Pediatrie providers are all too familiar with the clinical manifestations of typical influenza infections each winter. Children present with abrupt onset of high fever, pharyngitis, rhinorrhea, cough, headache, muscle aches, and malaise. Vomiting, abdominal pain, and diarrhea can also be prevalent. For most, fever and other symptoms peak in the first 3 to 5 days of illness and improve by the end of the first week, except for residual cough and congestion. Results of laboratory studies, if undertaken, commonly show mild leukopenia, and results of a throat swab will be positive for influenza by rapid antigen assay or culture but negative for group A beta-hemolytic streptococcus.
For a significant minority of patients, however, influenza may be complicated by more serious effects of viral infection, secondary bacterial infection, and exacerbation of other conditions. This article focuses on these complications.
Concomitant infection of infants with influenza and Bordetella pertussis can be difficult to predict on clinical grounds and is often underrecognized.1 A dual infection with other respiratory viruses is more common in infants than in older children and is associated with higher rates of hospitalization.2
DISTINGUISHING PRIMARY VIRAL INFECTIONS FROM ASSOCIATED BACTERIAL INFECTIONS
An acute febrile illness from influenza infection may be difficult to distinguish from serious bacterial illnesses in infants and children. Furthermore, bacterial co-infections can occur at or near the outset of the viral infection or can be delayed for several days. The degree of fever may not be helpful. In infants and children, fevers up to 40° to 410C were as common in uncomplicated influenza infection as in proven bacterial infections.3 Fever in (mostly) hospitalized children lasted an average of 5 days in influenza A and B infections. Furthermore, a biphasic pattern of fever (ie, an afebrile period followed by the return of fever, which is typical of bacterial complications of viral infections) occurred in 12 of 74 children who had influenza without evidence of bacterial superinfection.3 Some studies have demonstrated that normal laboratory values for erythrocyte sedimentation rate, white blood cell count, and, especially, Creactive protein made bacterial infection much less likely than viral infection, but the discriminative ability of these tests was not entirely reliable.4
Comparison of Primary Viral Pneumonia and Secondary Bacterial Pneumonia Complicating Influenza\
RESPIRATORY TRACT COMPLICATIONS
Lower respiratory tract infection is a common and potentially deadly complication of influenza and accounts for most children hospitalized for influenza-related illness.5 Pneumonia can result from primary viral (influenza) or a secondary bacterial infection. The latter is most commonly due to Staphylococcus aureus or Streptococcus pneumoniae. The table compares the clinical presentation, etiology, treatment, and course of primary viral pneumonia versus secondary bacterial pneumonia.
Primary viral pneumonia is uncommon, appears early in the influenza illness, and can progress rapidly.6 In severe cases, worsening hypoxemia and respiratory distress can lead to death within a few days. Direct destruction of alveolar epithelium by influenza virus can lead to massive plasma leakage and pulmonary edema. Patients with preexisting cardiopulmonary or other chronic illnesses are at particularly high risk of severe or fatal primary influenza pneumonia,7 but this also occurs in otherwise healthy infants, children, and young adults.
Secondary bacterial pneumonia, on the other hand, is more common and typically presents at the end of the first week or the beginning of the second week of influenza illness. Patients frequently report that fever, cough, and other symptoms had started to improve, but then fever reappeared, accompanied by a worsening, productive cough.6 S. aureus, S. pneumoniae, and, to a lesser extent, Haemophilus influenzae are recovered most often from sputum of adult patients.8 We know less about children because bacterial etiologies are less frequently determined in pediatrie studies. In childhood pneumonias unrelated to influenza, S. aureus is not a frequent pathogen and therefore may not be routinely targeted by antibiotic treatment. However, it is important to use an antibiotic regimen that includes activity against S. aureus in a child with bacterial pneumonia following influenza. Response to antibacterial therapy is usually prompt and outcome is generally good.
A less common presentation is a concomitant viral and bacterial lung infection. This is associated with a more severe course and poorer outcome man secondary bacterial pneumonia. In one such report, two previously healthy children had severe pneumonia from S. aureus and influenza B within 3 to 4 days of the onset of influenza symptoms. Both had marked leukopenia, presented in severe distress requiring mechanical ventilation, and needed prolonged hospitalisation before ultimately recovering.9
Other Lowai Respiratory Tract Illnesses: Bronchlolltls and Laryngotracheobronchitls (Croup)
Although respiratory syncytial virus causes most bronchiolitis, influenza accounts for a small proportion of cases that are clinically indistinguishable. One 4-year study of infants and preschool children with bronchiolitis from whom a pathogen was isolated found respiratory syncytial virus in 40% of the infants, whereas influenza was identified in 16% (of which one-third were type B and two-thirds were type A).10
Although parainfluenza infection accounts for most croup, influenza has been implicated in 8% to 24% of such cases.11 Among children hospitalized for croup, influenza A was detected in 8% during the H2N2 era, but in 24% during the H3N2 era.12 During epidemics, the predominant influenza virus can account for an even greater proportion of croup cases. Overall, influenza A accounts for approximately 3 times as many cases of croup as does influenza B.11
Parotitis has been attributed to influenza A infection. Several such patients had only serologie evidence of influenza A infection and unusually mild symptoms.13 At least two other patients had onset of parotitis 7 days into a respiratory illness, and this was coincident with the appearance13 or reappearance14 of fever. Both showed rapid improvement while receiving antibiotics. Thus, although influenza may produce parotitis itself, causal evidence for a pure viral etiology is weak. Delayed appearance of parotitis accompanied by resurgent fever during influenza may thus warrant antibiotic treatment for presumed secondary bacterial parotitis.
Otitis Media and Sinusitis
Influenza infection also predisposes to secondary bacterial infections of the middle ear and the sinuses. For example, otitis media occurred in 15% to 35% of influenza cases in two series of children.11'15 Otitis media was more commonly associated with influenza A than with influenza B infections. Of cases of otitis media confirmed by tympanocentesis, 30% to 40% yielded S. pneumoniae, H. influenzae, or, less commonly, Moraxella catarrhalis. The middle ear fluid from these studies was not tested for influenza or other viral pathogens. Of 27 adult patients with experimentally induced influenza, 59% had negative ear pressures and 25% had otitis media. Tympanocentesis, performed in only 1 patient, yielded S. pneumoniae and influenza A by polymerase chain reaction.16 Another study of 84 children with otitis media found that 20% had positive results on viral cultures from middle ear fluid, of which influenza was one of the most common isolates.17 These studies suggest that influenza may cause otitis media primarily or may cause middle ear dysfunction that leads to a superinfection with the usual otitis media bacterial pathogens. In fact, influenza A vaccination of children 6 to 30 months old in day care reduced the rate of otitis media during an influenza season.18
OTHER BACTERIAL COMPLICATtOHS
Two studies reported an association between influenza infection and meningococcal disease as determined by case-control or regression analysis.19'20 Although the estimated risk of influenza inducing meningococcal disease is low (100,000 influenza infections to induce 1 case of meningococcal disease19), both reports concluded that the medical community should be alerted to the potential for increased rates of meningococcal disease when an influenza epidemic is identified.
Toxic Shock Syndrome
Some have attributed the plague of Athens (430 BC) to an epidemic of influenza followed by toxic shock syndrome, labeled the Thucydides syndrome.21 The Centers for Disease Control and Prevention definition for toxic shock syndrome includes fever, erythroderma, hypotension, evidence of multisystem involvement, and desquamation 1 to 2 weeks after the illness. Toxic shock syndrome following influenza A, influenza B, and influenza-like illness has been reported in contemporary children.21 Although this is rare, the reported mortality rate is approximately 40% (including adult cases).21 In most reported cases, the onset of the toxic shock syndrome occurred within 2 to 4 days of onset of influenza illness. S. aureus was usually recovered from the respiratory tract in most cases, and the isolate produced toxic shock syndrome toxin 1 (TSST-I) in many of diese. MacDonald et al. postulated that influenzainduced respiratory mucosal injury allows proliferation of organisms that produce toxic shock syndrome toxins in susceptible patients who are nasopharyngeal carriers of toxigenic S. aureus.22
By virtue of its ability to cause high fever in children, influenza can trigger febrile seizures in susceptible children between 6 months and 6 years of age. In one recent series of children presenting with febrile seizures, type A accounted for 6 and type B accounted for 2 of 144 total cases and of 68 cases for which a viral etiology was identified.23 Like any febrile illness, influenza infection also reduces the seizure threshold in children of any age with seizure disorders.
Reye syndrome is an acute illness that occurs primarily in children and is characterized by encephalopathy and fatty degeneration of the liver. Liver enzymes are elevated, but patients generally lack jaundice. The encephalopathy can vary from lethargy or mild impairment in consciousness to complete unarousability with flaccid paralysis, areflexia, and unresponsive pupils. The encephalopathy is accompanied by metabolic derangements, including elevated aminotransferases, hyperammonemia, fatty liver degeneration (by biopsy), or all three. Reye syndrome is usually preceded by a viral illness, especially chickenpox, but also by influenza A or B. The use of salicylates during these viral illnesses was a strong risk factor for Reye syndrome, and led to a warning against aspirin use during chickenpox or influenza-like illness from the Centers for Disease Control and Prevention (1980) and the Surgeon General (1982) and a warning label on aspirincontaining medications (1F86).24 Its dramatic decrease from a peak of 555 cases in 1980 to no more than 2 cases per year from 1994 to 1997 has been attributed to heeding these warnings.24
Among 50 children hospitalized for encephalitis during 2 years in Toronto, influenza A infection was detected in 4% overall and in 10% of all cases for which a pathogen was identified.25 During an influenza outbreak in Japan, the incidence of influenza-associated encephalitis among children younger than 5 years was 7 per 100,000 child-years.26
Most cases of influenza encephalitis present within 2 to 3 days of the onset of illness in children younger than 5 years.26 Altered mental status and focal or generalized seizures occur on presentation in most patients. Cerebrospinal fluid studies generally reveal absent to mild pleocytosis (usually < 23 white blood cells per microliter), normal protein, and normal glucose. Results of cerebrospinal fluid polymerase chain reaction were positive for influenza A in 5 of 6 Japanese patients with influenza A encephalitis.26 An electroencephalogram generally reveals diffuse slowing consistent with encephalitis. Typically, computerized tomography of the brain will reveal no abnormalities or diffuse edema and magnetic resonance imaging identifies T-2 hyperintense lesions scattered through the cortex and subcortical white matter, but no lesions in the brainstem, cerebellum, or basal ganglia.27 Persistent deficits or death have occurred in approximately onefourth of patients.
Influenza encephalitis might be confused with Reye syndrome. However, seizures occur earlier and more frequently in encephalitis, and the characteristic elevated liver enzymes, hypoglycemia, hyperammonemia, lactic acidemia, and mitochondrial deformation of Reye syndrome are not features of influenza encephalitis.28
Acute necrorizing encephalopathy of childhood has been recently described in Japan as an acute encephalopathy following the onset of influenza and other viral infections. As in influenza encephalitis, patients with acute necrotizing encephalopathy of childhood are usually younger than 5 years and present 2 to 3 days following onset of viral illness with seizures and progressive decline in mental status. However, it is distinguished on computerized tomography by the presence of multifocal, symmetric lesions in the thalamus, cerebral and cerebellar medullae, and brainstem tegmentum.28 Acute necrotizing encephalopathy of childhood occurs principally in Japan and the Far East and rarely in the West. Cerebrospinal fluid pleocytosis does not occur and cerebrospinal fluid protein is commonly elevated. The prognosis is relatively poor, with a case fatality rate of approximately 25%, but the prognosis for survivors has improved from a minority (15%) to a majority (60%) having no or only mild sequelae. The latter include tone and motor deficits such as tremor, ataxia, dysarthria, choreathetosis, and ocular dysmotility. Recovery from the acute illness generally begins on the fifth hospital day and is more likely in children older than 4 years, those who do not have elevated aminotransferases, and those who do not have brainstem lesions on neuroimaging.
Guillain-Barré syndrome is an acute, usually self-limited polyneuropathy characterized by progressive weakness, areflexia, and other sensory, motor, and autonomie abnormalities. It appears to be triggered by a preceding infection or immunization. In a study of 154 adult patients with Guillain-Barré syndrome compared with matched control subjects, the patients were no more likely to have had influenza infection than were the control subjects. However, recent infections with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae were more common in those with Guillain-Barré syndrome.29
The swine influenza vaccine of 1976-1977 was associated with a fourfold to eightfold increased risk of Guillain-Barré syndrome during the 2 to 3 weeks following vaccination. Studies of other influenza vaccines through the 1980s revealed no increased risk of Guillain-Barré syndrome, and vaccines used from 1992 to 1994 were associated with a small adjusted relative risk of 1.7 (confidence interval 1.0 to 2.8). This suggested a risk of approximately 1 additional case of Guillain-Barré syndrome per million influenza vaccinations. None of these apparent vaccine-associated cases occurred in children.30
Myocarditis and Pericarditis
Influenza A and B have been associated with pericarditis and myocarditis. Although prospective studies in adults show that subclinical disease is most common, severe illness and deaths have been reported.31,32 Prospective studies of cardiac complications of influenza in children have not been published, although individual case reports describe children with symptomatic pericarditis and fatal myocarditis.31,33
Ventricular arrhythmias during influenza are usually attributed to an associated myocarditis, which may otherwise be clinically subtle or silent. However, at least one case of sustained ventricular tachycardia has been reported in a 13-year-old girl with an influenza-like illness (no viral studies) but normal results on echocardiogram and no evidence of myocarditis on myocardial biopsy.34
Benign Acute Childhood Myosllls
In contrast to the typical myalgias associated with influenza infection, benign acute childhood myositis or myopathy is an uncommon complication characterized by the acute onset of leg pain and difficulty walking for days after the onset of influenza. It can occur in epidemic or nonepidemic fashion. Influenza A, influenza B, and other viruses have been implicated, but influenza B dominates the published case series.35"37 Boys are affected more often than are girls. The average age of patients is 8 to 9 years, with a range of 3 to 13 years. Patients experience typical influenza symptoms for 2 to 4 days, variably followed by 1 to 3 days of improvement before they have the sudden onset of severe pain, predominantly in the calf muscles (crural myositis). Many are unable to walk at presentation. Those who can walk exhibit an abnormal gait, typically toe walking, or a wide-based, stiff-legged gait. Extreme calf pain is elicited with passive ankle dorsiflexion and calf tenderness is invariably present. Strength and reflexes are preserved, but may be difficult to assess because of pain. Typical laboratory findings include a normal or mildly elevated erythrocyte sedimentation rate (almost always < 20), moderate to extreme elevations in creatine phosphokinase, variable leukopenia, neutropenia, or both, and lack of myoglobinuria. Complete resolution of clinical and laboratory abnormalities usually takes place in approximately 1 week and often within 2 to 3 days. Recurrence is uncommon and seems to be associated with a new viral infection. Muscle biopsy, although rarely indicated, reveals segmental muscle fiber degeneration and necrosis. The variable presence of mild, patchy inflammation leads some experts to prefer the term myopathy instead of myositis.37 It is not clear whether the pathogenesis is related to direct cytopathic effect or is immune mediated.
Influenza has been reported to produce extreme pain and tenderness in muscles of the neck (myalgia nuchae) out of proportion to muscle pain elsewhere.38 Such regional muscle involvement may be due to interaction of viral strain and host factors.
Rhabdomyolysls With Myoglobinuria
Rhabdomyolysis is a syndrome of diffuse muscle involvement producing elevated muscle enzymes and nephrotoxic myoglobinuria. Although it can be caused by almost any infection, influenza accounts for more than one-third of all reported cases with a known viral cause.39 In contrast to benign acute childhood myositis, this occurs more commonly in adults, but pediatrie cases caused by influenza A and B have been reported.40'41 Children present several days after the onset of typical influenza with more diffuse muscle pain and less severe muscle tenderness than in benign acute childhood myositis. The development of abdominal pain with dark urine, decreased urine output, or both often initiates medical attention. Positive results for urine "hemoglobin" in the absence of urine red blood cells then leads to a confirmatory test for myoglobinuria. Secondary acute renal failure required temporary hemodialysis in some cases, but was managed with alkalinization, hydration, and diuretics in others. Dehydration and nonsteroidal anti-inflammatory drug use before presentation may exacerbate the myoglobin nephropathy. Prompt diagnosis and management of acute renal failure was associated with normalization of kidney function in these cases.
Leukopenia is common in influenza, but marked leukopenia, neutropenia, thrombocytopenia, and anemia have also been reported in children.36-37'42 As already mentioned, lymphopenia and neutropenia were common in children with influenza B-associated crural myositis (see muscular complications). In a series of three such children,42 thrombocytopenia, anemia, leukopenia, or all three developed 2 to 4 days following the onset of influenza A infection, reaching a nadir around day 4. All of these abnormalities resolved without intervention during convalescence.
Influenza A infection has also been reported in connection with virus-associated hemophagocytic syndrome in three children receiving treatment for acute leukemia.43
Maternal Morbidity and Mortality
Excess mortality rates among pregnant women were documented during the pandemics of 1918 and 1957, but not between these epidemics.44 However, even in the absence of other risk factors, women who are in the second or third trimester of pregnancy appear more likely to be hospitalized for influenza and influenza-related cardiopulmonary illness than nonpregnant women, postpartum women, or women who are in the first trimester of pregnancy.44 For this reason, the Advisory Committee on Immunization Practices recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during influenza season.45
Neural Tube Defects
There are many conflicting reports about whether maternal influenza infection during the first trimester increases the risk of fetal anomalies, especially neural tube defects.46 The association of maternal influenza and birth defects was reported as early as the 1918 influenza pandemic, although the 1957 influenza A pandemic with the new subtype H3N2 was associated with the most reports of anencephaly and other neural tube defects. More recently, the comprehensive national registry of birth defects in Finland failed to confirm an increased risk of anencephaly during 14 influenza epidemics when compared with nonepidemic periods.46
Influenza causes excess hospitalization for cardiopulmonary illness in individuals with diabetes, malignancy, chronic renal disease, chronic lung disease, immunodeficiency disorders, and pregnancy.44,45 Influenza produced more severe pulmonary exacerbations in children and young adults with cystic fibrosis than did bacterial infections or other viral infections.47 In a 1977 series of 20 children and young adults with cancer, the clinical course of influenza A lasted twice as long as in the general population and resulted in interruption of this cancer therapy for days to weeks in 16 patients.48 Influenza and other respiratory viral infections were associated with an increased likelihood of exacerbation of primary nephrotic syndrome in 32 children.49 Although complicated influenza B infection has been reported in sickle cell disease,50 and febrile illness in this population often obligates testing and treatment for other illnesses, no studies quantifying increased complications of influenza in sickle cell disease have been published.
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Comparison of Primary Viral Pneumonia and Secondary Bacterial Pneumonia Complicating Influenza\