the world; infection with serotypes 4A and 4B has been reported less widely, probably because these types are more difficult than the other three to grow in tissue culture. Infection is acquired in early childhood; by 5 years of age, most children have antibodies to serotypes 1, 2, and 3. Types 1 and 2 cause epidemics during the fall, often occurring in an alternate-year pattern. Type 3 infection has been detected during all seasons, but epidemics have occurred annually in the spring.

The contribution of parainfluenza infections to respiratory disease varies with both the location and the year. In studies conducted in the United States, parainfluenza virus infections have accounted for 4.3–22% of respiratory illnesses in children. The major importance of these viruses is as a cause of lower respiratory illness in young children, in whom they rank second only to HRSV in that regard. Parainfluenza virus type 1 is the most common cause of croup (laryngotracheobronchitis) in children, whereas serotype 2 causes similar, although generally less severe, disease. Type 3 is an important cause of bronchiolitis and pneumonia in infants, whereas illnesses associated with types 4A and 4B have generally been mild. Unlike types 1 and 2, type 3 frequently causes illness during the first month of life, when passively acquired maternal antibody is still present. Parainfluenza viruses are spread through infected respiratory secretions, primarily by person-to-person contact and/or by large droplets, and by contact with fomites contaminated with respiratory secretions. The incubation period has varied from 3 to 6 days in experimental infections but may be somewhat shorter for naturally occurring disease in children.

In adults, parainfluenza virus infections are generally mild and account for fewer than 10% of respiratory illnesses. The advent of contemporary laboratory methods for diagnosis has increased awareness of the impact of parainfluenza infections in adults. In a recent study, parainfluenza virus was the third most common viral isolate from patients 16–64 years old who required hospitalization (0.7 isolate/1000 population). In the 2009 influenza pandemic, parainfluenza virus type 3 was the second most common cause of illness after influenza virus.

PATHOGENESIS

Immunity to parainfluenza viruses is incompletely understood, but evidence suggests that immunity to infections with serotypes 1 and 2 is mediated by local IgA antibodies in the respiratory tract. Passively acquired serum neutralizing antibodies also confer some protection against infection with types 1, 2, and (to a lesser degree) 3. Studies in experimental animal models and in immunosuppressed patients suggest that T cell–mediated immunity may also be important in parainfluenza virus infections. Lack of cellular immune responses is associated with an increased risk of progressive and fatal disease in HSCT recipients.

CLINICAL MANIFESTATIONS

Parainfluenza virus infections occur most frequently among children, in whom initial infection with serotype 1, 2, or 3 is associated with an acute febrile illness in 50–80% of cases. Children may present with coryza, sore throat, hoarseness, and cough that may or may not be croupy. In severe croup, fever persists, with worsening coryza and sore throat. A brassy or barking cough may progress to frank stridor. Most children recover over the next 1 or 2 days, although progressive airway obstruction and hypoxia ensue occasionally. If bronchiolitis or pneumonia develops, progressive cough accompanied by wheezing, tachypnea, and intercostal retractions may occur. In this setting, sputum production increases modestly. Physical examination documents nasopharyngeal discharge and oropharyngeal injection, along with rhonchi, wheezes, or coarse breath sounds. Chest x-rays can show air trapping and occasionally interstitial infiltrates.

In older children and adults, parainfluenza infections tend to be milder, presenting most frequently as a common cold or as hoarseness, with or without cough. Lower respiratory tract involvement in older children and adults is uncommon, although tracheobronchitis and community-acquired pneumonia have been reported in adults.

Parainfluenza viruses, most frequently type 3, are important pathogens in immunosuppressed patients—particularly in HSCT recipients but also in SOT recipients (especially recipients of lung transplants). Patients receiving cancer chemotherapy are also at risk for severe parainfluenza infection. Severe, prolonged, and even fatal parainfluenza-associated respiratory illnesses have been reported in children and adults with severe immunosuppression.

LABORATORY FINDINGS AND DIAGNOSIS

The clinical syndromes caused by parainfluenza viruses (with the possible exception of croup in young children) are not sufficiently distinctive to be diagnosed on clinical grounds alone. A specific diagnosis is established by detection of virus in respiratory tract secretions, throat swabs, or nasopharyngeal washings. Growth of the virus in tissue culture is detected either by hemagglutination or by a cytopathic effect. A rapid diagnosis may be made by identification of parainfluenza antigens in exfoliated cells from the respiratory tract with immunofluorescence or ELISA, although these techniques appear to be less sensitive than tissue culture. Highly specific and sensitive PCR assays have also been developed and have now become the standard for viral diagnosis. Serologic diagnosis can be established by hemagglutination-inhibition, complement-fixation, or neutralization testing of acute- and convalescent-phase specimens. However, because frequent heterotypic responses occur among the parainfluenza serotypes, the serotype causing illness often cannot be identified by serologic techniques alone.

Acute epiglottitis caused by Haemophilus influenzae type b must be differentiated from viral croup. Influenza A virus is also a common cause of croup during epidemic periods.

TREATMENT

PREVENTION

Vaccines against parainfluenza viruses are under development.

ETIOLOGIC AGENT

Adenoviruses are complex DNA viruses that measure 70–80 nm in diameter. Human adenoviruses belong to the genus Mastadenovirus, which includes 51 serotypes. Adenoviruses have a characteristic morphology consisting of an icosahedral shell composed of 20 equilateral triangular faces and 12 vertices. The protein coat (capsid) consists of hexon subunits with group-specific and type-specific antigenic determinants and penton subunits at each vertex primarily containing group-specific antigens. A fiber with a knob at the end projects from each penton; this fiber contains type-specific and some group-specific antigens. Human adenoviruses have been divided into seven subgroups (A through G) on the basis of the homology of DNA genomes and other properties. Revised criteria for classifying human adenoviruses have been proposed; reflecting recent approaches to the characterization of novel adenoviruses, the revised criteria include genome sequence and computational analysis in addition to traditional serologic criteria. The adenovirus genome is a linear double-stranded DNA that codes for structural and nonstructural polypeptides. The replicative cycle of adenovirus may result either in lytic infection of cells or in the establishment of a latent infection (primarily involving lymphoid cells). Some adenovirus types can induce oncogenic transformation, and tumor formation has been observed in rodents; however, despite intensive investigation, adenoviruses have not been associated with tumors in humans.

EPIDEMIOLOGY

Adenovirus infections most frequently affect infants and children. Infections occur throughout the year but are most common from fall to spring. In the United States, adenoviruses account for ~10% of acute respiratory infections in children but for <2% of respiratory illnesses in civilian adults. Nearly 100% of adults have serum antibody to multiple serotypes—a finding indicating that infection is common in childhood. Types 1, 2, 3, and 5 are the most common isolates from children. Certain adenovirus serotypes—particularly 4 and 7 but also 3, 14, and 21—are associated with outbreaks of acute respiratory disease in military recruits. Clusters of particularly severe disease have been seen with adenovirus 14.

Adenovirus infection can be transmitted by inhalation of aerosolized virus, by inoculation of virus into conjunctival sacs, and probably by the fecal-oral route as well. Type-specific antibody generally develops after infection and is associated with protection—albeit incomplete—against infection with the same serotype.

CLINICAL MANIFESTATIONS

In children, adenoviruses cause a variety of clinical syndromes. The most common is an acute upper respiratory tract infection, with prominent rhinitis. On occasion, lower respiratory tract disease, including bronchiolitis and pneumonia, also develops. Adenoviruses, particularly types 3 and 7, cause pharyngoconjunctival fever, a characteristic acute febrile illness of children that occurs in outbreaks, most often in summer camps. The syndrome is marked by bilateral conjunctivitis in which the bulbar and palpebral conjunctivae have a granular appearance. Low-grade fever is frequently present for the first 3–5 days, and rhinitis, sore throat, and cervical adenopathy develop. The illness generally lasts for 1–2 weeks and resolves spontaneously. Febrile pharyngitis without conjunctivitis has also been associated with adenovirus infection. Adenoviruses have been isolated from cases of whooping cough with or without Bordetella pertussis; the significance of adenovirus in that disease is unknown.

In adults, the most frequently reported illness has been acute respiratory disease caused by adenovirus types 4 and 7 in military recruits. This illness is marked by a prominent sore throat and the gradual onset of fever, which often reaches 39°C (102.2°F) on the second or third day of illness. Cough is almost always present, and coryza and regional lymphadenopathy are frequently seen. Physical examination may show pharyngeal edema, injection, and tonsillar enlargement with little or no exudate. If pneumonia has developed, auscultation and x-ray of the chest may indicate areas of patchy infiltration.

Adenoviruses have been associated with a number of non–respiratory tract diseases, including acute diarrheal illness caused by types 40 and 41 in young children and hemorrhagic cystitis caused by types 11 and 21. Epidemic keratoconjunctivitis, caused most frequently by types 8, 19, and 37, has been associated with contaminated common sources such as ophthalmic solutions and roller towels. Adenoviruses have also been implicated in disseminated disease and pneumonia in immunosuppressed patients, including recipients of SOTs or HSCTs. In HSCT recipients, adenovirus infections have manifested as pneumonia, hepatitis, nephritis, colitis, encephalitis, and hemorrhagic cystitis. In SOT recipients, adenovirus infection may involve the organ transplanted (e.g., hepatitis in liver transplants, nephritis in renal transplants) but can disseminate to other organs as well. In patients with AIDS, high-numbered and intermediate adenovirus serotypes have been isolated, usually in the setting of low CD4+ T cell counts, but their isolation often has not been clearly linked to disease manifestations. Adenovirus nucleic acids have been detected in myocardial cells from patients with “idiopathic” myocardiopathies, and adenoviruses have been suggested as causative agents in some cases.

LABORATORY FINDINGS AND DIAGNOSIS

Adenovirus infection should be suspected in the epidemiologic setting of acute respiratory disease in military recruits and in certain clinical syndromes (such as pharyngoconjunctival fever or epidemic keratoconjunctivitis) in which outbreaks of characteristic illnesses occur. In most cases, however, illnesses caused by adenovirus infection cannot be differentiated from those caused by a number of other viral respiratory agents and Mycoplasma pneumoniae. A definitive diagnosis of adenovirus infection is established by detection of the virus in tissue culture (as evidenced by cytopathic changes) and by specific identification with immunofluorescence or other immunologic techniques. Rapid viral diagnosis can be established by immunofluorescence or ELISA of nasopharyngeal aspirates, conjunctival or respiratory secretions, urine, or stool. Highly sensitive and specific PCR assays and nucleic acid hybridization are available and have become the standard for diagnosis based on clinical specimens. Adenovirus types 40 and 41, which have been associated with diarrheal disease in children, require special tissue-culture cells for isolation, and these serotypes are most commonly detected by direct ELISA of stool or by PCR. Serum antibody rises can be demonstrated by complement-fixation or neutralization tests, ELISA, radioimmunoassay, or (for those adenoviruses that hemagglutinate red cells) hemagglutination-inhibition tests.

TREATMENT

PREVENTION

Live vaccines have been developed against adenovirus types 4 and 7 and have been highly efficacious in control of acute respiratory disease among military recruits. These vaccines consist of live, unattenuated virus administered in enteric-coated capsules. Infection of the gastrointestinal tract with types 4 and 7 does not cause disease but stimulates local and systemic antibodies that are protective against subsequent acute respiratory disease due to those serotypes. These vaccines were not produced from 1999 to 2011 but are now available again and are being used effectively in military recruits. Adenoviruses are also being studied as live-virus vectors for the delivery of vaccine antigens and for gene therapy.