Influenza and Parainfluenza Viral Infections in Children

Abstract

After completing this article, readers should be able to:Influenza and parainfluenza viruses (PIVs) are among the most common respiratory pathogens that affect infants and children worldwide. Infections and their complications are responsible for a significant number of hospitalizations and fatalities on a yearly basis. In most temperate climate countries, seasonal patterns of disease are observed. In warmer climates, disease can be observed year round. The fear of an influenza pandemic looms when new strains are discovered. Recognition and prevention become pressing priorities. In recent years, a greater emphasis in preventing influenza through vaccination has emerged within the United States. Many health care systems have mandatory vaccinations programs for health care professionals. In addition, vaccination is now recommended for all persons 6 months or older. Available antiviral agents are effective not only as therapy but also as preventive agents.PIVs are the most common cause of laryngotracheitis or croup in children. In recent years, these viruses have become recognized as important pathogens in the immunocompromised host. Unfortunately, an effective antiviral regimen or vaccine still eludes us. In this review, we summarize the key aspects of what is known about influenza and PIVs, including their clinical manifestations, treatment, and prevention.The avian origin H1N1 influenza pandemic of 1918–1919 (Spanish flu) has been described as the single most fatal event in human history, responsible for more than 50 million deaths worldwide. (1) Subsequent pandemics occurred in 1957 (H2N2 Asian flu) and 1968 (H3N2 Hong Kong flu). The emergence of swine-origin novel H1N1 influenza in March 2009 heralded the fourth influenza pandemic in the last 100 years. Influenza epidemics can be traced back at least 2000 years, and the first true pandemic (intercontinental disease) occurred in 1580.Influenza viruses are classified as orthomyxoviruses and contain a negative sense single-stranded RNA genome. There are 3 major influenza types: A, B, and C. The individual virus is spherically shaped and studded with 2 major proteins: hemagglutinin and neuraminidase. Differences in the hemagglutinin and neuraminidase antigens form the basis for the nomenclature of influenza A subtypes (eg, H1N1 vs H3N2). Influenza strains are further categorized according to type, location, and year and are given a strain number (eg, A/California/7/2009 [H1N1]).Hemagglutinins facilitate attachment of the virus to the columnar epithelial cell in the respiratory tract. After uptake of the virion by endocytosis, an influx of protons through the virus M2 channel allows release of viral RNA, which is then imported to the nucleus. The virus hijacks the host’s cellular machinery to produce the proteins and genetic material needed for viral progeny. Neuraminidases function in the budding of the newly formed virion to aid in its release from the host cell. (2)The genetic characteristics of influenza viruses facilitate the generation of novel strains with the potential to cause human disease. The influenza genome is composed of 8 RNA segments that can rearrange if more than one influenza subtype infects the same host. The virus contains its own RNA polymerase, which, in contrast to DNA polymerase, lacks proofreading functions. Consequently, point mutations occur with regular frequency during genome replication. The accumulation of these point mutations is known as antigenic drift and is responsible for the seasonal variation of influenza A strains that cause annual epidemics. Antigenic shift occurs when an influenza A strain with a novel hemagglutinin (and sometimes a novel neuraminidase) enters the human population. A pandemic occurs if this newly generated strain causes disease in humans and can efficiently spread from person to person and throughout the world. To date, 17 unique hemagglutinin antigens and 10 unique neuraminidase antigens have been identified. (2) Many of these influenza subtypes naturally infect the hundreds of bird species susceptible to influenza. Birds can be infected by multiple different strains simultaneously and serve as a genetic pool for the generation of new influenza strains. The human population has so far been susceptible to a limited number of influenza subtypes. Human infection and effective human-to-human transmission has been achieved by only 3 hemagglutinins and 2 neuraminidases in 3 combinations: H1N1, H2N2, and H3N2. (3) Because of differences in preferred cellular binding sites, different influenza strains preferentially infect birds and humans. However, pigs (swine) are susceptible to infection from both avian and human strains. Swine can serve as mixing vessels to produce novel strains that subsequently infect humans. In recent years, 2 influenza A strains of avian origin, H5N1 and H7N9, were responsible for several clusters of human disease in Asian countries, resulting in many hospitalizations and a high fatality rate. (4)(5)In March 2009, a new strain of influenza A was identified that caused significant disease in humans and could efficiently spread from person to person, leading to the fourth influenza pandemic of the last 100 years. This virus was a novel combination of 2 individual swine viruses, hence the term swine-origin H1N1 or swine flu. From April 2009 to March 2010, novel H1N1 was responsible for an estimated 60 million illnesses, 270,000 hospitalizations, and 12,270 deaths in the United States. (6) As seen in previous pandemics, novel H1N1 disproportionately affected young adults and children, as well as pregnant and postpartum women. There were 317 confirmed pediatric deaths during the pandemic, significantly higher than prior years. The excess childhood deaths are probably explained by the increased attack rate in the young rather than enhanced virulence in this age group. (7)Epidemics of influenza occur annually during the winter months in temperate regions of the world, typically peaking in January or February in the Northern hemisphere. There is no clear influenza season in equatorial countries, where influenza can circulate year round. Children are important vectors of disease because of higher attack rates and more prolonged viral shedding compared with adults. The peak incidence of infection occurs earlier in the pediatric population. An increase in missed school days in children sick with influenza often precedes increased work absenteeism in adults.Influenza virus is transmitted primarily by large particle droplets, although contaminated surfaces can also spread disease. The incubation period is 1 to 4 days (mean, 2 days). Viral shedding correlates with fever intensity and begins 24 hours before symptom onset, peaks at day 3, and resolves by day 7. (8) However, young children and individuals with compromised immunity can shed virus for extended periods. The severity of disease may also correlate with duration of shedding.Hospitalization rates for influenza are highest in children younger than 2 years and adults older than 65 years. Children with certain comorbidities are at increased risk of hospitalization and influenza complications. These complications include hemoglobinopathies, diabetes mellitus, neuromuscular disorders, chronic kidney disease, and congenital heart disease. Children with underlying pulmonary disease, such as asthma and cystic fibrosis, are at risk for more severe disease.Classic influenza infection is characterized by the sudden onset of fever, chills, and myalgias followed by prominent upper respiratory tract symptoms, such as rhinorrhea, cough, and sore throat. It is critical to recognize that younger children are less likely to present with this flulike syndrome. This is especially true in infants, who can present with fever and irritability with minimal respiratory findings. It is difficult in younger children to distinguish clinically influenza infection from infections due to other respiratory viruses (eg, respiratory syncytial virus and PIV) that circulate in communities during the same periods, and the manifestations of disease can be identical. Table 1 provides a comparison of clinical features between influenza and PIVs. Upper respiratory tract infection (URI), laryngotracheitis (croup), bronchiolitis, and pneumonia are all possible presentations of influenza in the younger child. Gastrointestinal symptoms are uncommon in adults but can be the primary symptoms in children with influenza.Bacterial infection of the respiratory tract is the most common complication of influenza infection and includes otitis media, sinusitis, and tracheitis. Pneumococcal pneumonia is a relatively common complication and should be suspected in the child who develops fever and a lobar infiltrate during the convalescent period. Less common than Streptococcus pneumoniae, staphylococcal infection can complicate acute influenza and lead to a diffuse necrotizing pneumonia with a high mortality rate, especially if caused by methicillin-resistant Staphylococcus aureus. Parapneumonic effusions and empyemas are common complications.Acute myositis can occur during convalescence but is almost always benign. It occurs more commonly with influenza B. The typical presentation is a child who has sudden onset of severe pain in the calves and refusal to walk. The serum creatine kinase level is usually elevated. Severe encephalopathy and encephalitis have been reported with influenza infection. Reye syndrome is a rare form of encephalopathy that has been associated with influenza infection and salicylate (eg, aspirin) use.Laboratory testing is the mainstay in the diagnosis of influenza infection. Clinical findings alone are insufficiently sensitive or specific, especially in younger children who less often have classic findings. Accurate and rapid diagnosis of influenza infection can allow prompt initiation of antiviral therapy while simultaneously limiting antibiotic use. A variety of testing modalities exist, and each has its merits. Serologic (antibody) testing for influenza infection is important in the epidemiologic study of disease but does not play a role in clinical management. Similarly, although laboratory culture of influenza virus is essential for vaccine development and antiviral resistance testing, other methods have proven more clinically useful. (9)Regardless of the diagnostic method used, proper sampling is paramount. Nasopharyngeal specimens are preferred over throat swabs. (9) The timing of specimen collection will also affect the validity of the result. A sample obtained in a patient with an influenza-like illness on days 2 to 3 of symptoms (when influenza virus shedding is at its peak) will yield a more reliable result compared with one obtained later in the disease course. (9)Rapid antigen testing is the most commonly used method in the laboratory diagnosis of influenza infection and plays a vital role in high-volume patient settings, such as emergency departments, especially during epidemics of disease. In fact, the first case of 2009 pandemic influenza infection in the United States was diagnosed using a rapid antigen test. These assays work by measuring the immunologic reaction between influenza antigens from the patient’s secretions with a specific influenza antibody. The advantages of rapid antigen tests include quick results (≤15 minutes), bedside or point-of-care testing, and distinguishing influenza type A from B.Rapid antigen testing can be part of treatment algorithms in the management of patients with suspected influenza. (10) Rapid antigen tests for influenza are highly specific, allowing for efficient allocation of antivirals during peaks of activity. The major disadvantage of rapid tests is their low and highly variable sensitivity, ranging from 20% to 90%. (9) Therefore, a negative rapid test result in a patient presenting with sudden onset of high fever, myalgias, and cough during peak influenza activity could be falsely negative. One important aspect of rapid influenza testing—and rapid viral tests in general—is that the accuracy of the test result is directly correlated with the prevalence of disease in the community. As stated in the above example, during periods of peak viral activity, a negative rapid test result in a patient with an influenza-like illness could be falsely negative. If that same patient presents during a period with minimal circulating influenza but has a positive rapid antigen test result, the test result is likely to be falsely positive. However, influenza strains can cause infections in out-of-season times of the year like in the case of an influenza A (H3N2) variant that in the United States during the months with associated with with swine at and in the methods of are viral culture as the in the diagnosis of many viral including influenza. reaction assays and compared with viral culture and are more in many The tests for influenza are often part of assays that can influenza and other important viruses, in the diagnosis of respiratory influenza assays can distinguish influenza from tests specific subtype (eg, H1N1 vs which in antiviral therapy during the 2009 H1N1 of the rapid antigen tests can influenza A and testing can be on patient secretions and results within a These tests are highly specific but have variable The of the results can on the of the are more than rapid antigen infection is a disease in most children and of treatment is However, influenza infection can cause severe disease and in both patients and The of antiviral therapy in the of disease has been to symptom duration and the spread of It may also be in patients and in with severe disease, if later in the disease course. should be within hours of symptom to antiviral therapy as treatment or should be on the duration of symptoms and the risk of to severe disease. patients with suspected or confirmed influenza should at high risk for severe disease and complications should also be therapy and 2 and are 2 of antivirals for the treatment and of the and the neuraminidase The include and and work by with the viral M2 channel to the release of viral RNA the host cell The not have activity influenza B. because of resistance among influenza A their in the treatment and of influenza A is not recommended at this The neuraminidase have activity both influenza A and B, and although strains of influenza A have been most circulating influenza strains are viral which the budding and release of viral progeny. and are 2 neuraminidase for clinical use. of and a are is for the treatment of influenza in children older than 2 and for to age 3 However, according to can be used to influenza in both term and infants from is for in the treatment of children years and older and as in children years and older. can cause but in is well and have been associated with the of It should be used with in patients with underlying pulmonary (eg, antiviral and 2 and vaccination is the of prevention influenza. persons 6 months and older should be Influenza is responsible for its in young infants, children younger than years, and individuals 65 years and older. In addition, persons with chronic such as heart disease, cystic fibrosis, diabetes mellitus, neuromuscular disorders, and other are at an increased of severe disease and In recent years, a significant number of infants and children have of the disease. many underlying to of fatalities were in children. Unfortunately, only of children with and the younger than 6 months are at risk for severe disease. vaccination is not in this age have that influenza are and in infants as young as 6 to In an vaccination of infants of to in to the in One that will these young infants is the vaccination of during because in the infants have been to be to 6 The vaccination of was more than effective in preventing hospitalizations of their to be vaccination is not only of pregnant the If vaccination is recommended to the pregnant by a health care will The vaccination of children in has been to among of the are within the United States are but a vaccine and a vaccine are The antigenic of the is on a yearly basis on and of and influenza The of the influenza vaccine is A/California/7/2009 and The vaccine contains an influenza which will both the and This that contain antigens for 2 strains each of influenza A and are also in to individuals 2 years or older can an influenza vaccine or The is for persons 2 to years. It is in persons with underlying and of the vaccine to young infants has also to is individuals with systems not to have significant or prolonged viral shedding the to have of compared with In children 6 years or older and with the a increase in influenza infections when compared with Viral shedding from the occurs which peaks 2 days symptoms, such as and sore not correlate with viral duration of shedding was Viral shedding can be observed with to 6 to 8 days this in should when who should this for persons with to to the spread of If for persons who the should not this are used in individuals who are not for care who work with immunocompromised persons should this significantly among age and persons with Because of this is critical that more persons their yearly The higher the number of the the This is critical in with a large number of infants younger than 6 influenza viruses are type to of children 6 months or older 2 of In children 6 to will and in 3 to years, will according to patient type of and study vaccine between and Influenza have been to be and when given simultaneously with other infants and children younger than years will 2 of vaccine by 4 if the vaccine for the first influenza have been from In persons with to the of may be to be However, cell culture and have become allowing for the vaccination of patients with to with a of to should not be with testing by an is no recommended for children with a of the of A recent study of children that patients a of to can the influenza vaccine the for of the for and and the of the of the vaccine for individuals to years with a of or to individuals with a of only vaccination with an can be infants and children 6 to a of of the is by the age 3 years, is The vaccine a of each an vaccine resulting in a less This vaccine was to be more than the There is limited with this vaccine in young have to increase in clinically important in the 2 respiratory acute otitis media, and asthma are less common in the pain at the of myalgias, and have been reported the of influenza and have been reported can occur However, its risk to be to a specific vaccine by Because of the this vaccine is not recommended for children younger than years. In vaccination not function or cause an reaction to that of cough, sore or has been reported 2 to 24 hours It resolves within This syndrome may a type of syndrome has been described influenza The risk is After 1 syndrome case 1 million was are of the are RNA viruses with a viral with such as and that are responsible for the respiratory epithelial where of this include respiratory syncytial and human There are 4 of and There are also 2 antigenic subtypes and of the disease caused by occurs in children younger than years and is responsible for to of hospitalizations due to respiratory hospitalizations are in infants younger than 1 viruses are responsible for of all respiratory tract with other respiratory viruses are a common with as high as children to have a duration of symptoms and prolonged viral age years, all children have been infected by all of are a cause of childhood disease, such as and and are the most common causes of especially during the is responsible for respiratory tract infections such as and in the and The of has been less but to be responsible for and in infants younger than 6 In a a prevalence with clinical features to of patients with infections the large of the respiratory tract of children. for this is by the large number of epithelial in the Many of the clinical features of infections are from observed with other viruses, such as influenza virus and are responsible for most pediatric disease, with responsible for of all In a study of children in was the most common of followed by of was in of children with infection. virus is transmitted through to contaminated secretions by or with contaminated The incubation period is 2 to 4 with viral shedding that may last to 1 onset of persons may shed virus to 1 before onset of The duration of shedding may be specific, with 3 to 4 otitis is by infections caused by are responsible for to of all rhinorrhea, and fever are common features of caused by is contrast to influenza viruses, in most communities circulate all of croup observed in the are caused by PIVs. The clinical presentation of croup is A sudden onset of a cough by and is usually last 3 to The of fever and from In young children, and can be observed. However, severe respiratory and a child and still at the of a are highly of an infection usually associated with type which now is rare to Children with croup not Children with croup caused by influenza virus to be more have and have more severe is a common complication of may lead to prolonged symptoms of and respiratory A is observed on an of the and The on a is in most children with in children is caused by a of but especially and cause bronchiolitis, which is from disease caused by respiratory syncytial virus and human to of are caused by and are common of are caused by and infants, especially can in the of an hospitalizations will occur in the first year of is observed in more than of infected children. The most severe will occur in or immunocompromised children. with such as with or who have cell are at risk of more severe disease, such as in this population can be with a fatality rate of have the highest especially in the first 100 days of the when is viral shedding is a common of children with primary are common but to be or in the the of and are no rapid diagnostic especially for point-of-care infection can be important because may the of and to be the most specimens for the of respiratory viruses by and However, are to and are by The of both methods was for respiratory viruses other than testing from has high and is no antiviral therapy for the treatment of or with and has been used as treatment in immunocompromised children and adults with severe disease. of the from or However, on the basis of the results of these limited this regimen should be in the compromised child with respiratory tract disease. of these infections is to proper so the child can secretions to be However, the of in a or has no for the child with In patients with the of and is associated with a of The of and and has been to be in patients with resulting in and In to be is associated with a in symptoms of will this in combination with a are no is an effective of preventing the transmission of respiratory to be to with