Frederick G. Hayden MD, FACP1
Professor of Internal Medicine and Pathology
Michael G. Ison MD, MSC2
Director
1University of Virginia School of Medicine
2Transplant Infectious Diseases, Northwestern University Feinberg School of Medicine
Frederick G. Hayden, M.D., F.A.C.P., has received grant or research support from Abbott Laboratories, Biota, Inc., Loders Croklaan, MedImmune, Inc., Perlan Therapeutics, Inc., Pfizer, Inc., and ViroPharma, Inc.; he is a consultant for Biota, Inc., Immuno-Rx, Inc., Perlan Therapeutics, Roche, and ViroPharma, Inc.; and he participates in the speakers' bureaus for MedImmune and Roche.
Michael G. Ison, M.D., M.Sc., is a consultant for Roche.
June 2006
The respiratory tract can be infected by a diverse group of viruses that produce syndromes ranging in severity from mild colds to fulminant pneumonias. Respiratory viral infections are a leading cause of morbidity, hospitalization, and mortality throughout the world; influenza and pneumonia were the most prevalent infectious causes of death during the 20th century in the United States.1 Respiratory viral infections are also the single most common cause of acute illness and physician visits in the United States and, ironically, a leading cause of prescriptions for antibiotics.2
Epidemiology
The high prevalence of respiratory viral infections results from the large number of infectious agents and serotypes and their efficiency of transmission from person to person; from incomplete immunity, with frequent reinfections by some respiratory viruses; and, in the instance of influenza viruses, from frequent changes in viral antigenicity. The frequency of viral respiratory illness is highest in children up to 4 years of age, gradually declines in teenagers, rises again in parents exposed to children, and is generally lowest in the elderly.3 In families, the average adult contracts two to four acute respiratory illnesses annually, about one quarter of which lead to physician contact. This age-related pattern reflects the gradual acquisition of immunity to some agents and the important role that children play in the transmission of infection. The major reservoir for most respiratory viruses is schoolchildren, who acquire infection in the classroom and introduce it into their homes.
Respiratory viral infections have strong seasonal patterns [see Table 1], but sporadic cases or nosocomial outbreaks can occur year-round. The presence or absence of a lipid-containing envelope affects viral survival in the environment. In temperate areas, the enveloped viruses, such as influenza virus, respiratory syncytial virus (RSV), and coronavirus, are characteristically prevalent during midwinter periods, whereas nonenveloped ones, such as rhinoviruses, are found most often in spring through fall. Although respiratory viruses spread from person to person, the relative importance of different routes depends on the virus. Large-droplet spread over short distances (< 1 m) appears common for many viruses. Viruses such as influenza virus and adenovirus spread efficiently in small-particle aerosols. Others, including rhinovirus and RSV, can spread by hand contact with contaminated skin and fomites, with subsequent inoculation onto the nasal mucosa or conjunctiva. A number of respiratory viruses, mainly RSV, influenza virus, and parainfluenza viruses (PIV), cause outbreaks of infection in closed populations, including hospitals, day care centers, and nursing homes. These outbreaks are associated with a high mortality in frail elderly or immunocompromised hosts.
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Table 1 Epidemiologic Features of Principal Human Respiratory Viruses |
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Pathophysiology
Viruses that infect the respiratory tract can be divided into primary respiratory pathogens, whose transmission and replication are generally restricted to the human respiratory tract, and pathogens that affect the respiratory tract as part of a systemic or, sometimes, locally reactivated infection. The latter group includes three types of viruses: (1) those that cause pneumonia occasionally in healthy persons but more often in immunocompromised or pregnant persons, such as measles virus and varicella-zoster virus (VZV) [see 7:XXVI Herpesvirus Infections]; (2) those that primarily affect immunocompromised hosts, such as cytomegalovirus (CMV) [see 7:XXVI Herpesvirus Infections], herpes simplex virus (HSV) [see 7:XXVI Herpesvirus Infections], and, less frequently, human herpesvirus type 6; and (3) several viruses that cause uncommon but severe zoonotic infections, such as severe acute respiratory syndrome coronavirus (SARS-CoV), avian influenza virus, hantaviruses, and zoonotic paramyxoviruses (e.g., Hendra and Nipah viruses) [see 7:XXXI Viral Zoonoses]. The primary human respiratory viruses (adenovirus, coronavirus, influenza virus, PIV, human metapneumovirus [hMPV], RSV, and rhinovirus) share global distribution, mucosal sites of infection, and person-to-person transmission, but they differ in many important features, including viral composition, seasonality, pathogenesis of disease, and availability of vaccines and specific antiviral agents.
Pathogenesis
Although the extent of viral replication correlates well with severity of illness for most respiratory viruses, the pathogenesis of infection differs for the various groups. Rhinovirus and coronavirus infections are largely limited to the upper respiratory tract, whereas influenza virus, RSV, PIV, SARS-CoV, and adenovirus commonly also infect lower airways. With all respiratory viruses, progression to severe lower respiratory tract disease is more common in patients with impaired immune systems. Respiratory viruses may also produce intra-alveolar inflammatory exudate with hemorrhage, hyaline membrane formation, and differing amounts of epithelial damage. Tracheobronchitis and damage to the respiratory epithelium are typical of influenza virus. RSV infection in young infants is associated with epithelial damage and desquamation, bronchial edema with inflammatory cells, and plugging of small airways. In contrast, damage to the nasal mucosa is modest during rhinovirus or coronavirus colds. Disease manifestations are associated with respiratory tract damage caused by the virus and with host responses to infection, including specific immunologic responses, release of host inflammatory mediators, and neurogenic reflexes. For example, increased levels of histamine, leukotriene C4, eosinophilic cationic protein, and virus-specific IgE occur in the respiratory secretions of children with RSV bronchiolitis. Influenza is associated with increases in the levels of interleukin-6 (IL-6), interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) in the nasal mucosa and the blood; correlations exist between viral replication, symptom expression, and IL-6 production.4,5 Severe avian influenza infections in humans have been associated with elevated serum levels of TNF-α, soluble IL-2 receptor, IL-6, and IFN-γ.6 In persons with colds from rhinoviruses, nasal secretions have higher concentrations of bradykinin, IL-1, IL-6, and IL-8. In addition, respiratory viral infections may alter bacterial colonization patterns, increase bacterial adherence to respiratory epithelium, reduce mucociliary clearance, and alter bacterial phagocytosis by host cells. The impairment of host defenses may foster bacterial infection of areas that are normally sterile, such as the paranasal sinuses, middle ear, and lower respiratory tract.
For many respiratory viruses, the presence of neutralizing antibody in serum and respiratory secretions correlates with protection against infection. Generally, immunity is longer lasting and reinfection less common with virus groups that have many serotypes (e.g., rhinovirus and adenovirus) than in those with only a few serotypes. Although reinfection is frequent with PIV and RSV, severity generally decreases with each episode. In addition to humoral responses, cell-mediated immunity appears to be important for recovery from infection by certain respiratory viruses. In patients who have undergone bone marrow or solid-organ transplantation and in other highly immunocompromised hosts (e.g., patients with acute leukemia or AIDS), many respiratory viruses can cause prolonged infection and severe pulmonary disease, graft dysfunction, and increased mortality.7
Diagnosis
CLINICAL MANIFESTATIONS
In general, respiratory viruses cause acute, spontaneously resolving illnesses, although involvement of the lower airways and certain complications (e.g., otitis media, sinusitis, and exacerbations of asthma or chronic obstructive pulmonary disease [COPD]) are common. Clinical diagnosis is difficult because there are a number of respiratory viruses that can cause a variety of overlapping clinical syndromes. Consequently, clinical diagnosis is accurate only under certain circumstances, such as during an influenza epidemic or outbreaks of RSV bronchiolitis. The limited correlation between virus and syndrome emphasizes the importance of rapid virologic techniques for making a specific etiologic diagnosis, particularly in hospitalized or severely affected patients [see Table 2]. Improvement in the accuracy of clinical diagnosis will require data from community-based surveillance programs, such as those that track which respiratory viral pathogens are circulating within a community.
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Table 2 Laboratory Methods for Diagnosis of Respiratory Viral Infections |
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LABORATORY TESTS
Most respiratory viruses can be isolated from nose and throat swabs, nasal washes or aspirates, sputum, and other lower respiratory samples. Tests done on nasopharyngeal samples taken early in illness provide the most sensitive results, although early samples in SARS may be falsely negative. In addition, some respiratory viruses are slow growing [see Table 2], and most are present in lower titers in adults than in children, so samples from adults may require longer periods for isolation or have lower yields on rapid diagnostic tests. Because temperature fluctuations and freezing may cause loss of infectivity, samples should be transported at refrigerator temperatures (4° C) or on wet ice. Cell culture inoculation (shell vials) followed by antigen detection has a sensitivity of 80% or greater at 1 to 2 days for adenovirus, influenza virus, PIV, and RSV.8
Immunofluorescence testing of exfoliated respiratory cells and enzyme immunoassay for viral antigens are reasonably sensitive, specific, and rapid techniques for detecting some respiratory viruses, particularly RSV and influenza virus.9 Nucleic acid amplification techniques appear to be the most sensitive direct detection methods for most viruses, including SARS-CoV. However, false negative results are possible (during the first days of infection, SARS-CoV may be undetectable even by polymerase chain reaction), and positive results must be confirmed to ensure accuracy. For simultaneous detection of respiratory viruses (influenza virus types A and B; RSV; and PIV types 1, 2, and 3), multiplex reverse transcriptase PCR (RT-PCR) has good sensitivity,10 and a commercial assay is available. Real-time quantitative RT-PCR tests offer a sensitive means of detection of many respiratory viruses and, potentially, of monitoring responses to treatment.
Serologic diagnosis requires paired serum specimens in most instances and is intrinsically slower than direct methods. A variety of serologic techniques are used to measure antibodies, including neutralization, hemagglutination inhibition, complement fixation, and enzyme-linked immunosorbent assay (ELISA). Measurement of complement-fixation antibodies is generally less sensitive than the other methods and does not provide a serotype-specific diagnosis. Immunocompromised hosts often fail to develop diagnostic increases in antibody titers. The combined use of cultures, antigen detection, nucleic acid detection, and serology provides the most comprehensive approach for identification of important respiratory viral pathogens in hospitalized adults.
Clinical Syndromes
COMMON COLDS
Diagnosis
The common cold is generally a mild illness of the upper respiratory tract, primarily affecting the nasopharynx and paranasal sinuses. Rhinoviruses, which cause about 50% of colds, and coronaviruses, which cause 10% to 20%, are the most important pathogens. RSV, PIV, influenza virus, adenovirus, and some enteroviruses also cause colds.
Adults with rhinovirus colds typically have prominent upper respiratory tract symptoms (i.e., sneezing, nasal discharge, nasal obstruction, sore or scratchy throat, and cough) and often have headache but little fever or few systemic complaints other than malaise. Physical findings are nonspecific and include nasal discharge and mucosal erythema. Although generally absent in adults, lower respiratory tract manifestations (e.g., cough, sputum, and wheezing) do occur in about 60% of cases in elderly persons, and lower respiratory tract illness and fever are common in young children infected with rhinovirus.
The differential diagnosis of the common cold includes allergic rhinitis, bacterial nasopharyngitis in infants, and, in rare instances, nasal diphtheria or bacterial nasal infection in adults. Because nearly 50% of colds last longer than 1 week and 25% last up to 2 weeks, it is often unclear whether a complicating viral or bacterial sinusitis has occurred. More than 80% of patients with uncomplicated colds have reversible sinus abnormalities demonstrable on computed tomography,11 and sinusitis is an inherent part of rhinovirus colds. Fever, purulent nasal drainage, cough productive of purulent sputum, increasing symptoms or malaise after 1 week, localized facial pain, or maxillary toothache suggests a bacterial sinusitis.12 Otitis media complicates approximately 2% of colds in adults and 5% of colds in children.13
Treatment
Treatment of the common cold is directed toward specific symptoms. Saline nose drops may be helpful for relief from obstructing secretions, particularly in young children, and warm saline gargles reduce sore throat. Topical decongestants such as phenylephrine and the longer-acting oxymetazoline provide prompt relief of nasal obstruction but may be associated with rebound congestion and possibly throat irritation. Oral pseudoephedrine also provides partial relief of nasal obstruction but may cause anxiousness and insomnia in some patients. The oral decongestant phenylpropanolamine was removed from the market because of increased risk of hemorrhagic stroke. It is uncertain whether topical or oral vasoconstrictors alter the risk of bacterial complications. First-generation oral antihistamines, such as chlorpheniramine and clemastine, reduce sneezing and, to a lesser extent, rhinorrhea, but they are often associated with excess sedation. Nonsedating antihistamines such as loratadine and astemizole are not effective for colds in nonallergic persons. Intranasal ipratropium, a quaternary anticholinergic, reduces cold-associated rhinorrhea by about 30% and may also reduce sneezing, but excess nasal drying may result in blood-tinged mucus.14 Cough suppressants with codeine or dextromethorphan may be used if the cough is severe or disturbs sleep, but they should be used cautiously in patients with underlying chronic obstructive disease. Specific antiviral therapy is not currently available. Two intranasal antiviral agents from different classes, the 3-C protease inhibitor ruprintrivir and the capsid inhibitor pleconaril, are being investigated. Although effective in treating rhinovirus colds, oral pleconaril was not approved by the Food and Drug Administration because of concerns about safety and drug interactions, most notably with oral contraceptives.15 A number of other remedies (e.g.,Echinacea preparations, zinc lozenges or nasal gels, and hot-air inhalation) are of unproven or doubtful value.16,17,18
PHARYNGITIS AND LARYNGITIS
Pharyngitis usually is associated with the same viruses that cause common colds and occurs concurrently with the common cold, but it is also often a prominent complaint of persons with adenovirus and influenza virus infections. Enteroviruses are also important causes of fever and pharyngitis during the summer and early fall.
Diagnosis
Pharyngitis may be associated with characteristic clinical findings, such as palate vesicles and ulcers caused by coxsackievirus-induced herpangina, acute ulcerative stomatitis and pharyngitis caused by HSV, or exudative pharyngitis related to Epstein-Barr virus mononucleosis. Pharyngitis occurs with primary HIV infection and may be associated with mucosal erosions and lymphadenopathy. Pharyngitis caused by group A streptococci and other bacteria (anaerobes, Corynebacterium diphtheriae, Chlamydophila pneumoniae, andMycoplasma pneumoniae) are generally not associated with acute rhinorrhea [see 7:XIX Bacterial Infections of the Upper Respiratory Tract].
Treatment
Treatment for most cases of viral pharyngitis is symptomatic. However, HSV stomatitis, particularly in immunocompromised patients, should be treated with specific antiviral therapy (e.g., acyclovir, famciclovir, or valacyclovir).
Hoarseness caused by laryngitis frequently occurs during acute viral infections and is more common during infections caused by viruses that invade the lower airways. Treatment is primarily voice rest.
ACUTE BRONCHITIS
Diagnosis
Acute bronchitis manifests as a severe or prolonged cough that is usually nonproductive or productive of scant mucoid sputum. Bronchitis can follow infection by any of the respiratory viruses and is a hallmark of influenza. Viral infections commonly cause exacerbation of preexisting airway disease, including chronic bronchitis, emphysema, asthma, and cystic fibrosis. Rhinoviruses are the most frequently implicated viral pathogens.19 HSV can cause bronchospasm and sometimes ulcerative tracheobronchitis in immunocompromised persons and, less often, in immunocompetent persons.
Cough production in acute bronchitis results from direct viral damage to the respiratory mucosa, release of inflammatory mediators, stimulation of airway irritant receptors, and increased production and decreased clearance of respiratory secretions. Infection may also enhance airway hyperreactivity, characterized by increased sensitivity to cold air and pollutants such as smoke.
The differential diagnosis of acute viral bronchitis includes bacterial, mycoplasmal, chlamydial, and pertussis infections, as well as noninfectious entities such as asthma.
Treatment
Treatment of acute bronchitis in otherwise healthy persons is directed at suppression of the cough with codeine or dextromethorphan. However, these agents should be used cautiously in patients with underlying chronic obstructive disease. Antibiotics are generally not indicated.20
INFLUENZA SYNDROME
Diagnosis
The influenza syndrome is characterized by the rapid onset of constitutional and respiratory tract symptoms. Constitutional symptoms, which include fever, chills, prostration, muscle aches, and headache, tend to dominate during the first several days of illness. Respiratory complaints are sore throat, coryza, hoarseness, and, especially, cough. Persistent nonproductive cough, easy fatigability, and asthenia are common in the second week of illness.
Epidemic influenza A and B viruses are the principal causes of the influenza syndrome, but other respiratory viruses, including RSV, PIV, adenovirus, and, sometimes, rhinovirus, can cause influenzalike illness.
Treatment
Treatment for the influenza syndrome is usually symptomatic and includes bed rest, oral hydration, antipyretics, and antitussives. Specific antiviral therapy for influenza virus infection is available [see Influenza Virus, below].21,22,23 Fever should be treated in patients in whom it would contribute to disease, such as children with previous febrile convulsions or patients with preexisting cardiac disease. Aspirin should be avoided in pediatric patients because of its association with Reye syndrome.
CROUP
Diagnosis
Croup, or laryngotracheobronchitis, is a characteristic pediatric syndrome characterized by brassy or barking cough, inspiratory stridor, dyspnea, and hoarseness. Symptoms are often preceded by several days of upper respiratory tract illness and typically become worse at night. Croup is seen primarily in children younger than 5 years and is associated most closely with PIV infections and less often with RSV, hMPV, influenza viruses, adenoviruses, and rhinoviruses. Measles virus is an important cause of severe croup. Acute spasmodic croup is characterized by recurrent attacks precipitated by viral infections, allergies, and, possibly, other factors. The differential diagnosis of croup includes foreign-body aspiration or trauma, bacterial epiglottitis or tracheitis, localized abscess, and angioedema.
Inflammation of the larynx and trachea with subglottic narrowing causes localized obstruction; this obstruction is enhanced by inspiration, because of the extrathoracic location of the obstruction and the compliance of the airway walls in children. In addition, inflammatory changes occur throughout the lower respiratory tract. Symptoms usually abate in 3 to 4 days.
Treatment
Most cases of croup can be managed at home, with moist air. Correction of hypoxemia is essential for hospitalized patients. Aerosolized racemic epinephrine provides transient benefit for those with persistent stridor. Systemic glucocorticoids appear to be effective in moderating the severity of illness and shortening hospitalization; inhaled steroids are beneficial in less severe cases.
BRONCHIOLITIS
Diagnosis
Bronchiolitis is an acute inflammatory disorder of the small airways that is characterized by airway obstruction with wheezing, hyperinflation, and atelectasis. It is associated most closely with RSV infection, which is detected in about 75% of infants hospitalized with bronchiolitis, and less often with rhinoviruses, hMPV, PIV, influenza viruses, and adenoviruses. The peak incidence is in infants from 2 to 6 months of age, and over 80% of cases occur in the first year of life. Premature infants and young children with underlying pulmonary conditions are at high risk for RSV bronchiolitis or pneumonia. After several days of coryza and possibly fever, patients experience acute respiratory distress with wheezing, cough, and, often, inspiratory rales; apnea may occur in babies. Characteristic radiologic features are atelectasis and signs of hyperinflation. In mild cases, bronchiolitis symptoms resolve within several days, but prolonged or severe disease may occur in premature infants or those with underlying cardiopulmonary or immunodeficiency disorders. The major differential diagnosis is asthma, which is uncommon in children younger than 2 years.
The bronchiolitis syndrome results from viral destruction of the respiratory epithelium and associated peribronchiolar mononuclear inflammation, which is perhaps in part immunologically mediated. In infants, because of their disproportionately narrow airways, bronchiolar obstruction causes distal collapse or air trapping and abnormal gas exchange.
Treatment
Correction of hypoxemia is the most important aspect of managing RSV bronchiolitis. Bronchodilators, glucocorticoids, and routine antibiotics are not of proven value. Aerosolized ribavirin therapy is available for selected infants hospitalized with RSV bronchiolitis or pneumonia, but it is an expensive intervention of uncertain value.24
REACTIVE AIRWAY DISEASE EXACERBATION
Infection with respiratory viruses, most commonly rhinoviruses,19 can precipitate exacerbations of chronic respiratory illness. Respiratory viral infections, half of which are rhinovirus infections, can worsen asthma in patients of all ages but are associated with up to 85% of asthma exacerbations in schoolchildren.25 Young children hospitalized with wheezing illness are in most cases infected with rhinoviruses, RSV, hMPV, or PIV. Exacerbations of COPD often result from respiratory viral infections. Approximately 25% of hospitalizations for COPD exacerbations have been associated with a documented respiratory tract viral infection; this percentage increases to 45% of COPD patients admitted between December and March.26
PNEUMONIA
Viral infections have been associated with at least 10% to 15% of community-acquired pneumonias in hospitalized adults and with as many as half of cases in hospitalized infants.27 The relative importance of different viruses depends heavily on the geographic location of the outbreak, the season, and patient age and immune status. Influenza A and, less often, influenza B viruses are the most common causes of community-acquired viral pneumonia in adults and the elderly. In children younger than 3 years, RSV accounts for about 50% of all hospitalizations for pneumonia28; PIV type 3 is also prominent. PIV, hMPV, adenovirus, rhinovirus, and non-SARS respiratory coronavirus infections have been implicated as causes of pneumonia in children and adults.
Respiratory viruses reach the lung by contiguous spread from the upper respiratory tract or inhalation of small-particle aerosols. Depending on the agent, nonrespiratory viruses infect the lung parenchyma by hematogenous dissemination (e.g., CMV, VZV, HSV, and measles) or, less often, by contiguous spread from the tracheobronchial tree (e.g., HSV).
SARS
SARS is a unique form of viral pneumonia. In contrast to most other viral pneumonias, upper respiratory symptoms are usually absent in SARS, although cough and dyspnea occur in most patients. Typically, patients present with a nonspecific illness manifesting fever, myalgia, malaise, and chills or rigors; watery diarrhea may occur as well [see SARS Coronavirus, below].29
Diagnosis
The clinical and radiographic features of most viral pneumonias are not distinctive. Unless a typical exanthem of measles or varicella is present, identification of a specific pathogen requires a careful epidemiologic history and appropriate virologic studies. The clinical and radiologic appearance of viral pneumonia is often indistinguishable from that of bacterial infection, and mixed infections are common. Differentiation between pure viral pneumonias, mixed viral-bacterial pneumonias, and viral infections of the tracheobronchial tree with complicating bacterial pneumonia is usually not possible on clinical grounds.
When taking the history, the clinician should ask about risk factors for exposure, including illness in contacts, institutional residence during an outbreak of illness, travel history, and contact with animals associated with zoonotic transmission. Knowledge of local patterns of viral circulation (e.g., epidemic influenza) and of the patient's immune status are also important in diagnosis. SARS should be suspected in any patient with radiographically confirmed pneumonia who has one or more epidemiologic risk factors for the syndrome [see SARS Coronavirus,below].30
Treatment
Management of viral pneumonia is primarily supportive; ventilatory support has improved the prognosis for patients with extensive viral pneumonia. Specific antiviral therapy for respiratory viruses is limited, and there are no controlled data regarding the use of these agents in pneumonia. Antiviral agents are available to treat influenza31,32 [see Influenza Virus, below]. Inhaled ribavirin is available for RSV and other viral infections but is of uncertain value; it has been used intravenously for adenovirus, hantavirus, measles, PIV, and influenza virus infections. Intravenous acyclovir is effective in HSV or VZV pneumonia.
Pneumonia in Immunocompromised Hosts
Immunocompromised hosts, particularly patients undergoing organ transplantation, experiencing chemotherapy-induced neutropenia and immunosuppression, or with HIV-related immunosuppression, are at risk for reactivation of latent viruses (e.g., HSV, CMV, or adenovirus) or acquisition of community respiratory viruses. Bronchoalveolar lavage yields viruses in up to half of immunocompromised patients with acute pneumonia.33 CMV is the most frequently recovered, accounting for more than 80% of isolates; fewer than 10% of isolates are HSV or various respiratory viruses.34 In immunosuppressed patients, influenza viruses, PIV, RSV, hMPV, rhinovirus, and adenoviruses can cause severe pneumonia35 that is often nosocomially acquired and usually associated with a preceding upper respiratory tract illness.7 It seems prudent to delay chemotherapy or transplantation in the presence of an upper respiratory tract illness.
Intravenous acyclovir is recommended for patients with HSV or VZV pneumonia. Ganciclovir with immunoglobulin appears to be effective in reducing the mortality associated with CMV pneumonia in bone marrow transplant (BMT) recipients and has been used as monotherapy in other patient groups.36 Aerosolized ribavirin and RSV-specific antibodies (RSV immunoglobulin [RespiGam] or palivizumab), if given early, may be effective for preventing progression of RSV pneumonia or treating established disease in such patients [see Respiratory Syncytial Virus, below]. Aerosolized and intravenous ribavirin have been used for adenovirus37 or severe measles. Intravenous cidofovir has been effective in the management of severe adenoviral infection in immunocompromised patients but may cause nephrotoxicity.38
Infections Caused by Specific Agents
ADENOVIRUS
Adenoviruses cause a variety of respiratory tract syndromes, ranging from pharyngoconjunctival fever (often contracted while swimming in contaminated water) to severe pneumonia in infants, immunosuppressed patients, and, uncommonly, healthy adults. Epidemics of acute respiratory disease and pneumonia caused by adenovirus have been recognized for decades in United States military recruits and are expected to continue, given the cessation of immunization programs in the military. However, a new manufacturer for adenovirus vaccine has been identified, and vaccination of military personnel is expected to resume.39
Classification and Pathogenesis
Adenoviruses are medium-sized (65 to 80 nm), nonenveloped, double-stranded DNA viruses, of which 49 antigenic types (divided into six subgroups) are associated with human infections. The protein coat of the virus is composed of hexagonal and pentagonal subunits (capsomers) with long fibers at each vertex, which are the sites of host cell attachment. Type-specific antigens, which give rise to neutralizing antibody, are present on the hexons and fibers of the capsid. The hexons also contain a group-specific antigen with cross-reactivity among most adenoviruses. Only about one half of serotypes cause disease. Immunity correlates with the presence of type-specific neutralizing antibody.
Epidemiology and Transmission
Adenovirus infections may be endemic or epidemic. Lower-numbered serotypes routinely infect infants and young children, although types 3, 4, and 7 can also be acquired later in life and are typically associated with epidemic respiratory disease. In addition to transmission by direct contact with respiratory secretions or infectious aerosols, fecal-oral transmission occurs. Infection may be acquired by pharyngeal or conjunctival inoculation from contaminated water. Adenovirus infection occurs throughout the year but is often recognized during the summer in association with outbreaks of pharyngitis or bronchitis. Adenovirus probably accounts for about 5% of total acute respiratory infections in civilian adults. Nosocomial transmission, including clusters of pneumonia in long-term care facilities and large outbreaks of epidemic keratoconjunctivitis, is well documented.40,41 Persistent infections occur in the tonsils and gastrointestinal (GI) tract, and prolonged viral shedding is common in immunocompromised hosts and in the GI tract of children.
Diagnosis
Clinical features
The incubation period for adenovirus infection of the respiratory tract is usually 4 to 7 days. Adenovirus respiratory infection typically causes a moderate to severe pharyngitis, which is sometimes exudative, and tracheobronchitis. Fever and systemic symptoms are often prominent, and rhinitis, cervical adenitis, and follicular conjunctivitis are common. Pharyngoconjunctival fever, usually associated with serotypes 3, 4, and 7, tends not to be accompanied by lower respiratory tract symptoms. In infants and young children, infections also cause a pertussislike syndrome, croup, and bronchiolitis.
Adenovirus pneumonia is similar to other viral pneumonias; it usually begins with pharyngitis, rhinitis, fever, and cervical adenopathy—conjunctivitis may or may not be present—and then spreads to involve the lower airways and lungs. Bilateral interstitial or alveolar infiltrates are common, although focal consolidation or effusion also occurs.
Laboratory findings
The presence of cells with large basophilic, intranuclear inclusions (smudge cells) in lower respiratory tract biopsy specimens may provide early histopathologic diagnosis. A variety of serotypes have been recovered from stool, urine, and lower respiratory tract specimens of immunocompromised patients.42 Rapid methods of virus detection include enzyme immunoassay (EIA), immunofluorescence, antigen immunochromatography,43 and RT-PCR. Quantitative PCR to measure blood adenoviral DNA levels is emerging as a useful marker for predicting the risk of progression of disease and for monitoring responses to antiviral therapy in immunocompromised patients.
Complications
Acute complications, which occur mainly in children and in immunocompromised hosts, are leukopenia, lymphocytopenia, thrombocytopenia, rhabdomyolysis, disseminated intravascular coagulation, renal failure, and bacterial infection. Survivors may acquire restrictive lung disease or bronchiectasis; children in particular are at risk for bronchiolitis obliterans. Mortality in BMT recipients with adenovirus pneumonia is as high as 60%.44
Adenoviruses are also associated with extrarespiratory infections, including epidemic keratoconjunctivitis; hepatitis and genitourinary infections in immunosuppressed hosts; myocarditis; arthritis; meningoencephalitis; and, especially in children, hemorrhagic cystitis, mesenteric adenitis, intussusception, and gastroenteritis. Adenovirus commonly complicates hematopoietic stem cell transplantation, especially in children, and is often associated with invasive disease, which is associated with reduced survival.45
Treatment
Antiviral therapy of proven value is not available, but intravenous ribavirin, ganciclovir, cidofovir, and immunoglobulin have been used to treat severe adenoviral infections. In invasive adenoviral infections, including pneumonia, mortality appears to be lower in patients who have received cidofovir than in those who have received intravenous ribavirin, but further studies are needed.33,46,47,48 Treatment of invasive adenoviral infections is otherwise supportive.
Prevention
Live attenuated vaccines for adenovirus types 4 and 7 were used in the military but are not licensed for civilian use.39,40 Other control measures are swimming-pool chlorination, careful hand washing, and, in the instance of nosocomial keratoconjunctivitis, use of gloves and proper sterilization of equipment.
CORONAVIRUSES
Classification
Coronaviruses are moderate-sized (100 to 150 nm), enveloped, single-stranded RNA viruses named for their distinctive club-shaped surface projections, which resemble a crown. Three major groups of human respiratory corona-viruses (group 1 [229E and NL63 or NH], group 2 [OC43 and HKU1], and group 3 [SARS-CoV]) have been found to cause disease in humans.49
Epidemiology and Transmission
Coronaviruses are the second most frequently documented cause of common colds. Coronaviruses account for 4% to 15% of cases of acute respiratory disease annually and as many as 35% during peak periods. Most coronavirus infections occur in winter and early spring, but infections have been detected throughout the year. Immunity to infection is incomplete, and reinfection is common. SARS-CoV causes a clinical syndrome unique among the coronaviruses and is discussed separately [see SARS Coronavirus, below].
Diagnosis
Clinical features
The incubation period of coronavirus colds ranges from 2 to 5 days, longer than that of rhinovirus colds. Infections produce a typical coryzal illness that is indistinguishable from colds caused by other viruses. Lower respiratory tract manifestations include pneumonia in children, military recruits, and possibly immunocompromised hosts; exacerbation of asthma in children; and exacerbation of chronic airway disease in adults. In one study, a strong association between HCoV-NL63 infection and croup was reported.50 Reported associations with GI disease, including necrotizing enterocolitis in infants, are controversial. A possible association between NL63 and Kawasaki disease51 requires confirmation, as other studies have not found such an association.52
Laboratory findings
Virus isolation is insensitive; infections are usually identified by serology or by detection of coronavirus RNA. Culture of virus in human embryonic trachea cells is the most sensitive cell culture system for recovering human respiratory tract coronaviruses but is impractical.
Treatment
Effective antivirals or vaccines are unavailable, although intranasal IFN-α is protective against experimental coronavirus colds. Treatment is symptomatic.
SARS CORONAVIRUS
Epidemiology
SARS-CoV is a novel coronavirus identified as the cause of a clinical syndrome, SARS, that was first recognized as an unusual atypical pneumonia in Guangdong Province, China, in November 2002. Over the ensuing 6 months, the virus spread to multiple areas of the world and resulted in over 8,000 illnesses and 774 deaths. China, Hong Kong, Singapore, Taiwan, and Toronto, Canada, were most severely affected. The virus is of animal origin, but the primary reservoir remains uncertain. It possibly originated from Himalayan palm civets found in live-animal markets, but it is infectious for a wide variety of species, including civets, raccoon dogs, ferrets, cats, mice, and monkeys.
Molecular epidemiology has shown that SARS viruses from outbreaks in Hong Kong, Vietnam, Singapore, Toronto, and Taiwan are clonally related to the index case from Hong Kong, whereas viruses from Guangdong Province are genetically more diverse. It is possible that different strains of SARS-CoV have different characteristics, including efficiency of transmission and virulence. Future SARS outbreaks may differ from the outbreak of 2002–2003. Unlike diseases from other respiratory coronaviruses, SARS does not have any recognized seasonality.
Transmission
SARS-CoV spreads efficiently between humans. The primary mode of transmission appears to be through close personal contact: infectious droplets from the cough or sneeze of an infected person travel through the air a short distance and land on respiratory or, possibly, conjunctival mucous membranes or are deposited there indirectly. Other possible modes of spread include fomites, with hand contamination and subsequent self-inoculation; small-particle aerosols; and perhaps fecal-oral transmission. Transmission may be amplified by certain aerosol-generating procedures, such as endotracheal intubation, bronchoscopy, and treatment with aerosolized medications. Recently, modeling was used to substantiate airborne spread of SARS as the cause of the large outbreak at the Amoy Gardens housing complex in Hong Kong.53 Person-to-person spread has been especially common in health care and hospital settings, but transmissions have occurred in homes and hotels, in the workplace, on aircraft, and in taxis. Laboratory transmission of SARS-CoV and presumed acquisition from animals have also occurred.54 No transmission of SARS has been documented before the onset of symptoms or more than 10 days after resolution of fever.
Diagnosis
SARS is diagnosed on the basis of epidemiologic evidence, clinical suspicion, and diagnostic testing. The current case definition of SARS, as well as the most current recommendations on diagnosis, can be found at the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/ncidod/sars).
Epidemiologic evidence
SARS should be included in the differential diagnosis of pneumonia in patients of all ages who have one or more of the following risk factors:
Clinical features
The incubation period of SARS typically ranges from 2 to 7 days but may be as long as 10 days or even, in rare cases, 14 days. Patients present with fever, myalgia, malaise, and chills and may have a nonproductive cough. Other upper respiratory symptoms are usually absent. Fever may be absent, particularly in the elderly, in the initial phase of the illness. Diarrhea may occur.
Laboratory findings
Lymphocytopenia is common in SARS, as are elevations in D-dimer levels and activated partial thromboplastin time. Chest radiographs show evidence of pneumonia in 60% to 100% of patients. Distinctive radiographic findings include a predominant peripheral lung involvement; initial unilateral (typically, in the right lung) focal air-space opacity; and absence of cavitation, lymphadenopathy, and pleural effusion.55High-resolution CT scans are abnormal in up to 67% of patients with normal chest radiographs.
Current diagnostic tests for SARS include RNA detection by RT-PCR, virus culture, and serology. Virus is detectable in respiratory secretions (from the nasopharynx, throat, nose, and lower respiratory tract), as well as in feces, serum, and plasma. Initial RT-PCR techniques were associated with poor sensitivity, particularly in early infection, but improved extraction methods and real-time RT-PCR assays have been developed that allow for more sensitive testing during the first days of infection.56 Any positive test result must be confirmed by testing another clinical sample, reextracting and testing the original specimen, or retesting with an assay that targets different parts of the viral genome. Measurement of specific antibodies at 21 days or later after illness onset using whole-virus immunofluorescence or ELISA remains the gold standard for retrospective confirmation of SARS-CoV infection, because a negative RNA assay does not rule out infection.
Treatment
Initial treatment in patients with suspected SARS is with empirical antimicrobials directed against the typical pathogens in community-acquired pneumonia. There have been no prospective studies of antiviral agents in the treatment of SARS. Ribavirin, lopinavir-ritonavir, IFN-α, and traditional Chinese medicines were used during the 2002–2003 outbreak. In vitro studies, animal testing, and limited human experience suggest that IFN-α has activity against SARS-CoV; IFN-β also has efficacy in vitro.57 Ribavirin is not active in vitro at clinically achievable concentrations and was associated with significant toxicity and no obvious antiviral effects in SARS. Neutralizing antibodies, including recently described humanized monoclonal antibodies, are active in animal models58 and are promising for prophylaxis and perhaps early treatment.
Lung biopsies in patients with SARS suggest a possible immune component; the samples reveal diffuse alveolar damage with desquamation of pneumocytes, inflammatory infiltrates, edema, and hyaline membrane formation. Consequently, high-dose methylprednisolone has been used to modify the disease course and has produced short-term reductions in fever and infiltrates. However, steroid therapy offers uncertain overall benefit and poses such risks as enhanced viral replication, superinfection, and late aseptic necrosis. Thymic peptides, intravenous immune globulin (IVIg), and plasma from patients in the convalescent phase of illness are likewise of unclear benefit. Neutralizing human monoclonal antibodies against S protein are active in experimental animal infection and may prove useful in prophylaxis or possibly early treatment.59
Prevention of exposure is the key to limiting future outbreaks. All patients with suspected SARS should be isolated for at least 10 days; in patients with documented SARS, isolation should be continued for at least 10 days after defervescence. Quarantine of contacts has been used in some outbreaks. Current recommendations regarding appropriate infection control practices can be found at the CDC Web site (http://www.cdc.gov/ncidod/sars). In health care settings, precautions against transmission through airborne respiratory droplets and contact should be strictly enforced, with enhanced airborne precautions used during aerosol-generating procedures.
Prognosis
One third of patients with SARS defervesce and improve clinically. The remainder experience progressive illness, with diarrhea and increasing tachypnea, shortness of breath, and abnormal findings on pulmonary examination and radiography; 20% to 30% of patients require admission to an intensive care unit, usually for mechanical ventilation, and approximately 10% succumb. Death typically results from respiratory failure, multiple organ failure, sepsis, or intercurrent medical illness. More severe disease and higher mortality occur in older adults (≥ 60 years) and those with underlying medical conditions.
HUMAN METAPNEUMOVIRUS
hMPV is a respiratory pathogen that causes infections ranging from colds to severe bronchiolitis and pneumonia. The first metapneumovirus associated with human infection, hMPV was discovered in 2001 when viruses that had been isolated from children presenting with RSV-like illnesses failed to be identified by standard techniques. After random-primer RT-PCR was used, the virus was identified as a new metapneumovirus related to turkey tracheitis virus. Serologic studies demonstrated that by 5 years of age, all children were seropositive and that sera originally collected in 1958 were also positive for hMPV antibodies.60 Two genetic clusters of hMPV that correspond to two different serotypes of hMPV have been recognized on every continent.61
Epidemiology
Infections by hMPV occur worldwide and year-round, with a winter predominance. The season peaks between December and February in the Northern Hemisphere, with a longer season in temperate climates. hMPV can be isolated from 5.5% to 6.5% of children hospitalized with respiratory symptoms. The peak incidence is between 4 and 6 months of age, with most children being younger than 5 years. Coinfection with hMPV and RSV has been documented frequently, and several cases of concomitant hMPV and SARS-CoV infection have been documented.
Asymptomatic or mild illness appears to be much more common with hMPV. hMPV has been detected in 20% of ambulatory young children presenting with respiratory illness in whom no other cause was found. Most cases occurred between December and April.62 In infirm elderly patients, the incidence is 6.5%. The incidence of hMPV in general-community persons presenting with influenzalike illness is only 2%, whereas hMPV can be isolated from 3% to 6.6% of the general community with acute respiratory illnesses.
Diagnosis
Clinical features
hMPV causes clinical syndromes indistinguishable from RSV, including bronchiolitis, croup, asthma exacerbation, and pneumonia. Studies attempting to differentiate hMPV from other respiratory viruses have found that hMPV infection appears to occur at a slightly older age and causes slightly milder symptoms than RSV. Infections in adults manifest as colds, influenzalike illness, bronchitis, exacerbations of underlying airway disease, or, uncommonly, pneumonia. hMPV infections in immunocompromised patients can be severe and have been associated with at least three deaths.
Laboratory tests
RT-PCR has become the standard method of detecting hMPV in respiratory samples. Methods that use primers targeted at the polymerase (L) and fusion (F) protein genes have shown adequate sensitivities. The presence of antibodies is not diagnostic by itself, although seroconversion or a greater than fourfold rise in titer is indicative of recent infection. The virus can be grown in cell culture, but the cytopathic effect may not be seen for up to 14 days.
Treatment
In vitro data suggest that ribavirin has activity against hMPV similar to that against RSV. Likewise, neutralizing antibody titers against hMPV in IVIg are similar to titers against RSV. Clinical studies are required to determine the possible clinical efficacy of ribavirin and IVIg.63
INFLUENZA VIRUS
Classification and Pathogenesis
Influenza viruses belong to the orthomyxovirus family and consist of types A, B, and C. These medium-sized (80 to 120 nm), enveloped, single-stranded RNA viruses contain eight gene segments (seven for influenza C). The segmented nature of the genome allows reassortment of RNA segments between two influenza viruses during dual infection and facilitates antigenic variation. Surface glycoprotein spikes possess either hemagglutinin or neuraminidase activity. Hemagglutinin mediates cell attachment and fusion of virus and cell membranes. By cleaving terminal sialic acid residues and destroying the receptors recognized by hemagglutinin, neuraminidase promotes release of virus from infected cells and spread within the respiratory tract.
Influenza A viruses are further classified into subtypes on the basis of their surface proteins (15 hemagglutinins and nine neuraminidases are recognized in animal influenza viruses). Three A hemagglutinin subtypes (H1, H2, and H3) and two neuraminidases (N1, N2) have caused extensive human infections. Influenza C viruses have seven gene segments and lack a neuraminidase. Influenza viruses are named by the type; location of isolation; isolate number; year of recovery; and, for influenza A type viruses, the subtype (e.g., A/Texas/36/91[H1N1]).
The surface glycoproteins induce host humoral and cellular immune responses and are responsible for the changing antigenicity of influenza viruses. Two major types of antigenic change can occur: drift and shift. Antigenic drift refers to relatively minor changes in hemagglutinin and, less often, neuraminidase antigenicity that occur frequently (usually every few years) and sequentially in the setting of selective immunologic pressure in the population. Drift results from point mutations of the corresponding RNA segment. Antigenic shift occurs only in influenza A viruses and results from acquisition of a new gene segment for hemagglutinin with or without one for neuraminidase. This may occur through genetic reassortment during dual infections with human and animal influenza type A viruses; by the reintroduction of a virus that has not circulated recently in the human population; or by direct transmission to humans of an animal influenza virus that is capable of efficient human-to-human transmission.
Aquatic fowl are the main reservoir for influenza A viruses in nature, although some subtypes also infect other species, including swine, horses, and marine mammals. Swine are susceptible to infection with viruses from both birds and humans and may serve as a so-called mixing vessel, providing an opportunity for the generation of new pathogenic viruses.
Epidemiology and Transmission
Influenza viruses A and B cause annual outbreaks of illness affecting approximately 5% to 10% of adults, with higher rates in children. In the United States, influenza causes an average of over 36,000 deaths64 and 130,000 to 170,000 hospitalizations during each epidemic.21The appearance of a new strain for which most of the population lacks immunity can result in worldwide outbreaks, or pandemics. Pandemic strains are associated with global spread over months and with high attack rates. Three such pandemics occurred during the 20th century; the most severe was the Spanish influenza pandemic in 1918 and 1919, which caused 20 to 40 million deaths worldwide and over 500,000 deaths in the United States.
Epidemic influenza occurs annually in temperate areas, typically between the months of December and March in the Northern Hemisphere, and follows the reintroduction of virus each year. Influenza activity usually occurs in May through August in the Southern Hemisphere and can be year-round in the tropics. Regional outbreaks caused by a particular strain are usually short (6 to 8 weeks), although successive waves of infection by different influenza viruses can occur. Influenza activity in the community is marked by increased medical contacts for febrile respiratory illness, increased absenteeism from school and the workplace, subsequent increased hospitalizations for pneumonia and other cardiopulmonary disorders, and increased mortality. Pneumonia hospitalizations increase by two to five times in high-risk patients. Persons 65 years of age and older constitute nearly 50% of excess hospitalizations and over 85% of deaths from influenza.65
Influenza viruses are transmitted principally via large and small aerosolized particles. Direct transmission of influenza A virus to humans from animals has been documented.66 Although animal-to-human transmission has typically been from swine, direct transmission from birds has resulted in human infections by avian H5, H7, and H9 viruses. At present, an unprecedented epizootic of avian influenza A subtype H5N1 (A/H5N1) virus is causing mortality in some migratory waterfowl and many millions of poultry in Asia, with recent expansion to the Middle East, the Balkans, sub-Saharan Africa, and Europe. Initially recognized in Hong Kong when poultry die-offs and six deaths among 18 affected humans occurred, the virus has been recovered from healthy migratory birds that presumably have been the vehicle for geographic dissemination and infection of domestic poultry. In addition, multiple sublineages of A/H5N1 viruses have become established in poultry in Southeast Asia.67 Sporadic human infections have occurred in China, Thailand, Vietnam, Cambodia, Indonesia, Turkey, and Iraq. Direct contact with infected domestic poultry is the principal route of human infection, although exposure to contaminated environmental sources may account for some infections. Isolated instances of human-to-human transmission have been reported, but there is no evidence of sustained human transmission.
Recognized cases of avian influenza have manifested as severe viral pneumonia and sometimes multiorgan dysfunction. Fatality for patients with confirmed A/H5N1 infection averages about 50% (ranging from 30% to over 80%),68 with many fatalities occurring in otherwise healthy, young individuals.
Avian influenza A subtype H9N2 virus infection has been documented in several children, and a large outbreak of avian influenza A subtype H7N7 virus in the Netherlands was associated with at least one death.69 H7 subtype viruses have also caused outbreaks, predominantly of conjunctivitis, in British Columbia, Canada,69 and infected an immunocompromised man in New York. Influenza A/H5N1 and other avian viruses pose a pandemic threat70; the likelihood of such a pandemic depends on the extent to which viral adaptation through either reassortment with human viruses or mutational evolution might facilitate efficient human-to-human transmission of the virus.71
Diagnosis
Clinical features
The incubation period for influenza virus is short, averaging 2 days (range, 1 to 4 days). Classic influenza is distinguished by abrupt onset of prominent systemic symptoms, including fever, chills, headache, myalgia, malaise, and anorexia. Fever usually lasts for an average of 3 days in adults. Sore throat, dry cough, photophobia, and pain on eye movement occur frequently early in the illness. Mild conjunctivitis, clear nasal discharge, pharyngeal injection, and small, tender cervical lymph nodes are also common. As systemic illness abates, respiratory symptoms become more apparent. The most troubling respiratory symptom is protracted cough, which results from viral tracheobronchitis. Airway hyperactivity and abnormalities in pulmonary function may last from weeks to several months in previously healthy persons. Exacerbations of asthma and other types of preexisting airway disease are often severe. Infections may be subclinical or cause milder illness, including colds. In comparison with typical human influenza, patients with A/H5N1 infections have a higher frequency of diarrhea (perhaps related to direct gastrointestinal infection in some patients) and lower frequency of upper respiratory complaints during the initial phase of illness.68 Most patients develop cough and dyspnea by the end of the first week of illness, and they present with radiographically documented pneumonia. Uncommon presentations have included febrile diarrhea and encephalopathic illness.72
Primary influenza virus pneumonia is a heterogeneous condition, ranging from mild disease with patchy infiltrates to rapidly fatal infection. Severe pneumonia generally accounts for 2% of influenza-associated pneumonia, but during pandemics, it can account for up to 20%; severe pneumonia is the usual presentation of avian A/H5N1 infection. Human influenza A viruses cause more than 90% of cases.73 As many as 40% of patients with influenza pneumonia have no prior underlying disease. Pneumonia usually begins with typical influenza, followed within 1 to 3 days by rapidly progressive dyspnea, cyanosis, diffuse rales, and wheezing. Pleuritic chest pain and blood-tinged sputum or frank hemoptysis occur. Patients with influenza virus pneumonia have a high mortality.
Laboratory tests
Multiple rapid assays are commercially available in the United States to detect influenza A and B antigens or neuraminidase activity; some of these assays differentiate between influenza A and B, and several can be performed by clinical personnel at the point of care [see Table 2]. The specificity of these assays is good to excellent, but the sensitivity varies between approximately 60% and 90%, depending on the sample type, the age of the patient, and the duration of the illness.70,74 Diagnosis can also be made by viral culture or by RT-PCR; virus cultures should be performed only in high-containment laboratories. Rapid antigen assays are less sensitive in detecting A/H5N1 infections than are RT-PCR assays. Nucleic acid amplification assays can detect viral RNA in respiratory tract, blood, and stool samples; pharynx sampling appears to have a higher yield than nasal sampling.68 The Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set can detect the presence of the H5 strain in suspected influenza samples within 4 hours. Further testing can identify the specific H5 subtype.75 When viral pneumonia is present, Gram stain of sputum shows few to many polymorphonuclear leukocytes, but only rarely does it show bacteria. The chest radiograph shows bilateral infiltrates that may be in the form of diffuse interstitial infiltrates, perihilar pulmonary edema, or dense opacifications. On blood counts, leukocytosis with a left shift is variably present.
A definitive diagnosis of influenza can have a significant impact on medical management. In a pediatric population, detection of influenza A antigen resulted in a decrease in antibiotic use, a decrease in duration of antibiotic use in hospitalized patients, and an increase in antiviral use.76
Complications
Secondary bacterial pneumonia should be suspected when fever, increasing cough, and sputum production develop after several days of improvement. Streptococcus pneumoniae is the most common bacterial pathogen, but Staphylococcus aureus, including community-acquired methicillin-resistant strains, causes up to 25% of cases and is associated with high mortality. S. aureus and certain other bacteria produce proteolytic enzymes that activate influenza hemagglutinin and enhance viral replication. Haemophilus influenzae and S. pyogenes are also recognized as causes of bacterial complications. Bacterial infections of the sinuses and ears are frequent. Toxic-shock syndrome and invasive meningococcal disease have also been known to complicate influenza.
Uncommon complications are myositis with rhabdomyolysis, renal failure, disseminated intravascular coagulopathy, myocarditis, pericarditis, myelitis, Guillain-Barré syndrome, and Reye syndrome. Neurologic complications, including encephalopathy or encephalitis, are unusual and occur mainly in children.66,77
Treatment
A variety of antiviral agents are available for treatment of influenza [see Table 3]. The M2 inhibitors amantadine and rimantadine are active against influenza A only, although almost all A/H3N2 viruses and many human isolates of avian A/H5N1 viruses are resistant to these agents.70,78,79 Oral amantadine and rimantadine reduce the duration of fever and symptoms of uncomplicated influenza A virus infection by 1 to 2 days and provide more rapid overall functional recovery. Effectiveness in preventing complications or treating severe illness in hospitalized patients is uncertain. Resistant viruses may arise during treatment and are transmissible to close contact as well as in the community.80 Side effects of amantadine are GI upset and minor, reversible central nervous system symptoms (e.g., insomnia, dizziness, and difficulty with concentration). Rimantadine appears to be as effective as amantadine and is associated with a lower risk of CNS side effects.
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Table 3 Agents Used to Prevent and Treat Influenza123,124 |
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The neuraminidase inhibitors, zanamivir and oseltamivir, are active against influenza A and B viruses,32 including the avian A/H5N1 strain. Resistance to oseltamivir may emerge during treatment; it may also occur in immunocompromised hosts and in some patients with A/H5N1 infection that is associated with treatment failure.81,82 Zanamivir is administered by inhalation and may, in rare cases, cause bronchospasm, which can be severe. Oseltamivir is administered orally and is associated with self-limited GI upset in about 10% to 15% of treated patients; this can be reduced by taking the medication with food. Treatment of acute uncomplicated influenza in adults with inhaled zanamivir or oral oseltamivir provides symptomatic relief, reduces time to functional recovery, and decreases the likelihood of lower respiratory tract complications leading to antibiotic use.22,23 In children 1 to 12 years of age, oseltamivir provides symptomatic relief and also reduces the likelihood of otitis media.21 Oseltamivir treatment has been associated with reduced risk of hospitalization in both previously healthy and high-risk or elderly adults.83
Influenza pneumonia
Treatment of influenza virus pneumonia is primarily supportive. Improvements in assisted ventilation techniques have raised the survival rate above 50%, although pulmonary fibrosis develops in some patients. M2 inhibitors, NA inhibitors, and aerosolized or I.V. ribavirin, which is active against influenza A and B viruses, have been used with uncertain benefit. Combination therapies (e.g., an M2 inhibitor plus a neuraminidase inhibitor for influenza A) show enhanced activity in animal models. Although unstudied, the use of neuraminidase inhibitors, either alone or in combination with other agents, seems reasonable in the treatment of influenza virus pneumonia.
Prevention
Chemoprophylaxis
In the past, antiviral chemoprophylaxis with amantadine or rimantadine was about 70% to 90% effective in preventing illness caused by influenza A virus. Unfortunately, the emergence of resistance to M2 inhibitors in the majority of circulating influenza A viruses suggests that amantadine and rimantadine should not currently be used for prophylaxis.78,84
The neuraminidase inhibitors are also effective for prophylaxis of influenza A and B infections. Chemoprophylaxis can provide several weeks' protection to patients immunized after influenza A activity has begun; it can be given throughout the influenza season to those who cannot receive influenza vaccine (e.g., those with egg allergy) or who are unlikely to respond to the vaccine. Chemoprophylaxis also can be used for protection of high-risk persons at times when the epidemic strain diverges significantly from the vaccine antigens. Both inhaled zanamivir85,86 and oral oseltamivir87,88 prevent influenza when used for seasonal prophylaxis or after exposure (e.g., for family or nursing home contacts), but only oseltamivir has been approved by the Food and Drug Administration for this indication. Oseltamivir has been found to be safe for the treatment of children as young as 1 year, as well as for prophylaxis in these patients89; inhaled zanamivir has been found to be safe in children as young as 5 years. Of note, both the M2 and the neuraminidase inhibitors may reduce the efficacy of live attenuated influenza vaccine, if the vaccine and the antiviral agent are given together.
Immunization
Influenza vaccines are available in two forms: (1) an intramuscular preparation containing formalin-inactivated virus and purified surface antigen and (2) an intranasal spray containing live attenuated viruses.21 Both are made from egg-grown virus. Vaccine composition is reviewed annually and adjusted to reflect changes in antigenicity and anticipated circulation of viral strains; current vaccines contain one influenza B and two influenza A (H1 and H3 subtypes) antigens.21 The efficacy of these vaccines is approximately 70% to 90% in young adults, especially when the vaccine antigen and the circulating strain are closely matched. Immunization in healthy working adults is associated with fewer upper respiratory illnesses and fewer visits to physicians' offices.90,91 The intranasal vaccine is currently approved only for healthy persons 5 to 49 years of age; it appears to be less effective in the elderly but possibly superior to inactivated vaccine in young children. Immunization with inactivated vaccine reduces influenza-related hospitalizations, including acute cardiovascular events and COPD exacerbations,92 and reduces mortality in ambulatory elderly patients by 40% to 60%.93 Wide-scale immunization of schoolchildren may reduce influenza-related mortality in older adults.94 Although inactivated vaccine is less effective in infirm elderly patients, it provides partial protection against pneumonia and death.
The highest priority for vaccination should be given to persons at increased risk for influenza-related complications and their contacts [seeTable 4]. Administration of the inactivated vaccine is associated with soreness at the injection site in as many as one third of recipients, but fever or systemic reactions are uncommon in adults. Influenza vaccination does not adversely affect CD4+ T cell counts or accelerate progression to AIDS or death in HIV-infected patients.95
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Table 4 Indications for Influenza Vaccination*21 |
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The intranasal vaccine causes transient coryza and sore throat. Vaccine viruses are recoverable from nasal samples in low titers for up to 1 week in adults and are genetically stable. Although viral transmission is rare between children and has not been documented in adults to date, vaccine recipients should avoid close contact with highly immunocompromised hosts (e.g., stem cell transplant recipients) for 1 week after immunization.21 Veterinary vaccines for A/H5N1 infection are available. Various strategies are being pursued to develop human vaccines, although the H5 hemagglutinin appears to be poorly immunogenic in humans, such that at least two doses, preferably combined with an adjuvant agent, will be required.
PARAINFLUENZA VIRUSES
PIV infections are the most commonly recognized cause of croup, accounting for up to 75% of cases with a documented viral etiology, and they are a leading cause of lower respiratory tract disease resulting in hospitalization of infants. Infection with PIV induces partial immunity that moderates disease severity; reinfection in older children and adults produces milder respiratory illness and colds.
Classification and Pathogenesis
Human PIVs are medium-sized (120 to 150 nm), enveloped RNA viruses belonging to the Paramyxoviridae family and are classified into four antigenically stable types (1, 2, 3, and 4); type 4 is further classified into subtypes A and B. PIV replicates in epithelial cells of the upper and lower respiratory tract, and antibodies to the two major envelope surface glycoproteins—namely, the hemagglutinin-neuraminidase protein and the fusion protein—confer protection against infection. These proteins are necessary for attachment of virus to host cell receptors and membrane-fusing activity. PIV type 1 and type 2, which cause croup and laryngitis, probably replicate principally in the major airways, whereas PIV-3 causes lower respiratory tract infections.
Epidemiology and Transmission
PIV infections occur initially during childhood; PIV-3 infections often occur during infancy and are an important cause of illness in infants younger than 6 months, as well as in immunocompromised persons. The incidence of croup and respiratory disease caused by PIV-1 or PIV-2 infections is highest between the ages of 6 months and 5 years. PIV-1 typically causes epidemics lasting several months, peaking in October or November of alternating years, whereas PIV-2 activity is more sporadic. PIV-3 causes infections throughout the year, with outbreaks during the spring and summer.
PIVs are transmitted from person to person, either by direct contact with respiratory secretions or by large aerosol droplets. Transmission occurs readily in families, and reinfections in older children and adults are common. Outbreaks occur in nurseries, day care centers, and hospitals, with attack rates of 40% or higher in susceptible patients.
Diagnosis
Clinical features
The incubation period of PIVs is approximately 3 to 6 days. Virus replication is generally limited to the respiratory tract, although viremia and CNS infections96 have been rarely documented. Initial infections cause fever, rhinitis, pharyngitis, laryngitis, croup, and bronchitis in children.
Laboratory tests
Immunofluorescence testing of respiratory secretions and RT-PCR have been used for rapid PIV detection. Culture is generally slow, requiring days to weeks. Serologic assays, including complement fixation, ELISA, and hemagglutination assays, are used for retrospective diagnosis.
Treatment
Specific antiviral therapy of proven value has not been established. Early treatment with aerosol ribavirin may benefit some immunocompromised patients with serious infections, and intravenous ribavirin has been used for treatment of PIV pneumonia in BMT patients.97
Prevention
An effective PIV vaccine is not yet available, but live attenuated vaccines derived from either human or bovine PIV have been developed and appear to be safe and immunogenic in children. Infection control measures, with an emphasis on exclusion of sick caregivers and isolation protocols, may reduce the risk of nosocomial acquisition in compromised hosts.
Complications
In adults and older children, reinfections are often asymptomatic but may cause serious lower respiratory tract disease, including exacerbations of chronic airway disease and pneumonia. During periods of circulation, about 2% to 3% of cases of community-acquired pneumonia in adults are linked to PIV infection.98 Severe pneumonia, sometimes in the absence of upper respiratory tract illness, occurs in immunosuppressed adults and children, particularly after BMT.5
RESPIRATORY SYNCYTIAL VIRUS
Classification and Pathogenesis
RSV is a paramyxovirus with surface glycoproteins that have neither hemagglutinin nor neuraminidase activity. The F protein is responsible for fusion of the viral envelope with the host cell membranes. Antibody against this protein neutralizes RSV infectivity and blocks syncytial cell formation. The G protein is responsible for attachment. Two major subgroups (A and B) are distinguished primarily by antigenic differences in the G glycoprotein, and multiple strains are recognized within each subgroup.
Epidemiology and Transmission
RSV is the major cause of lower respiratory tract disease in infants and young children, accounting for 45% to 90% of bronchiolitis cases and up to 40% of pneumonia cases. Approximately 40% of infections in the first year of life cause lower respiratory tract illness, and 1% to 2% result in hospitalization; about 10% of hospitalized infants require ventilatory support.
As many as 100,000 hospitalizations and 510 deaths of infants and children are attributed to RSV each year in the United States.99 RSV is also increasingly recognized as a cause of lower respiratory tract disease in older adults and immunocompromised persons.100,101 Mortality is usually less than 1% in previously healthy infants but is much higher in persons with primary immunodeficiency, persons undergoing cancer chemotherapy, and persons with preexisting pulmonary and heart disease.102 The number of RSV-related deaths in the elderly is estimated to be 10-fold higher than that in infants.103 In elderly persons, it is estimated that RSV is associated with 2% to 9% of hospitalizations or deaths caused by pneumonia100 and about 10% of hospitalizations for acute cardiopulmonary conditions.99 Each year, RSV is responsible for an estimated 11,321 deaths in the United States.64
RSV causes prolonged outbreaks of infection from late fall to spring annually in temperate climates.94 Most outbreaks peak between January and March in the Northern Hemisphere, but sporadic cases can occur year-round. Epidemics are associated with increased pediatric hospitalizations and deaths from lower respiratory tract illness. Essentially all children are infected within several years after birth. Immunity is incomplete, and reinfections in children and adults are common. Higher titers of circulating and mucosal antibody occur with successive infections and appear to be associated with milder illness.
RSV appears to be spread by large-particle aerosols during close personal contact and by hand contamination with self-inoculation of the eye or nose. RSV is a major nosocomial pathogen, and high attack rates occur during outbreaks in hospitals, transplantation units, day care centers, and geriatric homes.104 Illness rates are commonly 20% to 50% among hospital staff and patients during epidemics. In households, secondary infection occurs in about one third of adults.
Diagnosis
Clinical features
The incubation period of RSV averages 4 to 5 days but ranges up to 1 week. In infants and young children, almost all primary infections are symptomatic, and 40% or more are associated with bronchiolitis or pneumonia. Febrile upper respiratory tract illness and otitis media are common.
Most recurrent infections in adults are associated with upper respiratory tract illness. Adults typically experience coryza, pharyngitis, and cough, often with low-grade fever. Bronchitis, influenzalike illness, pneumonia, and exacerbations of asthma and chronic bronchitis also occur. In the elderly, the clinical manifestations and outcomes of RSV infections are similar to those of influenza.99,105 Elderly adults hospitalized with RSV commonly have dyspnea, wheezing, and sputum production. Viral bronchopneumonia or secondary bacterial pneumonia appears to complicate a high proportion of RSV infections in such patients.
RSV causes severe lower respiratory tract disease in immunosuppressed patients, particularly BMT recipients and acute leukemia patients receiving chemotherapy.6 Most cases are nosocomial; mortality exceeds 60% when pneumonia develops. Rhinitis with sinusitis or otitis often precedes the development of pneumonia by several days and may provide a clue to diagnosis.
Laboratory tests
Testing of bronchoalveolar lavage samples with RSV antigen or RNA detection provides rapid diagnosis in pneumonia cases. Commercially available ELISAs are sensitive to RSV in children, but nasopharyngeal samples are an insensitive means of detecting RSV antigen in adults, who have low titers of virus in the upper respiratory tract. RT-PCR is a reasonably sensitive technique to detect RSV infection, whereas culture of virus is slow and less sensitive. Serology is more sensitive than cell culture for diagnosis in adults but is slow because of the need for paired sera.99
Treatment
The value of aerosolized ribavirin in the management of RSV disease in hospitalized children remains controversial, and studies of its value in mechanically ventilated infants have yielded conflicting results.23 Aerosolized ribavirin should be considered for infants hospitalized with RSV infections who are at high risk for severe or complicated illness (e.g., those with congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis, and immunodeficiency), for those who are already severely ill, and for those who are younger than 6 weeks. Treatment with polyclonal or monoclonal RSV antibodies does not provide clear therapeutic benefit for RSV-infected infants and young children. Aerosol ribavirin may reduce progression from upper to lower respiratory tract disease in highly immunocompromised hosts. Early treatment with aerosolized ribavirin plus IVIg, RSV immunoglobulin, or palivizumab appears to benefit immunosuppressed patients with RSV pneumonia.106
Prevention
Passive immunoprophylaxis by monthly administration of high-titer anti-RSV immunoglobulin or anti-F monoclonal antibody (palivizumab) reduces the risk of lower respiratory tract RSV disease and hospitalization in high-risk infants and children. Palivizumab is approved for prophylaxis in premature infants and children younger than 2 years with bronchopulmonary dysplasia and is appropriate for infants and young children with hemodynamically significant congenital heart disease.107 A phase I trial has found that palivizumab appears to be safe and well tolerated in recipients of hematopoietic stem cell transplants.108 No vaccine against RSV is available yet, but studies of intranasal live-attenuated vaccine in children and injected subunit vaccine in elderly persons are ongoing.
Interruption of nosocomial transmission may be facilitated by thorough hand washing,109 decontamination of fomites, early identification and rapid isolation of infected infants and other potential RSV cases,110 and cohorting of staff with infected infants.111 Regular use of gowns, gloves, disposable eye-nose goggles, and possibly masks by hospital staff caring for infected children may further reduce the risk of nosocomial RSV spread.
RHINOVIRUS
Classification and Pathogenesis
Rhinoviruses are small (30 nm), nonenveloped viruses that belong to the Picornaviridae family. They have a single-stranded RNA genome and are composed of four structural proteins. Three of the proteins induce neutralizing antibodies and form the basis for serotyping. The large number of serotypes (> 110) makes the development of an effective vaccine unlikely. Nearly 90% of rhinovirus serotypes use intercellular adhesion molecule-1 as a common cellular receptor. Although replication of rhinovirus was thought to be limited to the upper respiratory tract, increasing data suggest that rhinovirus can replicate and cause disease in the lower airways.112
Epidemiology and Transmission
Rhinoviruses cause approximately one infection per person per year in adults, and rates are even higher in children. Rhinovirus causes about 50% of colds in adults each year and up to 90% during the fall months.113 Immunity to rhinovirus is serotype specific and relatively enduring after infection, although reinfection can occur. Rhinoviruses cause infections year-round but are most prevalent in early fall and late spring. The relative importance of fomite spread with hand contamination and self-inoculation into the eyes or nose and aerosols in rhinovirus transmission is uncertain under natural conditions.
Diagnosis
Clinical features
The incubation period of rhinoviruses averages about 2 days, with a range of 1 to 5 days. Rhinovirus colds vary in severity from mild episodes characterized by 1 to 2 days of coryza or scratchy throat to illnesses with profuse rhinorrhea, pharyngitis, and tracheobronchitis. Symptoms usually peak on the second and third days of illness, and the median duration is 1 week.
Rhinovirus infections are associated with more frequent lower respiratory tract illness in the elderly and with bronchospasm and protracted cough in persons with preexisting airway disease.114,115 Rhinovirus is the major infectious cause of asthma exacerbations in children and in adults. In addition, rhinovirus infections are associated with acute sinusitis,116 otitis media,117 exacerbations of chronic bronchitis, and lower respiratory tract disease in infants and young children. In BMT recipients, rhinovirus infection has been associated with pneumonia and poor prognosis.1
Laboratory tests
No rapid diagnostic test for rhinovirus infection is routinely available; detection is usually by virus isolation and, more recently, by RT-PCR.118
Treatment
No antiviral therapy of proven clinical value is currently available, but several approaches are under investigation. Oral administration of the capsid-binding antirhinoviral compound pleconaril reduces the severity and duration of uncomplicated rhinovirus colds in adults but is associated with a risk of drug interactions.119 Nonselective regimens such as high-dose vitamin C, Echinacea preparations, inhalation of heated air, and zinc lozenges are of doubtful value.
Prevention
Barrier control measures may be beneficial, although tissues impregnated with virucides have proved disappointing in this regard. Hand washing and avoidance of finger-to-nose and finger-to-eye contact should reduce the risk of infection. Because of the risk of nosocomial transmission of rhinovirus infections, adherence to infection control precautions in cases of upper respiratory tract illness is important.
BOCAVIRUS
With the use of a virus screening library, a novel parvovirus—human bocavirus (HBoV)—was recently discovered.120 One study detected the virus in 3.1% of nasopharyngeal aspirates collected in children hospitalized with acute respiratory illness. Half of the children had an underlying history of asthma. All had some degree of respiratory distress and fever at the time of presentation.120 Another study documented HBoV infection in 5.6% of children presenting to a hospital with respiratory symptoms in the winter months; interestingly, half of the patients with HBoV had evidence of coinfection with another virus.121 Further studies are needed to fully identify the epidemiology, clinical presentation, and preventive and therapeutic options for this new virus.
HANTAVIRUS
Hantavirus causes hantavirus cardiopulmonary syndrome (HCPS).122 Most HCPS cases have occurred in young to middle-aged adults with no underlying disease. The largest number of cases have occurred in New Mexico, Arizona, and California, but cases have also been identified throughout western North America and sporadically in the eastern United States. HCPS is typically a zoonosis; the principal animal reservoir is the deer mouse. Human infections occur by inhalation of aerosols of infectious excreta. Detailed discussion of HCPS is provided elsewhere [see 7:XXXI Viral Zoonoses].
INTERNET RESOURCES
A listing of Internet resources with information about respiratory viral infections is provided [see Sidebar, Internet Resources for Respiratory Viral Infections].
Internet Resources for Respiratory Viral Infections
o National Respiratory and Enteric Virus Surveillance System http://www.cdc.gov/ncidod/dvrd/revb/respiratory/eadfeat.htm
o Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/sars
o World Health Organization http://www.who.int/csr/sars/en/
o World Health Organization http://www.who.int/csr/disease/influenza/en
o Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm
o National Foundation for Infectious Diseases http://www.nfid.org/library/influenza
o American Lung Association http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35426
o World Health Organization http://www.who.int/csr/disease/avian_influenza/en/index.html
o Centers for Disease Control and Prevention http://www.cdc.gov/flu/avian/index.htm
o U.S. Department of Health & Human Services http://www.pandemicflu.gov
o National Respiratory and Enteric Virus Surveillance System http://www.cdc.gov/ncidod/dvrd/revb/respiratory/hpivfeat.htm
o National Respiratory and Enteric Virus Surveillance System http://www.cdc.gov/ncidod/dvrd/revb/respiratory/rsvfeat.htm
o American Lung Association http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35695
o Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/diseases/hanta/hps/index.htm
o Emerging Viruses Research Center Hantavirus Reference Laboratory http://www.hsc.unm.edu/pathology/research/Hjellelab
o American Lung Association http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35428
References
Editors: Dale, David C.; Federman, Daniel D.