Respiratory viral infections are a major cause of morbidity in children around the world. Healthy infants and preschool children experience between 6 and 10 respiratory illnesses per year, and school-age children and adolescents experience 3 to 5 illnesses annually. Respiratory viral infections are classified into (1) upper respiratory tract infections (URIs), also known as the common cold, rhinitis, pharyngitis, otitis media, and conjunctivitis; and (2) lower respiratory tract infections (LRTIs), namely croup, laryngitis, tracheobronchitis, bronchiolitis, and pneumonia. With molecular techniques becoming the new gold standard for the detection of respiratory viruses, important changes have occurred in our understanding of the role of these viruses in respiratory illnesses in children, particularly in LRTIs. Newly discovered viruses have been identified in the last decade (eg, human bocaviruses, human coronaviruses) that have been associated with respiratory illnesses. In addition, areas that require further research have been uncovered such as the causality between newly discovered viruses and clinical disease, the significance of viral co-detections, and the role of viral quantitation and its correlation with disease severity. Despite these changes, epidemiologic studies have demonstrated that the major associations established by traditional techniques (eg, viral culture, antigen detection, and serology) remain valid. Despite the major advances observed with the development of diagnostic tools, there has been a paucity of major changes in the availability of specific antivirals and vaccines, although many are currently under investigation with the potential to become available in the next few years.
RESPIRATORY SYNCYTIAL VIRUS
Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract disease in infants and toddlers. It accounts for approximately 60% of all LRTIs in preschool-aged children worldwide. In the developing world, RSV is second only to malaria as a cause of death during the first year of life. Severe disease is generally associated with primary infection, although LRTI can also occur upon reinfection. Bronchiolitis, which refers to inflammation of smaller intrapulmonary airways, is the single most distinctive clinical syndrome of RSV infection.
PATHOGENESIS AND EPIDEMIOLOGY
RSV belongs to the genus Pneumovirus within the Paramyxoviridae family. It is an enveloped, single-stranded, negative-sense RNA virus with a diameter spanning 100 to 350 nm. The viral envelope is studded with spike-like projections that include the fusion (F) and attachment (G) surface glycoproteins, but unlike most paramyxoviruses, RSV surface proteins lack both hemagglutinin (HA) and neuraminidase (NA) activity. The G protein initiates the infection, while the F glycoprotein mediates viral penetration by fusing viral and cellular membranes, contributing to syncytia formation. These 2 proteins carry the antigenic determinants that elicit the production of neutralizing antibodies by the host. Nevertheless, the F protein represents the major target for antiviral drug development, especially in its prefusion form (preF), which has been shown to be highly superior at inducing neutralizing antibodies compared to its postfusion (postF) form. Human RSV exists as 2 antigenic subgroups, A and B, which can co-circulate during the same season and exhibit genome-wide sequence divergence.
RSV infection is first established in the upper respiratory tract by infecting the ciliated cells of the nasopharynx, paranasal sinuses, or eustachian tubes of the inner ear. One to 3 days later, 30% of infants who experience their first infection will demonstrate involvement of the lower respiratory tract. In the lower respiratory tract, RSV infects the small bronchial epithelium, spreading to the type 1 and type 2 alveolar pneumocytes. RSV infection is restricted to the respiratory epithelium and rarely spreads outside the respiratory tract. Disseminated disease has been documented in patients with T-cell deficiency.
Infants are more likely to develop severe distal airway disease, because of an immature immune system, the lack of full protection from maternal antibodies, and also the smaller bronchiolar lumen of infants compared with older children and adults. In addition, in infants, collateral ventilation in alveolar regions is not well developed; thus, the impact of obstruction resulting from infection and inflammation is greater.
Histopathologically, airway plugging with mucus, necrosis of the bronchial and bronchiolar epithelium, and peribronchial inflammation with mononuclear cell predominance has been noted. The peribronchial infiltrate may extend into the adjacent pulmonary interstitium. Cytoplasmic inclusion bodies have been described, but syncytia formation is uncommon. Neutrophils are found between small airways and vascular structures and represent the predominant cell type in the bronchoalveolar lavage of RSV-infected infants.
During RSV infection, a number of cytokines and chemokines (eg, interleukin [IL]-8, IL-6, interferon-γ) are released and appear to play a role in the pathogenesis of the disease. Recent data suggest that host innate immune responses are actually inadequately activated or even suppressed in infants with severe RSV disease. With regard to adaptive immunity, the immune response to RSV is neither complete nor long lasting, and reinfections are the rule. Protection against reinfection is greater with homologous than heterologous RSV subtypes. Cellular immunity is not well understood in humans. Nevertheless, the role of CD8+ T cells in viral clearance is highlighted by the fact that patients with profound T-cell deficiency (eg, bone marrow transplantation, severe combined immunodeficiency) often have prolonged viral shedding and develop fatal disease. Regarding humoral immunity, as noted, it appears that antibody responses are important in ameliorating the severity of the disease rather than completely preventing the infection. In addition, passively acquired maternal antibody is not adequate to ensure complete protection from RSV infection and disease. However, children with high titers of maternally derived neutralizing antibody usually have milder symptoms, and the infection is restricted to the upper respiratory tract. These observations have led to use of passive immunoprophylaxis with antibodies as a method for protecting children at highest risk of severe RSV disease.
RSV has a worldwide distribution. In temperate climates, RSV annual midwinter epidemics occur predictably; in the United States, epidemics usually begin in November or December and last until March or April. In the tropics or subtropical areas, RSV activity is present all year long (eg, Florida).
RSV is the single leading cause of infant hospitalization, causing approximately 150,000 hospital admissions per year in children under 2 years of age in the United States. Globally, it is estimated that RSV causes about 34 million episodes of acute LRTIs in children under 5 years of age, resulting in approximately 3.4 million hospitalizations per year. The burden of RSV, however, is significantly larger in the outpatient setting, accounting for 18% of emergency department visits in children less than 5 years of age. In addition, RSV is also a major pathogen in immunocompromised and elderly individuals.
Disease in the immediate neonatal period is uncommon; however, by their first birthday, nearly one-half to two-thirds of infants have been infected with RSV. Seropositivity approaches 100% by 2 years of age. Reinfection with RSV occurs throughout life and may occur even during the same winter season. The annual risk of reinfection falls from between 33% and 75% in the preschool years to approximately 20% among school-age children. The risk of severe LRTI from reinfections also falls with increasing age and number of exposures, likely from the presence of partially neutralizing antibodies following previous infection.
Besides young age (< 6 months) at the start of the RSV season, epidemiologic studies have identified select groups of infants at high risk for severe disease and mortality including premature birth, compromised cardiopulmonary function (chronic lung disease or congenital heart disease [CHD]), trisomy 21, or immunocompromise). Males with severe RSV LRTI outnumber females by 1.6 to 1. Risk factors such as low socioeconomic status and modifiable risk factors such as exposure to secondhand smoke or out-of-home daycare attendance have also been associated with an increased risk for more severe RSV disease.
Humans are the only known reservoir for RSV. Studies of transmission dynamics suggest that infection of infants often follows infection of older siblings. The incubation period ranges from 2 to 8 days, most commonly 4 to 6 days. In infants hospitalized with primary RSV infection, continuous viral shedding for 10 or 11 days detected by polymerase chain reaction (PCR) is commonly observed; young infants and immunocompromised children may shed the virus for 3 to 4 weeks.
Transmission primarily occurs by inoculation of nasopharyngeal or ocular mucous membranes after direct contact with contaminated secretions or fomites. RSV can persist for 30 minutes or more on hands and for several hours on environmental surfaces. Close adherence to infection control policies is critical to limit healthcare-associated transmission. Nosocomial outbreaks of RSV infection in hematopoietic stem cell transplant units and neonatal units have been reported and carry significant morbidity and mortality. Therefore, strict hand-washing and contact precautions using gown and gloves for the duration of the RSV-associated illness must be practiced routinely.
The vast majority of infants with RSV infection develop a mild illness with upper respiratory tract symptoms; however, 20% to 30% will develop lower respiratory tract disease (eg, bronchiolitis and/or pneumonia) with the first infection. Of those, 2% to 3% will require hospitalization.
RSV infection is heralded by initial symptoms indistinguishable from those of the common cold. The infant may show rhinitis and cough, and there may be fever. Within 1 to 2 days, the cough becomes more prominent and tachypnea may develop. With increasing respiratory effort, substernal and intercostal retractions are noted along with nasal flaring and abdominal breathing. Grunting can be present in more severe cases. The expiratory phase is prolonged, and the chest is hyperexpanded and hyperresonant, providing further evidence of generalized expiratory airflow obstruction. Crackles or rales with or without diffuse expiratory wheezing are usually heard. In children requiring hospitalization, hypoxemia is typical, reflecting ventilation-perfusion mismatch. Chest radiographs reveal hyperinflation, increased peribronchial markings, and frequently, areas of atelectasis or infiltrate. Densities on chest radiographs are predominantly areas of atelectasis, and although these patients may be labeled as having RSV pneumonia rather than bronchiolitis, this distinction is often arbitrary.
Apnea can be an early manifestation of RSV infection in young infants, particularly infants < 8 weeks old or those with a history of premature birth or apnea of prematurity. Apnea can occur associated with respiratory tract symptoms or may be the only sign at presentation.
Severe bacterial infections, namely bacteremia or meningitis, are extremely rare in infants with RSV bronchiolitis, while urinary tract infections have been documented in approximately 5% of patients. Acute otitis media during or after RSV bronchiolitis occurs in approximately 60% of children. RSV-related fatality rates for hospitalized children in developed countries are < 1%. Although children with underlying conditions such as prematurity or cardiopulmonary disease are at increased risk of death, most fatalities occur in previously healthy infants. The average duration of hospitalization for previously healthy infants without complications is approximately 2 to 3 days. Full recovery may take 2 to 3 weeks. Approximately 50% of infants who develop RSV LRTI will develop recurrent wheezing during childhood. The highest risk for wheezing occurs in the first 6 years of life. It is still unclear whether RSV infection plays a causal role in this pulmonary sequela or whether it is simply a sign of individuals predisposed to asthma. The agent is nevertheless an important precipitant of wheezing in children with reactive airway disease.
Bronchiolitis is a clinical diagnosis; however, other respiratory viruses also cause bronchiolitis in young children, and clinical features are insufficient to reliably distinguish RSV from these other viral infections. Specific viral diagnosis may be helpful in certain scenarios: when the diagnosis is uncertain; to reduce unnecessary use of antibiotics; or in hospitalized children at risk for severe disease or for infection control purposes. Detection of RSV from nasopharyngeal specimens may be achieved by rapid antigen tests including fluorescence-based methods such as direct fluorescent antibody (DFA: sensitivity 90–95%, specificity 92–97%) or immunoassays such as enzyme immunoassay (EIA: sensitivity 80%, specificity 75–100%). Molecular-based methods such as real-time reverse transcriptase (rt) polymerase chain reaction (PCR) also may be used to detect RSV. The sensitivity of rapid antigen tests may be lower in older children and is poor in adults, because they shed low concentrations of RSV. Detection by viral culture or by serology is not clinically practical for early diagnosis of acute RSV infection. Serology also is challenging to interpret in young infants because of the presence of maternal antibodies.
In cell culture, RSV growth is detected within 5 to 7 days by the typical plaque morphology with syncytium formation. Cell culture was traditionally the gold standard for diagnosis, but this technique has been replaced by the more rapid and sensitive rt-PCR assays, although many outpatient settings still rely on rapid antigen detection by DFA or EIA due to operational challenges and costs. rt-PCR is the most sensitive method for RSV detection and allows the differentiation between A and B subgroups (which is useful for surveillance purposes in cases of respiratory disease outbreaks). Multiplex PCR assays allow the simultaneous detection of several respiratory viruses, including RSV. Recently, an automated real-time molecular station was developed (FilmArray, Biomerieux, Marcy-l’Étoile, France) that performs nucleic acid extraction, then reverse transcription, followed by PCR identification of as many as 20 respiratory pathogens within 1 hour. Using these assays, studies have shown that approximately 30% of children hospitalized with RSV bronchiolitis may be co-infected with another respiratory virus. Whether children with RSV bronchiolitis who are co-infected with another respiratory virus develop more severe disease is still unclear.
Currently, the primary treatment for RSV infection is supportive and includes nasal suctioning, hydration, and, in hospitalized patients, close cardiorespiratory monitoring and measurement of oxygen saturation. Nasal suctioning may provide relief of upper airway obstruction, but deep suctioning of the nasopharynx is not recommended. Nasogastric or intravenous fluids may be used to maintain hydration or when severe tachypnea is present. Although infants with bronchiolitis are at risk of developing subsegmental atelectasis, chest physiotherapy has not been shown to be of clinical benefit. Humidified oxygen is frequently required when managing hospitalized infants since hypoxemia is common (oxygen saturation < 90%) in more severe illness. The complications associated with hypoxemia and carbon dioxide (CO2) retention generally begin when the respiratory rate surpasses 60 breaths per minute. Admission to pediatric intensive care units and use of noninvasive or invasive ventilatory support because of severe respiratory distress, hypoxemia, or apnea are required in 10% to 20% of children hospitalized with RSV bronchiolitis.
Inhaled bronchodilators, such as albuterol or racemic epinephrine, or inhaled or systemic corticosteroids are not recommended for the management of children with RSV bronchiolitis. Nebulized hypertonic saline has been shown to increase mucociliary clearance and may be beneficial in infants who are expected to have prolonged hospitalizations (> 72 hours). Last, except for acute otitis media, bacterial infections of the lower respiratory tract are rarely associated with RSV infection; thus, antibiotic treatment is usually not indicated for LRTI.
Ribavirin is a broad-spectrum virostatic antiviral agent with activity against RSV and other RNA viruses. Early on, small, double-blinded, placebo-controlled studies showed a beneficial effect in infants treated with aerosolized ribavirin soon after onset of disease. The required aerosol route of administration, concerns about potential toxic effects among exposed healthcare personnel, possible teratogenicity in pregnant women, conflicting results of efficacy trials, and high cost have led to infrequent use of ribavirin. The American Academy of Pediatrics (AAP) does not recommend its routine use in children but notes that it may be considered for use in selected patients with, or at risk for, life-threatening RSV infection (Table 236-1). It is also important to note that in immunocompromised children at high risk for severe disease, treatment with ribavirin is most helpful during the stage of URI before LRTI has developed. Uncontrolled studies in hematopoietic stem cell transplant recipients using combination therapy with ribavirin and intravenous polyclonal immunoglobulin or monoclonal antibodies (palivizumab) or in lung transplant recipients using ribavirin and intravenous immunoglobulin or corticosteroids have been performed demonstrating potential benefit. There are a number of promising antiviral drugs currently under development, including new monoclonal antibodies with extended half-life, fusion inhibitors, nucleoside analogs, and small molecules. These newer antivirals have the potential to impact both the prevention and treatment of RSV disease in the main target populations. In hospitalized patients, standard and contact precautions are recommended for the duration of the RSV illness, including patients receiving antivirals. Children with RSV should be cared for in single rooms or cohorted with other RSV-infected children.
TABLE 236-1ANTIVIRALS FOR RESPIRATORY VIRUSES ||Download (.pdf) TABLE 236-1ANTIVIRALS FOR RESPIRATORY VIRUSES
|Virus ||Clinical Situation ||Agent of Choice ||Alternative/Comment |
|Respiratory syncytial virus (RSV) ||Treatment ||Ribavirin aerosols: ||Ribavirin treatment of RSV is controversial and should be limited to patients with severe disease or at high risk for severe disease.
| || Continuously as 6 g over 18 hours per day |
| || || Alternatively, 2 g/dose over 2–3 hours 3 times daily (only in patients who are not mechanically ventilated) |
| ||Prophylaxis ||Palivizumab 15 mg/kg IM monthly || |
| || || Duration: RSV season || |
|Human metapneumovirus ||Treatment ||None ||Ribavirin (as above) |
| ||Prophylaxis ||None ||None |
|Parainfluenza virus ||Treatment ||None ||Ribavirin (as above) |
| ||Prophylaxis ||None ||None |
|Influenza Aa ||Treatment ||Oseltamivir: ||Amantadine and rimantadine currently not recommended for treatment or prophylaxis in the United States because of high rates of resistance. |
| || || Age < 1 year: 3 mg/kg/dose twice daily |
| || || Age > 1 year weight based: |
| || || – weight ≤ 15 kg: 30 mg PO twice daily || |
| || || – weight 15–23 kg: 45 mg PO twice daily || |
| || || – weight 23–40 kg: 60 mg PO twice daily || |
| || || – weight > 40 kg: 75 mg PO twice daily || |
| || || Duration: 5 days || |
| || ||Zanamivir: || |
| || || Age ≥ 7 years: 2 inhalations (one 5-mg blister per inhalation, for total 10 mg per dose) twice daily || |
| || || Duration: 5 days || |
| || ||Peramivir: || |
| || || Age > 18 years: 600 mg via intravenous infusion for 15–30 minutes || |
| || || Duration: 1 day || |
| ||Prophylaxis ||Oseltamivir: ||Zanamivir: |
| || || Age 3 months to 1 year: 3 mg/kg once daily || Age ≥ 5 years: 2 inhalations (one 5-mg blister per inhalation, for total of 10 mg per dose) once daily |
| || || Age > 1 year weight based: same dose as for treatment but once daily ||Duration: 7 days |
| || || Duration: 7 days || |
|Influenza Ba ||Treatment ||Oseltamivir or zanamivir as for influenza A ||None |
| ||Prophylaxis ||Oseltamivir as for influenza A ||Zanamivir as for influenza A |
|Influenza C ||Treatment ||None ||None |
| ||Prophylaxis ||None ||None |
|Adenovirus ||Treatment ||None ||Cidofovir 5 mg/kg once weekly or 1 mg/kg 3 times a week |
| ||Prophylaxis ||None ||None |
Preventive strategies against RSV infection are available. Education of parents and other caregivers on ways to decrease the infant’s exposure not only to RSV but also to factors that may contribute to the severity of the infection must form the basis of any RSV prophylaxis program. Hand hygiene is crucial in all settings. High-risk infants and children should not be exposed to individuals with respiratory infections, and if at all possible, they should not be in settings (eg, childcare centers) where such exposures are likely. Exposure to tobacco smoke must be eliminated since it has been associated with more severe RSV disease. These measures will have the added benefit of decreasing transmission of other respiratory pathogens.
Passive immunoprophylaxis to prevent RSV infection in infants and children at increased risk for severe disease is available in the form of a monoclonal anti-RSV antibody. Palivizumab targets the F surface glycoprotein of RSV, which is highly conserved among RSV isolates. In the original randomized clinical trials, safety and efficacy were established in infants with a history of premature birth (≤ 35 weeks of gestational age), children with chronic lung disease of prematurity (CLD), and children with hemodynamically significant CHD. Mainly because of costs, the AAP has updated the guidance on palivizumab prophylaxis on different occasions. For the specific updated recommendations, see the current edition of the AAP Report of the Committee on Infectious Diseases. The following recommendations are based on the committee’s 2015 report. Palivizumab prophylaxis should be considered at the start of the RSV season for: (1) infants or children with CLD of prematurity born at < 32 weeks of gestation who are younger than 12 months, or younger than 24 months and require medical therapy for their CLD within 6 months before the RSV season; (2) infants born before 29 weeks of gestation who are younger than 12 months at the start of the RSV season; and (3) infants younger than 12 months of age with acyanotic CHD with congestive heart failure and possibly cyanotic CHD. Others to consider palivizumab prophylaxis include children during the first year of life with neuromuscular disorders or pulmonary abnormalities that impair their ability to clear secretions from the lower airway and hematopoietic stem cell transplant patients who are profoundly immunosuppressed during the RSV season.
Palivizumab has a half-life of 28 days, and thus, it is administered once a month during the RSV season intramuscularly. It should be initiated immediately before the RSV season and continued monthly until the end. Although there is significant regional and year-to-year variability in the season onset and offset in the United States, administration of 5 monthly doses starting in November will usually ensure adequate serum concentrations throughout the season. Practitioners outside the United States or in regions with different RSV seasonality should contact their health departments or diagnostic virology laboratories to determine the optimal time to initiate prophylaxis.
Epidemiologic and clinical studies suggest that there are different target populations that will benefit from active immunization with RSV vaccines and that they might require different approaches: young RSV-naïve infants (< 6 months), children > 6 months, pregnant women, and the elderly. Although a safe and effective RSV vaccine has not yet been developed, there are many vaccine candidates currently undergoing testing in preclinical and phase I, II, and III clinical trials.
First described in 2001, human metapneumovirus (hMPV) is now recognized as a globally distributed respiratory pathogen affecting children and adults. hMPV is one of the causes of bronchiolitis in infants and is also associated with different presentations of URIs and LRTIs in children.
PATHOGENESIS AND EPIDEMIOLOGY
hMPV is an enveloped, single-stranded, negative-sense RNA virus that belongs to the Paramyxoviridae family. Like RSV, which is of the genus Pneumovirus, hMPV has projecting F and G envelope glycoproteins and lacks HA activity. However, differences in its genomic sequence and structure result in its placement in the separate genus Metapneumovirus. There are 2 major groups of hMPV, A and B, which are further divided into 4 clades: A1, A2, B1, and B2. These different subgroups co-circulate each year in different proportions.
The pathogenesis of hMPV is based on limited studies in children, but it appears that the virus causes inflammatory changes of the lower airways once infection has become established. The interaction of hMPV and the immune system is poorly understood. Although humans mount a very robust antibody response to hMPV, immunity wanes over time and provides limited cross-protectivity between genotypes of the virus.
hMPV causes respiratory infections across the globe. Although discovered in 2001, archived sera from the 1950s contain antibodies against this agent, suggesting that this virus has been circulating for at least 60 years. In temperate regions, the virus is present year-round but peaks in late winter and early spring, later than the usual peak of RSV infection. In subtropical areas, hMPV circulation is most prevalent during the spring and summer. It may account for approximately 10% of LRTIs and 3% of URIs in young children. Almost all children are infected at least once by age 5. LRTIs from hMPV are usually associated with primary infection, and the peak age for severe disease and need for hospitalization is older than for RSV, often between 6 and 12 months of age. Studies have demonstrated symptomatic subsequent infections with hMPV from different hMPV subgroups in young children, although most reinfections are generally limited to the upper respiratory tract, which suggests partial immune protection and cross-protection against other hMPV subgroups following natural infection. Limited data suggest that co-circulation of related viruses, such as RSV or parainfluenza virus (PIV), may reduce the incidence of hMPV infections due to the presence of partial cross-protective immunity. Waning immunity is suggested by the fact that hMPV can cause severe respiratory infections in older adults including pneumonia requiring hospitalization. Asymptomatic infections are rare but may be seen in healthy young adults. Humans are the only reservoir, and like RSV, hMPV is thought to be transmitted through direct contact or contact with contaminated secretions. The incubation period is 3 to 5 days, and viral shedding in otherwise immunocompetent infants may last up to 2 weeks. Healthcare-associated infections have been reported.
Children infected with hMPV cannot be distinguished clinically from those infected by other respiratory viruses such as RSV or PIVs. URIs with rhinorrhea, cough, or fever are common and can be present in 50% to 90% of cases. Pharyngitis and croup have been described in 40% and 18% of cases, respectively. Acute otitis media is a common complication, occurring in 25% to 50% of children with hMPV infection. Between 5% and 10% of children may also develop a rash during the infection. The most common lower respiratory tract syndromes include bronchiolitis (59%), asthma exacerbation (14%), and pneumonia (8%). When compared to RSV, more children with hMPV are diagnosed with pneumonia versus bronchiolitis, with a higher incidence of radiologic findings such as alveolar disease, focal infiltrates, bronchopneumonic changes, and pleural effusions. Like RSV, prematurity, cardiopulmonary disease, and immunosuppression are associated with more severe infection and higher hospitalization rates.
In the clinical setting, rt-PCR of respiratory specimens is the most sensitive technique and the gold standard for diagnosis of hMPV. In many clinical laboratories, hMPV is included in the multiplex diagnostic PCR assays, allowing for simultaneous detection of other respiratory pathogens, with a rapid turnaround time. Antigen detection by immunofluorescence using monoclonal antibodies is quite specific, but sensitivity is typically reported as < 75% with these assays. hMPV growth is fastidious in cell culture, with cytopathic effect often not apparent until after 10 to 14 days of incubation, which is not clinically useful. Shell vial culture with immunofluorescence staining improves speed and sensitivity over traditional viral culture but does not reach that of PCR. Serology is useful for epidemiology purposes. A definitive serologic diagnosis requires seroconversion or at least a 4-fold increase in convalescent samples.
Care for children infected with hMPV is supportive and includes fever control, hydration, and close monitoring of respiratory status and oxygen saturation. Ribavirin is effective against hMPV in vitro and in animal models. In humans, there are a few small studies as well as anecdotal data with conflicting results regarding its benefit. There are also case reports of successful treatment of severe hMPV infection in immunocompromised patients with combined intravenous immunoglobulin and ribavirin. Antibiotics are not indicated for the treatment of hMPV bronchiolitis or pneumonia unless there is evidence of a concurrent bacterial infection.
In hospitalized patients, standard and contact precautions are warranted for the duration of illness.
PIVs are common causes of acute respiratory infections in young children. Croup is the most distinctive clinical syndrome caused by these agents, although bronchiolitis and pneumonia also occur. The initial infection usually occurs in the first few years of life, and reinfections are common.
PATHOGENESIS AND EPIDEMIOLOGY
PIVs are negative-sense, single-stranded, enveloped RNA viruses belonging to the genus Paramyxovirus in the Paramyxoviridae family, which also includes RSV and hMPV. The 4 PIVs have been separated into 2 genera, Respirovirus (serotypes PIV-1 and PIV-3) and Rubulavirus (PIV-2 and PIV-4 with 2 PIV-4 serotypes A and B). The large viral envelope (150–200 nm) is covered with spike-like projections containing 2 glycoproteins, the hemagglutinin-neuraminidase (HN) and fusion (F) proteins. These proteins are important for viral attachment and fusion with host cell membranes and are the major targets for neutralizing antibodies. The serotypes can be distinguished by type-specific antigens, but the viruses also share common antigens, such that infection with one PIV can lead to heterotypic serologic responses to the other serotypes. PIV-3 is the most prevalent serotype, with 90% to 100% of children demonstrating antibody by age 5.
Pathologic studies of children reveal that inflammation as evidenced by necrosis of the epithelium occurs throughout the respiratory tract with primary infection. In croup, the subglottic tissues appear particularly involved, but with primary infection, the airways at all levels, including the alveoli, can be involved. Most children with bronchopneumonia due to PIVs will have cellular necrosis and destruction of bronchial columnar epithelium in addition to diffuse alveolar damage. Infection with PIVs induces initial innate immune responses, serum and mucosal antibody responses, and cellular immune responses (both CD4+ and CD8+). Immunity to reinfections with PIVs is at best incomplete. Naturally acquired serum immunoglobulin (Ig) G provides the most durable protection against reinfection and may protect against LRTIs. However, infection of adult volunteers reveals that mucosal IgA was better correlated with protection from reinfection than serum IgG. After repeated infections, antibodies may develop that cross-neutralize different PIV strains, mostly noted within the genera (PIV-1 and PIV-3, or PIV-2 and PIV-4). Studies of hospital epidemics indicate a high attack rate and implicate shedding of virus before symptom onset.
Although all PIV serotypes are distributed globally and are capable of causing the full spectrum of respiratory illnesses, they tend to occur in distinct epidemiologic and clinical patterns. Humans are the only source of infection. PIV-1 causes the largest, most defined outbreaks of croup. In the United States, these have occurred for several decades during the fall of odd years. PIV-2 produces smaller, less severe epidemics of croup also in the fall months. PIV-1 and PIV-2 infections occasionally result in bronchiolitis or pneumonia. PIV-3 is the most frequently recovered PIV, is endemic, and circulates throughout the year with annual outbreaks typically extending from late spring through summer. It regularly causes bronchiolitis, pneumonia, or croup. The seasonal pattern of PIV-4 has been increasingly recognized with the use of molecular diagnostic tools. PIV-4 has been mainly associated with upper respiratory disease. A large retrospective study conducted in the United States from 2009 to 2012 showed that PIV-4 had year-round prevalence with biennial peaks during the fall of odd-numbered years. PIV infections are associated with substantial morbidity and mortality in immunocompromised hosts. Most PIV outbreaks in transplant units coincide with the peak incidence of these infections in the community.
Most children are infected with all PIV serotypes by age 5. Infection with PIV-1 usually occurs between year 1 and 5, whereas PIV-3 occurs earlier, with up to two-thirds of infants infected before age 1. Acquisition of PIV-4 also occurs during preschool years following the pattern observed with PIV-1 and PIV-2. Reinfection occurs in children and adults with all serotypes and is usually confined to the upper respiratory tract. Person-to-person transmission of PIV occurs via direct contact with large-droplet aerosols or fomites, and illness follows an incubation period of 2 to 6 days. Depending on the serotype, viral shedding can last up to 3 weeks after symptoms resolve.
PIVs cause a variety of URIs and LRTIs that may vary based on age and serotype. Most primary infections are symptomatic, and disease prevalence is greater in the outpatient setting. In healthy children, most illnesses involve the upper respiratory tract, and up to 35% are complicated with otitis media. In a subset of children, the infection progresses to the lower respiratory tract causing croup (acute laryngotracheobronchitis), bronchiolitis, or pneumonia. As noted, in general, PIV-1 and PIV-2 are associated with croup, and PIV-4 is associated with mild URI in both children and adults, whereas PIV-3 causes bronchiolitis and pneumonia. Overall, croup is the most common PIV-associated diagnosis. Croup begins with a URI of several days in duration, followed by hoarseness and a “barking seal” croupy cough. Inspiratory stridor and marked retractions are evident in more severe infections. Fever is usually mild. Most children recover after 48 to 72 hours, but some children progress to severe airway obstruction. When croup occurs in children younger than 6 months of age or is prolonged or recurrent, underlying anatomic pathology should be suspected. However, recurrent “spasmodic” (noninfectious) croup can occur in children with normal airway anatomy. The differential diagnosis for severe stridor includes bacterial tracheitis, which may be seen as a secondary bacterial infection following viral croup and is most commonly caused by Staphylococcus aureus, or epiglottitis, which is a life-threatening infection that was usually caused by Haemophilus influenzae type b or diphtheria. These last 2 entities are extremely rare now due to routine immunization. Bronchiolitis and pneumonia caused by PIVs are clinically indistinguishable from those associated with RSV, hMPV, or other respiratory viruses. Rare reports implicate PIVs in cases of aseptic meningitis, encephalitis, myopericarditis, Guillain-Barré syndrome, and parotitis.
PIV infection should be suspected in a child with compatible symptoms during a known outbreak, but definitive diagnosis requires identification by culture, antigen detection, or PCR from nasopharyngeal or lower respiratory tract specimens. PCR assays for detection of type-specific PIV RNA have the highest sensitivity and specificity, and thus, PCR is currently the preferred method for diagnosis. All 4 PIV serotypes are also included in available multiplex PCR assays, which may allow for simultaneous detection of several other respiratory viruses. Although used less frequently now because of availability of these other tests, if viral culture is performed, as with other respiratory viruses, care must be taken to promptly place specimens in viral transport media and maintain temperature near 4°C during transport due to the lability of these viruses. Antigen detection by immunofluorescent staining or EIA allows rapid diagnosis but is less sensitive than PCR assays. Serologic diagnosis can also be performed but has limited value in patient management.
In immunocompetent children, treatment of PIV infection is supportive. For the management of croup, nebulized epinephrine and steroids (parenteral, oral, or nebulized) can be used. Close monitoring is needed for those with severe disease, and occasionally, intubation of the airway is necessary. No specific antiviral treatment is currently available for PIV infections. Ribavirin has activity against PIVs in vitro, but retrospective studies in immunocompromised patients have failed to show benefit in preventing progression to the lower respiratory tract. Novel drugs are currently being evaluated in clinical trials. DAS181 is a recombinant sialidase fusion protein with activity against PIV that is currently undergoing phase II clinical trials. DAS181 has been used with success for the treatment of PIV LRTI in lung and stem cell transplant patients, including children, resulting in reductions of viral loads and improvement in clinical symptoms. BCX2798 and BCX2855 (hemagglutinin-neuraminidase inhibitors) have demonstrated antiviral activity against PIV-3 in vitro and in murine models, but no human studies are currently available.
There is no available PIV vaccine, but many clinical trials are being conducted on vaccine efficacy in healthy infants and children. In addition to standard precautions, contact precautions are recommended for hospitalized infants and young children for the duration of illness.
Influenza is an acute respiratory illness typically accompanied by fever and systemic symptoms. Annual global epidemics interspersed with occasional pandemics result in considerable morbidity and mortality in children and adults.
PATHOGENESIS AND EPIDEMIOLOGY
The influenza viruses are members of the Orthomyxoviridae family and are separated into 3 genera: Influenzavirus A, Influenzavirus B, and Influenzavirus C. These viruses contain a negative-sense, single-stranded, segmented RNA genome. Each of the 8 RNA segments codes for 1 or 2 of 11 viral proteins. The segmented nature of the influenza genome allows for exchange of RNA segments when 2 different influenza virions infect the same cell (genetic reassortment). This property is responsible for the antigenic shifts and drifts and has great significance for the epidemiology of influenza including pandemics.
The enveloped virion is about 100 nm in diameter and studded with spike-like projections consisting of its surface glycoproteins HA and NA. Influenza A viruses are further divided into subtypes based on these 2 surface glycoproteins. Major influenza A subtypes circulating in humans have been A (H1N1) and A (H3N2) and, most recently, the pandemic A (H1N1). Protective antibodies directed against particular subtypes of HA or NA are of little or no cross-protective benefit against alternative subtypes. Although human infections with avian influenza viruses are uncommon, they may result in severe lower respiratory tract disease, acute respiratory distress syndrome (ARDS), and death. There are 18 known HA subtypes and 11 NA subtypes of avian influenza viruses, and of those, H5N1 and H7N9 have been associated with severe disease and high mortality rates in humans. Humans are also occasionally infected with swine origin influenza viruses, which usually manifest as the typical influenza-like illness. Influenza B and C have less antigenic variability and are not divided into subtypes. Type C influenza viruses cause sporadic mild influenza-like illness in children, and type C antigens are not included in influenza vaccines.
Influenza infection is initiated by virus inoculation in the upper or lower airways. If present, virus-specific IgG and IgA antibodies against the surface antigens, particularly HA, may block the infection. Neuraminidase facilitates penetration through the sialyloligosaccharide-rich respiratory mucous layer for access to the epithelial cells and later is important for release of newly packaged viruses from cells. The viral HA allows viral attachment and later membrane fusion with respiratory epithelial cells. Upon infection and replication in the respiratory epithelium, virus is shed into respiratory secretions, and local spread ensues, with eventual desquamation. The entire airway from pharynx to alveoli may be involved. Diffuse pneumonia due to alveolar infection can be life threatening. Viral infection usually remains limited to the respiratory tract, although viremia has been described with specific strains and has been associated with enhanced disease severity. Systemic symptoms are mostly due to the high levels of cytokines and chemokines released upon infection. Influenza infection results in damaged mucociliary function, reduced neutrophil function, and impairment of other immune mechanisms that are probably responsible for the increased risk of bacterial superinfections.
The virus type and subtype have an effect on the virulence of the circulating influenza strain. The HA and NA represent the major determinants of immunity. Minor mutations in these enveloped glycoproteins are referred as “antigenic drifts” and occur almost annually. Antigenic drifts are responsible for the circulation of new viral variants to which the individual may be susceptible, perpetuating the annual epidemics of variable extent and severity. At varying intervals, major changes in the HA and NA occur and are referred as “antigenic shifts.” Antigenic shifts are associated with genetic reassortment of RNA segments between human and animal viruses or adaptation of a new animal virus to humans and are responsible for pandemics of influenza A. These events, which occurred 4 times during the 20th century and once in 2009, render antibody to previously circulating influenza A viruses unprotective. Worldwide pandemics associated with considerable excess mortality ensue.
In temperate climates, seasonal influenza epidemics occur during winter months. In the United States, influenza activity usually peaks between January and March, although occasionally, it can occur as early as November or as late as May. Community outbreaks usually last 4 to 8 weeks; however, circulation of 2 or 3 influenza viruses may be associated with a prolonged influenza season of 3 or more months and bimodal peaks in activity. Rates of hospitalization and death associated with influenza vary from year to year because influenza seasons are unpredictable and fluctuate in duration and severity. The severity of the disease is related in part to the presence of preexisting immunity as a result of prior exposure or immunization with a related strain and underlying risk factors (Table 236-2). In the United States, the annual epidemics usually result in more than 200,000 hospitalizations. Hospitalization rates are similarly high for children < 2 years of age and adults age 65 years or older. The number of influenza-associated deaths, which is probably underestimated due to underreporting, can vary from 3000 to 50,000 people annually, with the majority of deaths occurring in adults age 65 years or older. During influenza season, the virus accounts for approximately 20% of outpatient visits for children and adults with acute respiratory infections and fever (influenza-like illness). Surveillance activity is updated weekly during influenza season and available from the Centers for Disease Control and Prevention (CDC).
TABLE 236-2GROUPS AT HIGH RISK FOR COMPLICATIONS OF INFLUENZA INFECTION ||Download (.pdf) TABLE 236-2GROUPS AT HIGH RISK FOR COMPLICATIONS OF INFLUENZA INFECTION
|Children < 2 years of agea |
|Adults ≥ 65 years of age |
|Chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease), metabolic (including diabetes mellitus), neurologic, neuromuscular, and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) |
|Immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus) |
|Women who are pregnant or postpartum (within 2 weeks after delivery) |
|Children < 19 years of age receiving long-term aspirin therapy |
|Morbidly obese (body mass index [BMI] ≥ 40 for adults or BMI > 2.33 standard deviations above the mean for children) |
|Residents of chronic care facilities or nursing homes |
|Native Americans and Alaskan Natives |
Young children shed higher concentrations of virus for a longer duration than their older counterparts. The virus is highly contagious and is transmitted person-to-person primarily through contact with respiratory secretions (aerosolized droplets) generated by coughing or sneezing, or through contact with contaminated surfaces. Symptoms follow a 1- to 4-day incubation period, and patients may be infectious 24 hours before symptom onset. Viral shedding lasts for approximately 7 days, although virus can be shed for a longer period of time in young children or in patients with immunodeficiency. Viral shedding and fever are directly correlated.
In children, influenza typically presents with sudden onset of fever and respiratory symptoms, but ultimately, the clinical manifestations depend on the age of the child and his or her preexisting immunity. Fever is more prominent than with other viral respiratory infections, occurring in 95% of children, routinely reaching 39°C (102.2°F) to 40°C (104°F), and lasting 3 to 6 days in the absence of complications. In older children, the typical influenza-like illness starts with fever, often accompanied by chills or rigor, headache, myalgias, malaise, sore throat, and dry cough, followed later by a more productive cough and rhinitis. Children under age 5 usually present with a febrile URI, but some manifest severe croup, bronchiolitis, or pneumonia, while neonatal influenza may mimic bacterial sepsis. Tracheitis or tracheobronchitis may be particularly severe or complicated by bacterial superinfection (bacterial tracheitis). Asthma exacerbations are also common in children with influenza infection. The most common complication of influenza is acute otitis media, affecting approximately 10% to 50% of children, followed by pneumonia, especially in high-risk patients. Viral bronchopneumonia is more common in children < 2 years of age and is typically mild, rarely leading to severe disease or death in otherwise healthy children. Bacterial pneumonia has been reported in 2% of hospitalized children and usually manifests as recurrent fever and pulmonary symptoms after 5 to 7 days of influenza illness. The most common causative agents are Streptococcus pneumoniae and Staphylococcus aureus (including methicillin-resistant S aureus [MRSA]). S aureus pneumonia may be particularly severe and rapidly fatal and usually occurs in children with no underlying medical condition.
Other complications of influenza include Reye syndrome in association with aspirin use, toxic shock syndrome due to secondary bacterial infection, myositis or myocarditis and neurologic complications that range from febrile seizures to acute encephalitis, aseptic meningitis, Guillain-Barré syndrome, or transverse myelitis. Postinfectious encephalitis has also been reported.
Influenza virus infection should be considered when clinically compatible symptoms are present irrespective of the immunization status. However, diagnostic confirmation requires viral isolation or detection of viral antigens or viral RNA in respiratory samples (nasal swab or wash), ideally within the first 3 days of symptoms as viral load decreases afterward. Influenza can be cultured from respiratory secretions upon inoculation into monkey or canine kidney cell cultures or embryonated eggs. Viral growth can be detected after 2 to 6 days by hemadsorption, hemagglutination, or, on occasion, by evidence of cell destruction. However, with the availability of specific antiviral treatment and the need to initiate therapy quickly in high-risk or hospitalized patients, culture methods are not preferred in clinical practice. Similarly, serology testing requires acute and convalescent sampling and thus is not practical for clinical decision making. Rapid antigen detection assays (by immunofluorescence or EIA) are also available, with reported sensitivities of 45% to 97% and specificities of 76% to 100% compared with PCR. Most of these assays cannot differentiate between influenza subtypes, which may be needed for choice of antiviral agents. RNA detection by rt-PCR is the most sensitive and specific diagnostic method and allows for rapid diagnosis, differentiating between influenza types and subtypes. Influenza viruses are included in the commercially available multiplex PCR assays. Diagnostic testing also is helpful because it may reduce additional testing to identify the cause of the child’s influenza-like illness. Treatment should not be withheld in high-risk patients while awaiting rt-PCR test results.
In general, influenza infection in children is a self-limited condition. Supportive care includes antipyretics to reduce fever (and discomfort). Salicylates should not be used to treat influenza in children or adolescents because of the increased risk of Reye syndrome. Bed rest and maintenance of adequate fluid intake may also provide comfort.
Antiviral therapy is recommended regardless of the immunization status or whether or not symptoms have been present for more than 48 hours for any patient with confirmed or suspected influenza who is hospitalized, has severe or complicated disease, or is at high risk for complications (see Table 236-2). Clinical benefit is greater when antiviral therapy is initiated within 48 hours of symptom onset; however, treatment should be considered even if later in the disease course, especially in hospitalized patients, in whom antiviral therapy has been shown to shorten the duration of hospitalization and decrease mortality. The duration of treatment is 5 days.
Antiviral therapies are discussed in Chapter 240, and use in specific respiratory infections is outlined in Table 236-1. The CDC has a surveillance program in place to identify antiviral resistance each year and updates recommendations for influenza antiviral use accordingly. Two classes of antivirals are approved for treatment and prophylaxis of influenza infections in the United States: NA inhibitors (oseltamivir, zanamivir, and peramivir); and adamantanes (amantadine and rimantadine). NA inhibitors have activity against influenza A and B viruses and can be administered through different routes. Oral oseltamivir is the preferred antiviral and is approved for treatment in children as young as 2 weeks old. Inhaled zanamivir is an alternative, but it is difficult to administer. It is approved for treatment in children over 7 years of age and is not recommended in children with underlying airway disease because of association with bronchospasm. A parenteral form of zanamivir is currently in a phase III clinical trial for patients who cannot tolerate or absorb oseltamivir. Peramivir is another NA inhibitor approved for those over 18 years of age and is also administered intravenously. Dosages are detailed in Table 236-1. Laninamivir is a long-acting inhaled NA inhibitor available only in Japan. Amantadine and rimantadine are active against influenza A only, and levels of resistance in past seasons have been reported to be > 99%; thus, these agents are not recommended for treatment or chemoprophylaxis in the United States.
Immunoprophylaxis with trivalent and quadrivalent inactivated influenza vaccines (IIVs) or live attenuated, cold-adapted influenza vaccines (LAIVs) and chemoprophylaxis using NA inhibitors are available measures that are effective in reducing the number of influenza virus infections and the impact of influenza disease.
Since the late 1940s, the vaccination each year prior to the onset of influenza season of individuals at high risk for complications has been the most effective approach for reducing the impact of influenza. Each year, influenza vaccines are modified to contain 3 or 4 antigens (2 for influenza A and 1 or 2 for influenza B) based on the influenza circulation in the Southern Hemisphere, which precedes the circulation in the Northern Hemisphere. From 2005 to 2016, the overall adjusted vaccine effectiveness has varied widely from 10% to 60%. Vaccine effectiveness is highest when the vaccine strains and circulating strains are closely related. The IIVs contain no live virus and are administered either intramuscularly or intradermally. IIVs are available in both trivalent (IIV3) formulations, including a high-dose vaccine for those at least 65 years of age, and quadrivalent (IIV4) formulations. In addition, there are 2 trivalent IIVs that have been developed without using eggs and are available for people older than 18 years with severe egg allergy: recombinant influenza vaccine (RIV3), and cell culture–based influenza vaccine (ccIIV3), which contains trace amounts of ovalbumin. Although intramuscular IIV formulations are licensed for administration in children 6 months and older, the intradermal formulation is only licensed for use in those 18 to 64 years of age.
LAIV4 is a quadrivalent formulation that is administered intranasally and is licensed for healthy children older than 2 years of age and adults less than 50 years old. It is contraindicated in children < 5 years of age with a history of asthma or wheezing in the preceding 12 months, children between 2 and 17 years of age who are receiving chronic aspirin therapy, pregnant women, immunocompromised individuals, and people who have received influenza antiviral treatment within the previous 48 hours. Since 2016, the CDC does not recommend LAIV administration in children because of low effectiveness.
LAIV and most of the IIV formulations are produced in eggs. Except for severe, life-threatening allergic reactions to any ingredient in the vaccine, egg allergy is not a contraindication to influenza vaccination. Recent studies have shown that IIV administered in a single, age-appropriate dose is well tolerated by most recipients with a history of egg allergy. If a child with mild egg allergy (eg, hives) is vaccinated, close observation for 30 minutes and availability of appropriate resuscitation equipment are required. See the CDC recommendations for further information regarding use of influenza vaccines in egg-allergic individuals. The risk of developing Guillain-Barré syndrome is rare (no more than 1–2 cases per million doses).
All children 6 months and older should receive annual influenza vaccination. Children 6 months to 8 years who have not received influenza vaccine previously require 2 doses of vaccine in their first year of influenza vaccination, administered at least 4 weeks apart to boost antibody responses. Children older than 8 years require 1 dose of influenza vaccine regardless of their previous immunization status. Special emphasis for IIV administration should be directed to patients at increased risk (see Table 236-2). Influenza vaccination should be mandatory for healthcare workers. People who care for severely immunocompromised patients (eg, in bone marrow transplant units) should not receive LAIV unless patient contact can be avoided for 7 days following administration. See http://www.cdc.gov/flu for the Public Health Service Advisory Committee on Immunization Practices (ACIP) updated recommendations on influenza vaccine target populations, dosage, administration instructions, and adverse effects. For further discussion of influenza vaccination, see Chapter 239.
Chemoprophylaxis should not be substituted for vaccination, even in high-risk patients, but can be considered for prevention of infection in children at high risk of complications during the first 2 weeks following vaccination, children who may not respond to vaccination due to immunosuppression, or children who cannot receive vaccination due to a contraindication. It can also be used during influenza outbreaks for prevention of infection among residents of institutions. Chemoprophylaxis can be administered concomitantly with IIV formulations to provide protection until antibody develops but cannot be administered with LAIV formulations, since antivirals may have activity against vaccine strains. Chemoprophylaxis can be administered before or after exposure in children at high risk for complications. Given the development of resistance to other antiviral agents, the NA inhibitor oseltamivir is now the primary agent recommended for children. It is approved for use in children age 3 months and older. Zanamivir may also be used and is approved as a prophylactic agent for children over age 5. CDC recommendations should be consulted for further information regarding prophylaxis.
Other Preventive Measures
In hospitalized patients, strict infection prevention measures to avoid nosocomial infections should be implemented, and patients should be placed in droplet (and standard) precautions for the duration of illness. Hand washing is essential. Respiratory secretions should be considered infectious.
Other preventive measures that are key when managing children with influenza infection, especially those at increased risk of complications, include influenza vaccination of household contacts and out-of-home caregivers, general infection prevention measures, and avoidance of sick contacts.
Adenoviruses account for 5% to 10% of all febrile illnesses in children and are also important causes of ocular, gastrointestinal, and urologic infections. In addition, they are recognized as serious pathogens in immunocompromised hosts in whom fatal disseminated infection can develop following primary infection or viral reactivation.
PATHOGENESIS AND EPIDEMIOLOGY
Adenoviruses are nonenveloped, double-stranded DNA viruses that are icosahedral in shape and measure 70 to 80 nm in diameter. They are members of the Adenoviridae family in the genus Mastadenovirus and are divided into 7 species (A–G) on the basis of their DNA sequence. There are 57 recognized human adenovirus serotypes. Adenoviruses 1 to 5, 7, 14, and 21 are primarily associated with respiratory tract disease, while adenoviruses 40 and 41 mainly cause gastroenteritis. Antigenically important coat proteins include hexon, penton base, and fiber. Infection with one adenovirus type confers type-specific immunity.
In most respiratory disease, the initial infection by adenovirus involves the nose, oropharynx, and conjunctiva, but the severity will vary based on the serotype. In severe pneumonia, total destruction with necrotizing bronchitis, bronchiolitis, and pneumonia has been described. Hyaline membrane and necrosis may be present, whereas cilia and goblet cells may be absent. Often epithelial cells take on a characteristic appearance with adenoviral infection.
Adenoviruses have worldwide distribution, and infections occur throughout the year. Spread is primarily via respiratory droplets, but transmission can also occur by fecal routes or via contact with contaminated fomites. Most children have serologic evidence of prior adenovirus infection by age 10. Care must be taken in associating adenovirus detection with disease entities because these viruses, especially species C, are capable of establishing persistent or latent infection in lymphoid tissues including tonsils, adenoids, and the gut of infected children, and recurrent shedding without acute symptoms can occur. Nevertheless, many epidemics of adenovirus disease including keratoconjunctivitis, pharyngoconjunctival fever, or acute respiratory disease as well as nosocomial transmission have been described. The incubation period ranges from 2 to 14 days for adenoviral respiratory tract infections and 3 to 10 days for gastroenteritis.
Adenoviruses are capable of causing a broad spectrum of clinical diseases due to the organ tropism of different species. Species A is primarily associated with respiratory and gastrointestinal infections; species B, C, and E with respiratory infections; species D with ocular and gastrointestinal infections; and species F and G with gastrointestinal infections. The clinical manifestations of adenoviral disease vary based on the age and the host immune status. Severe disease has been reported with types 5, 7, 14, and 21.
Adenoviruses are some of the most common viruses that cause febrile respiratory illnesses in children. The usual duration of illness is 5 to 7 days, although symptomatology can last up to 2 weeks. Infants and children most commonly manifest URI symptoms with conjunctivitis, otitis media, coryza, or pharyngitis, and less commonly with croup or a pertussis-like syndrome. Exudative tonsillitis may be present, and systemic symptoms such as fever, malaise, and headache may be prominent. Respiratory symptoms may be accompanied by a benign follicular conjunctivitis, febrile pharyngitis. and cervical adenitis in a condition termed pharyngoconjunctival fever (adenovirus B types 3 and 7 are the most common isolates). Outbreaks of pharyngoconjunctival fever have been documented in summer camps and in association with public swimming pools. Bronchiolitis or pneumonia occurs in a small percentage of children and can be fatal in neonates and children with underlying medical conditions. The incidence of bronchiolitis obliterans or bronchiectasis is high following adenoviral pneumonia in young children. Although most children recover without complications, some outbreaks caused by species B types 3, 7, 11, 14, and 21 have resulted in fulminate disease with significant mortality.
In this more serious form of ocular adenovirus infection, conjunctivitis is followed by bilateral corneal infiltrates and enlargement of preauricular nodes. It has been associated primarily with adenovirus D types 8, 19, and 37 and causes severe pain and blurry vision. Outbreaks of keratoconjunctivitis have been reported in medical facilities.
The enteric adenoviruses, species F types 40 and 41 and species G type 52, are important causes of diarrheal illness that may last from 8 to 12 days. Adenoviruses (not necessarily the enteric serotypes) have been recovered from mesenteric lymph nodes of children with intussusception, suggesting a role for these viruses in the pathogenesis of the disease. Adenovirus species B types 11 and 21 are associated with acute hemorrhagic cystitis and hematuria lasting several days to 2 weeks. Adenovirus infection, especially subgroup C type 5, may cause severe hepatitis and liver failure, particularly in infants or immunocompromised patients. Viral myocarditis, meningoencephalitis, hepatitis, and rhabdomyolysis are occasionally associated with adenovirus infection. Severe disseminated adenovirus disease with or without exanthem has been reported in immunocompetent and immunocompromised children, including neonates, and is associated with high mortality.
Adenoviruses can be identified by PCR in nasopharyngeal, oropharyngeal, and eye secretions, blood, cerebrospinal fluid, urine, stool, and biopsy specimens. Other means less commonly used for adenovirus isolation include traditional culture in primary or permanent cell lines, shell vial culture, and antigen detection that is generally less sensitive than culture but may provide a rapid diagnosis. Serologic evidence of increasing antibody titers could be useful to confirm recent infection.
Because virus shedding from the pharynx may persist for weeks or even recurrently following adenovirus infection, the diagnostic significance of adenovirus detection in respiratory or fecal samples is not as strong as it is with many of the other respiratory viruses. In these cases, measuring viral burden may be useful to confirm acute infection. In immunocompromised patients, quantitative PCR for adenovirus in the blood may be useful for detecting patients at risk of dissemination.
For most healthy children, treatment is symptomatic. Antiviral therapy is reserved for immunocompromised children and patients with severe disease. Although there are no available controlled trials, the nucleotide analog cidofovir has been used at different doses and intervals for the treatment of adenovirus infection in immunocompromised patients. The major limiting factor of cidofovir is nephrotoxicity. CMX001 (brincidofovir) is a lipid conjugate form of cidofovir with enhanced in vitro activity against adenoviruses, improved bioavailability when administered orally, and lower potential for nephrotoxicity and myelosuppression. Brincidofovir is currently being evaluated in phase III clinical trials, and preliminary results have indicated good safety and efficacy in treating adenoviral infections in transplant recipients. Intravenous immunoglobulin has also been used for the treatment of adenovirus disease in immunocompromised patients. Other emerging therapies include the transfusion of donor-derived adenovirus-specific T lymphocytes, which is currently being used in some centers for stem cell transplant recipients who do not respond to antiviral therapy.
An effective, live, enteric-coated oral vaccine against serotypes 4 and 7 has been used in military recruits but has not been employed in civilian populations. Hospitalized children with conjunctivitis or gastroenteritis should be placed in contact isolation, and those with respiratory tract disease in contact and droplet isolation for the duration of illness. Adenoviruses are difficult to inactivate with alcohol-based gels and can remain viable on environmental surfaces for prolonged periods; thus, strict hand hygiene and use of disposable gloves are recommended when caring for infected patients.
RHINOVIRUSES AND RESPIRATORY ENTEROVIRUSES
Rhinoviruses have been known to cause the majority of URIs in adults and children, which are also known as the “common cold,” with a generally benign, self-limited course. Currently, they are also increasingly recognized as important triggers of LRTIs and asthma exacerbations.
PATHOGENESIS AND EPIDEMIOLOGY
Rhinoviruses and enteroviruses are small, nonenveloped, single positive-stranded RNA viruses belonging to the Enterovirus genus within the Picornaviridae family. They are divided into 7 species: 3 rhinovirus species (A, B, and C) and 4 non-rhinovirus enterovirus species (A, B, C, and D). There are more than 100 serotypes. Most rhinoviruses replicate optimally at low pH (< 5) and high temperature (> 34°C), the temperature of the upper respiratory tract mucosa. Cross-protection after rhinovirus infection is incomplete and short lasting.
Rhinoviruses infect and replicate in the upper respiratory tract through the intracellular adhesion molecule-1 (ICAM-1), the host receptor for most rhinoviruses. On the other hand, enteroviruses can replicate in different cells, causing clinical syndromes such as febrile illness, viral meningitis and encephalitis, and myopericarditis. Some species of enteroviruses, however, are mainly associated with respiratory tract infections (species C and D) and are clinically indistinguishable from those caused by rhinovirus.
Rhinovirus infections occur year-round, but 2 peaks have been classically reported, 1 between April and May and a second between September and October. Some studies have shown that species C has a different peak of infection, typically over the winter months. Children are the major reservoir for rhinovirus. Transmission occurs primarily by person-to-person contact through self-inoculation with contaminated secretions (hand-to-nose or hand-to-eye). Large-droplet spread is also possible. Viral shedding in respiratory secretions is greatest during the first 2 to 3 days of illness and can last from 10 to 21 days. The incubation period is 2 to 3 days.
Enteroviruses with respiratory tropism, such as species C and D, have a worldwide distribution and can cause respiratory disease with varying degrees of severity ranging from mild URI to pneumonia. Enterovirus D68 was first described in 1962 from children with bronchiolitis and pneumonia, with a few clusters of cases reported over the past decade in different parts of the world. The largest outbreak of enterovirus D68 occurred in the United States in 2014 with over 1000 cases reported in 49 states mainly affecting children with a history of asthma. In addition to its respiratory tropism, enterovirus D68 infection has been associated with neurologic disease including acute flaccid myelitis.
Rhinovirus infection can be asymptomatic or symptomatic. The most common manifestation of rhinovirus infection is the common cold—an illness dominated by nasal obstruction or discharge, with accompanying cough, sore throat, and mild or absent fever. It has also been linked to acute otitis media complicating approximately one-third of patients with URI. Rhinoviruses can also cause LRTI, such as bronchiolitis and pneumonia, and are well-established triggers of wheezing in children with asthma.
rt-PCR is the most sensitive and the preferred test for diagnosis and is the only method available to diagnose rhinovirus C. Commercially available multiplex PCR assays include both rhinoviruses and enteroviruses. Most of these assays target a region that is conserved among both species, making their differentiation difficult. Rhinovirus can be positive by PCR in asymptomatic children, which may indicate residual viral RNA from a prior rhinovirus infection.
No specific antiviral treatment is currently available for rhinovirus infections. Over-the-counter cough and cold preparations do not provide significant benefit for children with the common cold and are not recommended. Vitamins (ascorbic acid), minerals (zinc), and herbal remedies (Echinacea) are frequently used for the treatment and prevention of the common cold, with limited evidence of any benefit in reducing symptoms. To date, there are no vaccines available or in clinical trials.
Hand washing and avoidance of hand contact with respiratory secretions of affected individuals reduce viral transmission. For symptomatic hospitalized children, contact and droplet precautions are recommended for the duration of illness.
The human coronaviruses are enveloped, pleomorphic, nonsegmented, single-stranded RNA viruses named after their corona or crown-like surface projections that correspond to their surface glycoproteins. Coronaviruses have long been identified as causes of the common cold in adults and children, causing 5% to 18% of childhood respiratory infections. Cases of croup, bronchiolitis, and pneumonia are increasingly recognized. Emergence of 2 highly virulent coronaviruses with zoonotic transmission causing severe LRTI has been described in the past 15 years. In 2003, the SARS coronavirus was identified as a novel virus responsible for the 2002 to 2003 global outbreak that resulted in thousands of cases and more than 700 deaths. Technologies developed during the SARS epidemic contributed to the discovery of additional coronaviruses such that 4 non-SARS coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) are currently known to circulate in humans and have been associated with respiratory disease. Non-SARS coronavirus epidemics have also occurred. In 2012, the Middle East respiratory syndrome (MERS) coronavirus (CoV) was identified, and since then, hundreds of people have been affected in different countries. Most people affected with MERS-CoV developed acute febrile respiratory illness, and many died. The incubation period of non-SARS-CoV is approximately 3 days, for SARS-CoV approximately 4 days, and for MERS-CoV approximately 5 days. The growth of CoVs in tissue culture is limited, and rt-PCR has enhanced the ability to detect these viruses. The diagnosis of SARS-CoV or MERS-CoV should not be based on a single test and needs to be confirmed by an approved laboratory. Treatment is supportive, and no vaccines are currently available.
Human bocaviruses (HBoVs) of the family Parvoviridae are single-stranded DNA viruses that were discovered in 2005 using novel molecular techniques in children with respiratory infections. HBoVs circulate throughout the year, with peaks in winter and spring months. The virus is most frequently identified in children < 2 years of age. By age 6 years, most children have evidence of previous HBoV infection, with reinfections occurring into adulthood. Four genotypes are included in the Bocavirus genus (HBoV 1–4). HBoV1 is the genotype associated with respiratory disease in children, having been found in approximately 8% of young children with acute respiratory infections including otitis media, pneumonia, bronchiolitis, and wheezing. Although this virus is not commonly found in asymptomatic individuals, its causal role in childhood respiratory infections has been called into question because of the high frequency of co-detection with other respiratory viruses (as high as 80%) and the potential for asymptomatic persistence in some individuals. HBoV1 has also been detected in low levels in the stool of children with gastroenteritis; however, co-pathogens were detected in 100% of the patients, potentially reflecting ingestion of the virus without causation of disease. HBoV2, HBoV3, and HBoV4 seem to be associated with gastrointestinal symptoms, but their prevalence is low. Detection of HBoV1–3 from cerebrospinal fluid in children with encephalitis associated with seroconversion has occasionally been reported. Diagnosis is made mainly with rt-PCR, but serology is also available. Treatment is supportive.
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