Version May 2024
INTRODUCTION — Influenza is an acute respiratory illness caused by influenza A or B viruses, and rarely influenza C viruses. It occurs in outbreaks worldwide every year, mainly during the winter seasons in temperate climates. Signs and symptoms of upper and/or lower respiratory tract involvement are common, but the presentation varies with age and previous experience with influenza virus.
Although influenza generally is an acute, self-limited, and usually uncomplicated disease in healthy children, it can be associated with severe morbidity and mortality. Certain groups of children are at increased risk of severe or complicated influenza infection (table 1).
The clinical features and diagnosis of influenza in children will be reviewed here. The epidemiology of influenza, the prevention and treatment of influenza in children, the clinical manifestations and diagnosis of influenza in adults, and the clinical manifestations and diagnosis of avian influenza are discussed separately.
●(See "Influenza: Epidemiology and pathogenesis".)
●(See "Seasonal influenza in children: Prevention with vaccines" and "Seasonal influenza in children: Management" and "Seasonal influenza in children: Prevention with antiviral drugs".)
●(See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)
●(See "Avian influenza: Clinical manifestations and diagnosis".)
VIROLOGY — Influenza infection generally is caused by influenza virus types A and B. Influenza A viruses are classified into subtypes according to two surface antigens: the hemagglutinin (HA) and neuraminidase (NA) antigens, which determine influenza nomenclature (eg, H1N1, H3N2) [1]. Influenza C viruses also may cause influenza infection, particularly in young children [2-7]. Although the prevalence of influenza C usually is lower than that of influenza A or B, influenza C epidemics may occur [8,9]. (See "Influenza: Epidemiology and pathogenesis".)
EPIDEMIOLOGY — Influenza occurs in distinct outbreaks every year, mainly during the winter months in temperate climates, although the specific timing and duration of the influenza season vary from country to country and year to year [10]. The epidemiologic pattern reflects changes in the hemagglutinin and neuraminidase surface proteins (ie, antigenic shifts or drifts). The subsequent spread, duration, and severity of the outbreak depend upon the susceptibility of the population. (See "Influenza: Epidemiology and pathogenesis".)
Influenza activity — Information about influenza activity at the national, regional, and state level is available from the United States Centers for Disease Control and Prevention () and the World Health Organization (). Surveillance information is updated regularly during influenza season. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Influenza activity'.)
Transmission — Influenza viruses are spread from person to person, through contact with respiratory secretions (through sneezing, coughing, talking, touching) or contaminated objects (fomites) [11-13]. However, sneezing and coughing are not necessary for transmission. Influenza also may be spread by small particle aerosols that are released into the air during breathing [14-17]. Children are important vectors for the spread of disease.
The incubation period is usually one to four days (mean two days), resulting in rapid and high transmissibility [1].
Influenza A viral shedding peaks at 24 to 48 hours of illness and then rapidly declines; little or no viral replication is detectable in the respiratory tract after 5 to 10 days [18-21]. Influenza B viral shedding appears to be bimodal, with peaks 48 hours before and 24 to 48 hours after symptom onset [21]. This means that patients can be contagious before the onset of symptoms and for several days after. Longer periods of shedding can occur in immunocompromised hosts and young children, especially those with primary infection, due to the relative lack of immunity [22-26].
The magnitude of shedding varies from patient to patient and appears to correlate with symptoms and severity of illness, particularly with influenza A [14,19,21,27]. However, even children with mild symptoms remain an important reservoir of disease given their prolonged viral shedding.
Burden of disease — The attack rate of influenza in children (<18 years) varies from year to year, ranging between 10 and 40 percent during a typical influenza season [1,28]. The estimated incidence of symptomatic influenza in children <18 years is approximately 9 percent [29]. Influenza virus infections in children are associated with increased frequency of outpatient visits, hospitalization, antibiotic utilization, missed school days for the patient and patient's siblings, and missed work days for the caregiver(s) [30-33].
Young children and those with certain underlying medical conditions (table 1) are at increased risk for hospitalization or severe or complicated influenza infection, which also can occur in healthy children [34-39]. (See 'Complications' below.)
The high burden of disease, including preventable mortality, highlights the importance of influenza immunization for all individuals ≥6 months of age (especially contacts of infants <6 months of age) and of initiating antiviral treatment as early as possible for children who are <2 years old, are hospitalized, have severe illness, or have underlying medical conditions (table 1). (See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)
●Outpatient visits – The rate of influenza-related outpatient visits among children in the United States varies from year to year, ranging from 6 to 29 per 100 children [31,40].
●Hospitalization – The rate of influenza hospitalization is greater in children <5 years than in older children. In population-based surveillance during the influenza seasons from 2010-2011 to 2018-2019, the hospitalization rate was greatest for infants <6 months of age (237 per 100,000); mean hospitalization rates ranged from 55 to 118 per 100,000 for children 6 months through 4 years of age and from 25 to 40 per 100,000 for children age 5 through 17 years [41]. Among the 13,235 children hospitalized, 20 percent were admitted to the intensive care unit and 5 percent required mechanical ventilation.
Although influenza virus infection is associated with increased rates of hospitalization in children with high-risk medical conditions (table 1), approximately 50 percent of children hospitalized had no underlying condition [41].
The major cause of hospitalization in infants with influenza is an undifferentiated febrile illness, which may require an evaluation for serious bacterial infection because of the acute onset of fever and absence of localizing signs [42]. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Fever without a source in children 3 to 36 months of age: Evaluation and management".)
●Mortality – In population-based surveillance in the United States between 2010-2011 and 2018-2019, among 13,325 children <18 years with influenza-related hospitalization, 0.5 percent died during hospitalization [41]. During the 2021-2022 influenza season, 37 pediatric deaths were reported to the CDC [43].
Detailed information about influenza-associated pediatric mortality in the United States is available from the CDC [43].
Factors associated with increased mortality include [44-46]:
•Underlying medical problems associated with increased risk of severe or complicated influenza (table 1)
•Age <5 years (particularly <2 years, and among those <2 years, particularly those <6 months)
•Bacterial coinfection with Staphylococcus aureus or Streptococcus pneumoniae [47] (see 'S. pneumoniae or S. aureus coinfection' below)
•Increased circulation of influenza A H3N2 strains (ie, ≥20 percent of isolates) [48] (see 'Influenza activity' above)
Although the risk of death is increased among children with high-risk medical conditions, approximately one-half of pediatric influenza deaths occur among children without high-risk conditions [44,49,50]. Previously healthy children without high-risk conditions who acquire influenza may be more likely to die before hospital admission and within three days of symptom onset.
Reporting influenza mortality – Influenza-associated deaths in children (<18 years) should be reported to the CDC through the state health department [1,51]. If the death was complicated by S. aureus infection, the S. aureus isolate should be sent to the CDC.
UNCOMPLICATED INFLUENZA
Clinical features — The clinical manifestations of influenza virus infection vary with the child's age and previous experience with influenza virus. The classic symptoms of uncomplicated influenza virus infection include abrupt onset of fever, headache, myalgia, and malaise, accompanied by manifestations of respiratory-tract illness, such as cough, sore throat, and rhinitis [52,53]. Symptoms may be less severe in children who develop influenza despite influenza immunization [54].
Classic features may be absent in children with influenza virus infection. Young children may not be able to vocalize their symptoms; they tend to have higher fevers, febrile seizures, less prominent respiratory findings, and more gastrointestinal complaints (eg, nausea, vomiting, diarrhea, poor appetite) at the time of presentation (table 2) [52,55-58].
Children with uncomplicated influenza may have few localizing findings; fever and malaise may be the only recognized manifestations [22,59]. When present, localized findings are usually nonspecific and include tachypnea; conjunctival erythema; nasal injection, edema, and discharge; cervical adenopathy; and parotitis [45,60-62]. Oropharyngeal abnormalities other than slight to moderate hyperemia are uncommon, even with complaints of sore throat.
In a prospective cohort of 353 children (≤13 years) with laboratory-confirmed influenza who were treated as outpatients, clinical features at initial presentation included (table 2) [52]:
●Fever – 95 percent (50 percent had fever >39°C [102.2°F])
●Cough – 77 percent
●Rhinitis – 78 percent
●Headache – 26 percent (among children 3 to 13 years of age)
●Myalgia – 7 percent (among children 3 to 13 years of age)
The spectrum of clinical findings and the severity of infection may vary with the type or subtype of influenza. As examples, influenza B infection is more typically associated with musculoskeletal findings than influenza A [63-66]; 2009 pandemic H1N1 influenza (influenza A[H1N1]pdm09) and influenza A (H3N2) have been associated with more severe illness than other subtypes [67-75]. However, these observations are inconsistent, with some studies reporting no difference in clinical findings associated with influenza types and subtypes, particularly in children <13 years [52,76-79].
Factors determining the severity of an outbreak are discussed separately. (See "Influenza: Epidemiology and pathogenesis".)
Clinical course — Influenza in otherwise healthy children generally is an acute, self-limited, and uncomplicated disease; however, more severe illness requiring hospitalization and, rarely, death may occur. The risk of complicated or severe influenza infection is increased in children with high-risk conditions (table 1) [39,45,46]. (See 'Burden of disease' above and 'Complications' below.)
Patients with uncomplicated influenza usually improve gradually over approximately one week (with or without antiviral therapy) [77], but symptoms – especially cough – may persist, particularly in young children. Weakness and easy fatigability may last for several weeks in older children and are sometimes referred to as "post-influenza asthenia."
Children who recover from one episode of influenza infection may be infected with a different influenza type or subtype later in the season. In a retrospective review of 647 patients with laboratory-confirmed influenza, 13 children had consecutive influenza A and B infections during a single season [80]. None of the children had received influenza vaccine or antiviral therapy; all of the children presented with typical clinical manifestations of influenza for both episodes. This observation underscores the need to administer influenza vaccine even after the start of the season to protect against other circulating strains.
Laboratory features — Leukocyte counts are normal or low early in the illness but may become elevated later in the illness. White blood cell counts >15,000 cells/microL suggest bacterial superinfection [81-83].
COMPLICATIONS
Otitis media — Otitis media complicates the course of influenza in 10 to 50 percent of children [30,52,84]. The typical time of onset for otitis media is three to four days after the onset of influenza symptoms. (See "Acute otitis media in children: Epidemiology, microbiology, and complications", section on 'Pathogenesis'.)
Pneumonia and respiratory tract complications
●Pneumonia – Pneumonia is a major complication of influenza, particularly in high-risk patients (table 1). In children without underlying high-risk conditions, influenza pneumonia occurs most frequently in children younger than two years [40,81,85]. In population-based surveillance, 28 percent of children hospitalized with influenza during 2003 to 2010 had pneumonia [86].
Influenza pneumonia is usually mild and of short duration; however, in hospitalized children, it increases the risk of a severe clinical course [85,86]. Bacterial coinfection with S. aureus or S. pneumoniae may be particularly severe and rapidly fatal. (See 'S. pneumoniae or S. aureus coinfection' below.)
The radiographic pattern of influenza pneumonia is variable. In a review of 134 cases of radiographically-confirmed influenza pneumonia in children <4 years of age, the infiltrates were interstitial in one-half of cases, alveolar in one-fourth, and interstitial and alveolar in one-fourth [81].
●Other respiratory complications – Other respiratory tract complications of influenza infection include:
•Exacerbation of underlying chronic pulmonary conditions, particularly asthma [86-88] – In population-based surveillance, asthma exacerbation occurred in 22 percent of children >2 years of age who were hospitalized with influenza during 2003 to 2010 [86].
•Respiratory failure – In population-based surveillance, respiratory failure occurred in 5 percent of children hospitalized with influenza during 2003 to 2010 [86].
•Laryngotracheitis or tracheobronchitis (croup) – Influenza virus laryngotracheitis or tracheobronchitis may be particularly severe or complicated by bacterial superinfection (bacterial tracheitis) [40,86,89,90]. (See "Croup: Clinical features, evaluation, and diagnosis" and "Bacterial tracheitis in children: Clinical features and diagnosis", section on 'Presentation'.)
•Plastic bronchitis – Plastic bronchitis (thick, inspissated, tracheobronchial casts) is a rarely reported complication of influenza in children [91-95].
Secondary bacterial infection
S. pneumoniae or S. aureus coinfection — Secondary bacterial coinfection (eg, pneumonia or bacteremia), most commonly due to S. pneumoniae or S. aureus, may occur in children with or without high-risk conditions and can be particularly severe and rapidly fatal [47,86,96-103]. Bacterial coinfection should be suspected in children with severe influenza/influenza-like illness, children with clinical deterioration after initial improvement, children who fail to improve after three to five days of antiviral therapy, and children with abrupt recrudescence of fever one to two weeks after influenza-like illness [45].
In population-based surveillance, bacterial coinfection occurred in 2 percent of children hospitalized with influenza during 2003 to 2010 [86]. In a 2016 systematic review of the frequency of influenza and bacterial coinfection, the rate of bacterial coinfection ranged from 2 percent in studies of children seen in mixed settings (emergency department, hospital) to 26 percent in hospitalized children to 50 percent in children hospitalized in the intensive care unit [101]. S. pneumoniae accounted for 35 percent of coinfections, and S. aureus accounted for 28 percent. The risk of pneumococcal pneumonia associated with influenza virus may be reduced by immunization against S. pneumoniae. (See "Pneumococcal vaccination in children", section on 'Efficacy and effectiveness'.)
Most cases of severe coinfection with influenza and S. aureus occur in individuals with no previous medical problems. Coinfection with influenza and methicillin-resistant S. aureus (MRSA) appears to be associated with a personal history of methicillin-MRSA skin infection or contact with a person with MRSA skin infection [98]. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Epidemiology and risk factors'.)
Toxic shock syndrome, associated with acute influenza and S. aureus infection, has been described after both influenza A and B infections [104-106]. (See "Staphylococcal toxic shock syndrome", section on 'Clinical manifestations'.)
Fatal cases of coinfection with influenza and S. aureus in the United States should be reported to the Centers for Disease Control and Prevention (CDC) through the state health department [1]. In such cases, the S. aureus isolate should be sent to the CDC.
Other bacterial coinfections — Serious bacterial coinfections of the head and neck (eg, orbital cellulitis, retropharyngeal abscess, peritonsillar abscess, Pott puffy tumor, subdural empyema, septic thrombophlebitis of the internal jugular vein [Lemierre syndrome]) have also been reported in children with influenza infection [107].
Secondary fungal infection — Invasive pulmonary aspergillosis has been reported as a complication of influenza in critically ill patients (mostly adults) admitted to the intensive care unit. The frequency of influenza coinfection with invasive aspergillosis varies geographically and by institution [108-112]; the risk is increased in immune-compromised patients undergoing chemotherapy for hematologic malignancies, immune suppression after solid organ transplantation, particularly lung transplant, and treatment for graft versus host disease in allogeneic stem cell transplant recipients.
Central nervous system — Central nervous system (CNS) complications occur in approximately 8 to 10 percent of children hospitalized with influenza and 25 percent of children hospitalized with severe influenza [113-117]. CNS complications are associated with increased severity of illness (eg, increased duration of hospitalization, increased rates of intensive care and/or mechanical ventilation, death). Although the risk of CNS complications is increased in children with pre-existing neurologic conditions, most children with CNS complications do not have pre-existing neurologic conditions [117].
In a cross-sectional study of >29,000 children hospitalized with influenza during 2015 to 2020, 7.6 percent had a neurologic complication [113]. The complications included:
●Febrile seizure in 5 percent of children (53.7 percent of complications)
●Encephalopathy in 1.7 percent of children (18.7 percent of complications)
●Nonfebrile seizure in 1.2 percent of children (13.2 percent of complications)
●Encephalitis, aseptic meningitis, brain abscess/bacterial meningitis, cerebral infarction, and Reye syndrome in ≤0.12 percent of children (≤1.3 percent of complications)
Other reported CNS complications include acute cerebellar ataxia, transverse myelitis, Guillain-Barré syndrome, and postinfectious encephalitis (also known as acute disseminated encephalomyelitis) [118-120].
Musculoskeletal — Acute myositis is a rare and severe complication of influenza [63,121]. The hallmark of acute myositis is extreme tenderness of the affected muscles, most commonly the calves. In severe cases, swelling and bogginess of the muscles may be noted. Serum creatine phosphokinase (CPK) concentrations are markedly elevated, and myoglobinuria with associated renal failure has been reported [64,121]. (See "Muscle enzymes in the evaluation of neuromuscular diseases", section on 'Infectious myopathies' and "Overview of viral myositis", section on 'Benign acute childhood myositis'.)
Mild, transient myositis with mild CPK elevation is more common than classic acute myositis in children with influenza. It is more frequently observed with influenza B than influenza A infections [63-66].
Cardiac — Influenza-related myocarditis and pericarditis are uncommon in children but may be severe and fulminant, particularly with influenza A(H1N1)pdm09 virus [122-124]. (See "Clinical manifestations and diagnosis of myocarditis in children", section on 'Clinical manifestations'.)
DIAGNOSIS
Clinical suspicion — During the influenza season, influenza virus infection should be considered (regardless of influenza immunization status or previous episode of influenza infection during the current season) in [45,80]:
●Febrile infants
●Children with fever and acute onset of respiratory illness (even if these symptoms develop during hospitalization)
●Children with fever and exacerbation of underlying chronic pulmonary disease (eg, asthma, cystic fibrosis)
●Children with community-acquired febrile pneumonia
●Children with fever (≥37.8°C [100°F]) and cough, sore throat, or both in the absence of another known cause of illness when influenza virus is known to be circulating in the community
Influenza virus infection also should be considered at any time of year in children with febrile respiratory illness who are epidemiologically linked to an outbreak of influenza [45].
Clinical diagnosis of influenza in children is difficult, particularly in infants and young children [40,125,126]. Other viruses, particularly respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and parainfluenza viruses, may cause similar clinical syndromes in children during influenza season [52,127-129]. (See 'Differential diagnosis' below.)
It is usually not necessary to differentiate between influenza and other respiratory viruses. Laboratory confirmation of influenza is not necessary for initiation of antiviral therapy, and supportive care does not differ for influenza and other respiratory viruses. (See "Seasonal influenza in children: Management".)
Whom to test — Laboratory testing for influenza virus should be performed in patients with clinical features compatible with influenza when the results will affect management (eg, initiation of antibiotic or antiviral therapy, performance of other diagnostic tests, infection control, need for immunization of contacts) [1,45,130].
Laboratory confirmation is not necessary before initiation of antiviral therapy or contact prophylaxis and should not delay initiation of this intervention in individuals for whom it is indicated. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)
During the influenza season, indications for laboratory testing in children include [45,131]:
●Suspected influenza in patients with high risk of complications (table 1), including underlying medical conditions and age <2 years
Febrile young infants (zero to three months) with a positive rapid diagnostic test for influenza may require additional evaluation. The approach to febrile young infants (zero to three months) with a positive rapid diagnostic test for influenza is discussed separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Influenza' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Diagnosed with viral infections'.)
●Hospitalization and acute febrile respiratory illness (even if symptoms develop during hospitalization)
●Hospitalization and severe respiratory illness, including community-acquired pneumonia
●Hospitalization and neurologic complications of influenza (eg, meningitis, encephalitis, encephalopathy)
●Hospitalization and acute worsening of chronic cardiopulmonary disease (eg, asthma, heart failure)
The duration of symptoms may affect testing and treatment decisions. Although antiviral therapy is most effective when it is administered within the first 48 hours of symptom onset, it is indicated beyond 48 hours in severely ill patients and patients with certain underlying medical conditions, such as the immunocompromised. (See 'Respiratory specimen collection' below and "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)
Our approach to testing for influenza is consistent with that of the American Academy of Pediatrics [1,132], Infectious Diseases Society of America [45], and the Centers for Disease Control and Prevention (CDC) [133].
Approach to testing — Laboratory confirmation of influenza virus infection requires detection of viral proteins or viral ribonucleic acid (RNA), or viral isolation, in respiratory-tract secretions or other relevant samples (eg, cerebrospinal fluid). A negative antigen test does not exclude influenza infection. A positive influenza test does not exclude other respiratory pathogens. A positive test for another respiratory pathogen does not exclude influenza. (See 'Testing for SARS-CoV-2' below.)
Seasonal influenza — The approach to testing for seasonal influenza depends upon test availability and how soon the results are needed (table 3) [45,134]. Laboratory confirmation is not necessary for treatment. For patients at increased risk of severe or complicated influenza (eg, those who are immunocompromised), treatment should be initiated as soon as possible based on clinical findings and local influenza activity. (See "Seasonal influenza in children: Management", section on 'Indications and preferred regimens'.)
If available, we prefer molecular assays (eg, reverse-transcriptase polymerase chain reaction [RT-PCR] or rapid molecular assays) to antigen detection tests. Antigen detection tests (eg, direct and indirect immunofluorescence assays, traditional rapid influenza diagnostic tests [RIDTs]) may be used if molecular assays are not available; in hospitalized (symptomatic) patients, negative antigen test results should be confirmed with a molecular assay [45]. Although digital immunoassays (DIAs) appear to have sensitivity approaching that of molecular tests and are commercially available, additional clinical experience is necessary to confirm their utility at the point of care [135,136].
During the winter respiratory virus season, for hospitalized patients who are immunocompromised, we use a two-step process: PCR for influenza, respiratory syncytial virus (RSV), and SARS-CoV-2, followed by multiplex PCR if influenza, RSV, and SARS-CoV-2 PCR are negative. Other institutions perform multiplex PCR without initial PCR for influenza and RSV.
Testing for multiple pathogens also may be warranted for hospitalized patients who are not immunocompromised if the results would affect management (eg, antimicrobial therapy, isolation, additional testing) [45]. During the coronavirus disease 2019 (COVID-19) pandemic, children who are hospitalized for influenza generally should be tested for SARS-CoV-2. (See "COVID-19: Diagnosis".)
●Molecular assays – Molecular assays include RT-PCR assays (singleplex or multiplex) and rapid molecular assays. A summary of available molecular assays for influenza viruses is provided on the CDC's website [137].
Molecular assays that identify influenza viral RNA or proteins in respiratory specimens are preferred to antigen detection methods because molecular assays are more sensitive and specific [45,134,138,139]. Some molecular assays can differentiate between influenza types and subtypes (including pandemic influenza and H5N1 avian influenza) (table 3) [45,140-142]. Identification of viral RNA does not necessarily indicate ongoing viral replication or viable virus [137].
•RT-PCR – Turn-around time for RT-PCR varies with the assay but typically ranges between one and eight hours [137]. RT-PCR can distinguish between influenza A and B and subtypes of influenza A. Sensitivity ranges between 86 and 100 percent [1]. Availability may be limited in certain settings.
•Rapid molecular assays – Rapid molecular assays provide results in <30 minutes [143]. They can distinguish between influenza A and B (but not subtypes). Rapid molecular assays are more sensitive than antigen-detection RIDTs [139]. Rapid molecular assays are widely available [144].
Several rapid molecular assays have been granted a waiver under the Clinical Laboratory Improvement Amendments (CLIA) and are available for use in nontraditional laboratory sites (eg, clinician's offices, emergency departments, health department clinics) [137].
In a meta-analysis of 63 studies evaluating rapid molecular assays (results available in <3 hours) for influenza in children and adults, the sensitivity and specificity were 91 percent (95% CI 89-93 percent) and 96 percent (95% CI 94-98 percent), respectively, using RT-PCR as the reference standard [139]. The sensitivity for individual assays ranged from 82 to 99 percent. In subgroup analysis, pooled sensitivity was higher in children than in adults (93 versus 80 percent) and pooled specificity was lower (81 versus 99 percent).
It is important to obtain the influenza vaccination history in children who undergo influenza testing with molecular assays. Molecular assays may detect live attenuated vaccine virus strains during the period of viral shedding (which peaks 2 to 3 days after administration but may persist for more than 10 days) [145,146]. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Adverse effects'.)
●Antigen detection assays – Antigen detection assays include direct and indirect immunofluorescence assays, DIAs – also called rapid immunochromatographic antigen detection tests – and traditional RIDTs. A summary of available antigen detection tests for influenza viruses is provided on the CDC's website [147].
Antigen detection assays are an alternative to molecular assays, but because they have lower sensitivity, results must be interpreted with caution, particularly results of direct and indirect immunofluorescence assays and traditional RIDTs [45,148,149]:
•A negative result when influenza prevalence is high does not exclude influenza and may warrant follow-up RT-PCR or other molecular assay if confirmation is necessary (eg, in hospitalized children)
•A positive result when influenza prevalence is low is more likely to be a false positive than a true positive (see "Evaluating diagnostic tests", section on 'Disease prevalence')
•A positive result in a patient with exposure to pigs or poultry may have a novel or variant influenza A virus rather than seasonal influenza virus, even when seasonal influenza prevalence is high (see 'Variant influenza viruses' below and "Influenza: Epidemiology and pathogenesis" and "Avian influenza: Epidemiology and transmission" and "Avian influenza: Clinical manifestations and diagnosis")
Three types of antigen detection tests are described below:
•Direct and indirect immunofluorescence assays – Direct and indirect immunofluorescence assays provide results in one to four hours [143,150]. They distinguish between influenza types and between influenza and other respiratory viruses. Direct and indirect immunofluorescence assays have moderate sensitivity (ranging from 70 to 100 percent), have high specificity, and generally perform better than antigen detection RIDT (table 3) [45,140,151]. However, their performance depends upon laboratory expertise and the quality of the respiratory specimen. These assays can be used to confirm influenza but not to exclude it.
•Digital immunoassays – DIAs (also called rapid immunochromatographic antigen detection assays) enhance accuracy of immunofluorescence assays by using a digital analyzer, which eliminates the need for a technician to view and interpret the results [152]. DIAs provide results in 10 to 15 minutes [152]. They distinguish between influenza A and B. They are less sensitive than molecular assays but more sensitive than traditional RIDTs [138].
Two commercially available rapid immunochromatographic antigen detection tests have been granted a waiver under CLIA [138] and are available for use in nontraditional laboratory sites (eg, clinician's offices, emergency departments, health department clinics).
In a meta-analysis analysis of 18 studies of DIA for influenza A and 17 studies of DIA for influenza B in children and adults, the sensitivity was 80 percent (95% CI 73-86 percent) for influenza A and 77 percent (95% CI 65-85 percent) for influenza B; specificity was >98 percent for influenza A and influenza B [138]. In subgroup analysis, sensitivity was greater for children than adults (88 versus 75 percent for influenza A and 83 versus 57 percent for influenza B).
•Traditional antigen detection RIDT – Traditional antigen detection RIDTs provide results in <15 minutes [143,148]. Antigen detection RIDTs include antigen detection (enzyme immunoassay) and neuraminidase detection assays.
Antigen detection RIDTs can be used to confirm influenza but not to exclude it [153,154]. Antigen detection RIDTs are less sensitive than molecular assays, direct and indirect immunofluorescence assays, and DIAs [138]. In a person who recently received live attenuated influenza vaccine, a positive RIDT result may indicate detection of vaccine virus [155].
In a meta-analysis of 94 studies of RIDT for influenza A and 30 studies of RIDT for influenza B in children and adults, the sensitivity was 54 percent (95% CI 49-60 percent) for influenza A and 53 percent (95% CI 42 to 64 percent) for influenza B; specificity was >99 percent for influenza A and influenza B [138]. In subgroup analysis, sensitivity was greater for children than for adults (61 versus 43 percent for influenza A and 66 versus 33 percent for influenza B).
The performance of RIDT varies with patient age, duration of illness, sample type, the prevalence of influenza in the community, virus type, and concentration of influenza virus in the sample [153,154,156,157]. Information regarding the sensitivity and specificity of a particular RIDT against the currently circulating strains of influenza may be obtained from local, state, and public health laboratories, or the CDC.
●Viral culture – Viral culture is not used for initial clinical management because the results are not available for 24 to 72 hours. However, it may be used for public health surveillance (eg, to provide isolates for further characterization).
●Serologic testing – Serologic testing is not helpful in clinical decision-making because diagnosis requires paired acute and convalescent sera. It is useful primarily for research purposes.
Variant influenza viruses — Variant influenza virus infection should be suspected in individuals with a febrile respiratory illness who have been exposed to swine or have contacts with close exposure to swine [158-160]. Cases of infection with influenza A(H3N2) variant and influenza A(H1N2) variant virus were reported to the CDC in August 2022 [159]. (See "Influenza: Epidemiology and pathogenesis", section on 'Role of animals'.)
Genome sequencing at the CDC can confirm isolates as variant influenza viruses [158,161]. Clinicians who suspect variant influenza virus infection should obtain a nasopharyngeal swab, place it in viral transport media, and contact their state or local health department for testing using real-time RT-PCR [161]. A negative rapid antigen test does not conclusively exclude variant influenza virus infection. The ability of rapid antigen tests to detect variant influenza varies substantially among the available tests.
Additional information about H3N2v influenza and other variant influenza virus infections is available from the CDC [160,162].
Testing for SARS-CoV-2 — In areas affected by the SARS-CoV-2 pandemic, children who are tested for influenza generally should also be tested for SARS-CoV-2, which causes COVID-19 [163]. The clinical features of influenza and SARS-CoV-2 overlap, and coinfection or sequential infection with these pathogens may occur. The clinical features and diagnosis of COVID-19 in children are discussed separately (See "COVID-19: Clinical manifestations and diagnosis in children".)
Respiratory specimen collection — Respiratory specimens should be obtained as soon as possible after illness onset [1]. The likelihood of a positive test is increased when specimens are obtained within 24 to 96 hours of symptoms onset, when the amount of influenza virus in the nasopharynx is at its peak [153]. In immunocompetent older children and adults, there is little viral shedding after five days of illness, and negative tests during this period do not reliably exclude influenza. In infants, young children, and immunocompromised hosts, the duration of viral shedding may exceed one week. (See 'Transmission' above.)
The appropriate specimen (eg, nasopharyngeal wash, aspirate, or swab; throat swab; lower respiratory secretions) depends upon the testing method (table 3). In general, nasopharyngeal specimens, midturbinate nasal swabs, or nasal specimens combined with throat specimens usually are more effective than throat swab specimens alone for viral isolation or rapid detection [45,164]. Midturbinate nasal swabs appear to be acceptable for molecular testing. In a convenience sample of 484 emergency department patients, midturbinate swabs were 98 percent sensitive (95% CI 94-100) but caused less discomfort than the reference standard nasopharyngeal swab [165].
Specimens for influenza testing should be transported on ice and then refrigerated.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of influenza in children includes infection or coinfection with other respiratory viruses, bacterial infections, and noninfectious causes of lower respiratory tract symptoms. Microbiologic testing generally distinguishes influenza from these conditions if differentiation will affect management. (See 'Diagnosis' above.)
●Other respiratory viruses include [51,52,127,128]:
•SARS-CoV-2, which causes COVID-19 (see "COVID-19: Clinical manifestations and diagnosis in children")
•Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Clinical manifestations')
•Parainfluenza viruses (see "Parainfluenza viruses in children", section on 'Clinical presentation')
•Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")
•Rhinovirus (see "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections", section on 'Clinical illness')
•Enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Clinical features of enterovirus infections')
●Bacterial causes of clinical syndromes that overlap with influenza include:
•Pneumonia (see "Community-acquired pneumonia in children: Clinical features and diagnosis")
•Tonsillopharyngitis (see "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis")
•Rhinosinusitis (see "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis")
●Noninfectious causes of lower respiratory tract symptoms are discussed separately (see "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Differential diagnosis')
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of seasonal influenza with antivirals".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)
●Beyond the Basics topics (see "Patient education: Influenza prevention (Beyond the Basics)" and "Patient education: Influenza symptoms and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Influenza occurs in distinct outbreaks every year, mainly during the winter months. Influenza viruses are spread from person to person, primarily through contact with respiratory secretions or contaminated objects (fomites). The incubation period ranges from one to four days (mean two days). (See 'Epidemiology' above.)
Young children and children with certain underlying medical conditions are at increased risk for hospitalization or severe or complicated influenza infection (table 1), which also occur in healthy children. Approximately one-half of pediatric influenza deaths occur in previously healthy children. (See 'Burden of disease' above.)
●Uncomplicated influenza – The classic symptoms of uncomplicated influenza virus infection include abrupt onset of fever, headache, myalgia, and malaise, accompanied by manifestations of respiratory-tract illness, such as cough, sore throat, and rhinitis. However, classic features may be absent in children (table 2). Influenza symptoms may last for more than a week, particularly among young children. (See 'Uncomplicated influenza' above.)
●Complications – Common complications of influenza include otitis media, pneumonia, and exacerbation of chronic pulmonary disease (eg, asthma). (See 'Complications' above.)
Secondary bacterial coinfection (pneumonia or bacteremia), most commonly due to Streptococcus pneumoniae or Staphylococcus aureus, may occur in children with or without high-risk conditions. Pneumonia coinfection with influenza and S. pneumoniae or S. aureus may be particularly severe and rapidly fatal. (See 'S. pneumoniae or S. aureus coinfection' above.)
●Diagnosis
•Clinical suspicion – During the influenza season or a known influenza outbreak, influenza virus infection should be considered (regardless of influenza immunization status or previous episode of influenza infection during the current season) in (see 'Clinical suspicion' above):
-Febrile infants
-Children with fever and acute onset of respiratory illness (even if these symptoms develop during hospitalization)
-Children with fever and exacerbation of underlying chronic pulmonary disease
-Children with community-acquired febrile pneumonia
-Children with fever (≥37.8°C [100°F]) and cough, sore throat, or both in the absence of another known cause of illness when influenza virus is known to be circulating in the community
•Whom to test – Laboratory testing for influenza virus should be performed when the results will affect decisions regarding treatment, prophylaxis of contacts, performance of other diagnostic tests, or infection control. Laboratory confirmation should not delay the initiation of antiviral therapy in individuals in whom treatment is indicated. (See 'Whom to test' above.)
•Laboratory confirmation – Laboratory confirmation of influenza virus infection requires detection of viral proteins or viral RNA, or viral isolation, in respiratory tract secretions or other samples. The approach to testing depends upon test availability and how soon the results are needed (table 3) (see 'Approach to testing' above):
-If available, we prefer molecular assays (eg, reverse-transcriptase polymerase chain reaction or rapid molecular assays) to antigen detection tests.
-Antigen detection tests (eg, direct and indirect immunofluorescence assays, traditional rapid influenza diagnostic tests [RIDTs]) may be used if molecular assays are not available. However, in hospitalized patients, negative antigen immunofluorescence assay and traditional RIDT results should be confirmed with molecular assays.
-Although digital immunoassays appear to have sensitivity approaching that of molecular tests and are commercially available, additional clinical experience is necessary to confirm their utility at the point of care.
-During periods of increased influenza activity, patients with negative antigen detection tests also may warrant confirmation with molecular assays or viral culture. (See 'Approach to testing' above.)
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