on 20-Jun-2025 (Fri)

The influenza virus, an enveloped RNA virus, has eight gene segments that encode proteins. Two of these genes, the hemagglutinin (HA) and neuraminidase (NA) genes, are important mediators of pathogenicity and immunogenicity

Virus binding and infection require HA, and virion release requires NA

The antibody responses to HA and NA are critical for protection against infection

Influenza strain nomenclature consists of the type (A or B), the geographic source of the initial isolate, the isolate number, the year of isolation, and the HA and NA gene subtypes. Thus, a strain of influenza A virus that was isolated in Hong Kong in 1968 is designated A/Hong Kong/03/68[H3N2]

Epidemics occur every 1–3 years, mainly in the winter

In the United States, 15 million infections occur annually in young people and 4 million in older adults

Influenza attack rates are highest in the very young, but the greatest morbidity and mortality are seen among elderly patients.

The virus is e iciently transmitted by aerosols of respiratory secretions generated by coughing, sneezing, and talking

The onset of influenza is abrupt. The patient can o en say exactly when they fell ill with fever, headache, shaking chills, and myalgias.

The fever may be quite high. It remains elevated for at least 3 days and usually resolves within 1 week. Fever and systemic symptoms predominate in the clinical picture, but a dry cough is invariably present and usually persists a er the fever is gone.

Rhinorrhea, cervical adenopathy, and nonexudative pharyngitis are common.

Recovery can be prolonged, taking up to 3 weeks or even longer; during this period, the patient experiences cough and persistent fatigue

Pulmonary function is abnormal even in normal hosts and may remain abnormal for a period of weeks a er recovery

It has become recognized that influenza may also cause a milder febrile upper respiratory disease or even mild illness without fever. The extent to which influenza causes milder diseases is not well characterized, due to the likelihood that the majority of such cases are not reported

Human cases of avian influenza di er from typical human influenza in several ways. Although experience with H5N1 avian influenza remains limited, the disease typically presents with fever, cough, and respiratory failure, o en accompanied by diarrhea. Almost all cases report close contact with poultry, and the virus has predominantly infected children. Lymphopenia and abnormalities on chest X-ray are common. Mortality has been high among hospitalized cases, although the full clinical spectrum of infection is not well established.

Unlike most previous influenza strains, H5N1 is particularly virulent in children over the age of 12 years with no underlying diseases (those that would be predicted to have a strong immune system). Within 6–29 days of the onset of fever, many of these patients develop a respiratory distress syndrome and die of respiratory failure. Of the 23 cases reported from Southeast Asia in 2004, 18 (78%) died.

Clinical manifestations of the 2009 SOIV were generally similar to those of seasonal H1N1 influenza. Gastrointestinal symptoms may be more common than in typical seasonal influenza

In influenza pneumonia, rapid progression to dyspnea and hypoxia occurs. The clinical and radiographic picture is that of ARDS, and antibiotics are ine ective. Mortality in this situation is very high. The lungs are hemorrhagic, and there is di use involvement, but little inflammation. This complication was a major cause of death among young adults during the 1918 pandemic, but is rarely seen today.

However, recent experience with avian influenza virus suggests that, if the H5N1 strain adapts to humans, the incidence of this complication could greatly increase

The most useful characteristic distinguishing influenza from other respiratory illnesses is the predominance of the systemic symptoms. In addition, the epidemic nature of the disease in the community is helpful in making a diagnosis

Rapid influenza detection tests (RIDTs) are now available, and some can detect both the A and B types of influenza in throat and nasal swabs. However, the sensitivity of these tests is somewhat variable, depending on the source and quality of the specimen and on other factors, possibly being as low as 60%. Further, the likelihood of false positives is high when influenza incidence is low and, conversely, the likelihood of a false negative is high when influenza is circulating in the community.

Resistance to oseltamivir mediated by an NA mutation has been documented in the 2009 H1N1 S-OIV, and has arisen during therapy in immunocompromised patients. Such strains have generally remained sensitive to zanamivir.

Amantadine and rimantadine should no longer be used because of widespread resistance

Oseltamivir associated with neurologic and behavioral side e ects, particularly in children

Treatment should be started as rapidly as possible, although treatment is still beneficial when started more than 48 hours a er onset of disease symptoms. Treatment is generally for 5 days, although it may be extended in cases of severe disease or in immunocompromised patients. Shedding may be prolonged in such patients although the significance of such shedding a er clinical improvement is unknown. Doubling of the NA inhibitor dose may be considered in severe cases of pneumonia and is generally well tolerated

Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications

Vaccination decreases both disease severity and the infection rate.

Typical uncomplicated influenza often begins with an abrupt onset of symptoms after an incubation period of 1 to 2 days. Many patients can pinpoint the hour of onset. Initially, systemic symptoms predominate, including feverishness, chilliness or frank shaking chills, headaches, myalgia, malaise, and anorexia. In more severe cases, prostration is observed

Usually, myalgia or headache is the most troublesome symptom, and the severity is related to the height of the fever. Myalgia may involve the extremities or the long muscles of the back. In children, calf muscle myalgia may be particularly prominent. Severe pain in the eye muscles can be elicited by gazing laterally, and arthralgia but not frank arthritis is commonly observed. Other ocular symptoms include tearing and burning

The systemic symptoms usually persist for 3 days, the typical duration of fever

Respiratory symptoms, particularly a dry cough, severe pharyngeal pain, and nasal obstruction and discharge, are usually also present at the onset of illness but are overshadowed by the systemic symptoms.

The predominance of systemic symptoms is a major feature distinguishing influenza from other viral upper respiratory infections.

Hoarseness and a dry or sore throat may also be present, but these symptoms tend to appear as systemic symptoms diminish, and thus they become more prominent as the disease progresses, persisting 3 to 4 days after the fever subsides.

Cough is the most frequent and troublesome of these symptoms and may be accompanied by substernal discomfort or burning

Older adults may simply present with high fever, lassitude, and confusion without the characteristic respiratory complaints, which may not occur at all.

In addition, there is a wide range of symptomatology in healthy adults, ranging from classic influenza to mild illness or asymptomatic infection

Fever is the most important physical finding. The temperature usually rises rapidly to a peak of 100°F to 104°F, and occasionally to 106°F, within 12 hours of onset, concurrent with the development of systemic symptoms. Fever is usually continuous but may be intermittent, especially if antipyretics are administered. On the second and third days of illness, the temperature elevation is usually 0.5°F to 1.0°F lower than on the first day, and as the fever subsides, the systemic symptoms diminish. Typically, the duration of fever is 3 days, but it may last 4 to 8 days

Early in the course of illness, the patient appears toxic, the face is flushed, and the skin is hot and moist. The eyes are watery and reddened. A clear nasal discharge is common, but nasal obstruction is uncommon. The mucous membranes of the nose and throat are hyperemic, but exudate is not observed. Small, tender cervical lymph nodes are often present. Transient scattered rhonchi or localized areas of rales are found in less than 20% of cases. A convalescent period of 1, 2, or more weeks to full recovery then ensues. Cough, lassitude, and malaise are the most frequent symptoms during this period.

Maximal temperatures tend to be higher among children, and cervical adenopathy is more frequent among children than among adults. Croup associated with influenza virus infection occurs only among children.130,131

Among older adults, fever remains a very frequent finding, although the height of the febrile response may be lower than among children and young adults. Pulmonary complications are far more frequent in older adults than in any other age group

In addition, less distinct and milder pulmonic syndromes often occur during an outbreak of influenza that may represent tra- cheobronchitis, localized viral pneumonia, or possibly mixed viral and bacterial pneumonia.

The syndrome of primary influenza viral pneumonia was first well documented in the 1957–1958 outbreak. However, many of the deaths of young healthy adults in the 1918–1919 outbreak may have been a result of this syndrome

In outbreaks since 1918, primary influenza viral pneumonia has occurred predominantly among persons with cardiovascular disease, especially rheumatic heart disease with mitral stenosis, and to a lesser extent in others with chronic cardiovascular and pulmonary disorders.

The illness begins with a typical onset of influenza, followed by a rapid progression of fever, cough, dyspnea, and cyanosis. Physical examination and chest radiographs reveal bilateral findings consistent with the adult respiratory disease syndrome but no consolidation.

Secondary bacterial pneumonia often produces a syndrome that is clinically indistinguishable from that occurring in the absence of influenza.132,133

The patient has a classic influenza illness followed by a period of improvement lasting usually 4 to 14 days. Recrudescence of fever is associated with symptoms and signs of bacterial pneumonia such as cough, sputum production, and an area of consolidation detected at physical examination and on a chest radiograph

The two pathogens that are currently most commonly associated with influenza are Strep- tococcus pneumoniae and Staphylococcus aureus, which is otherwise an uncommon cause of community-acquired pneumonia.

Community- acquired methicillin-resistant S. aureus (MRSA) has been seen in children following influenza,134 and a study has suggested that the addition of a second active antibiotic may be important in children with MRSA complicating infection.135

During an outbreak of influenza, many patients do not clearly fit into either of the aforementioned categories. The disease is not relentlessly progressive, and yet the fever pattern may not be biphasic.

In addition, milder forms of influenza viral pneumonia involving only one lobe or segment have been described that do not invariably lead to death, and that are more likely to be confused with pneumonia caused by Mycoplasma pneumoniae than to pneumonia produced by bacterial infection.

Influenza virus shedding can be quite prolonged in immunosuppressed children,141 particularly those with human immunodeficiency virus (HIV) and low CD4+ counts.142

Influenza has been noted to cause severe disease with an increased incidence of pneumonia in immunosuppressed children with cancer compared with age-matched individuals without immunosuppression.138

Bronchiolitis may also occur as a result of influenza A or B virus infection, but respiratory syncytial virus and parainfluenza virus type 3 are more important causes of bronchiolitis.

Myositis Myositis and myoglobinuria with tender leg muscles and elevated serum creatine phosphokinase (CPK) levels have been reported, mostly in children, but they can also occur in adults.147 Symptoms may be suf- ficiently severe to interfere with walking

Cardiac Complications Both myocarditis and pericarditis have been rarely associated with influenza A or B virus infection,148,149 although not observed at autopsy among those who died of primary influenza viral pneumonia.150

Toxic Shock Syndrome In recent outbreaks of influenza A or B, a toxic shock–like syndrome has occurred in previously healthy children or adults, presumably because viral infection changed colonization and replication characteristics of the toxin-producing staphylococci.154–156

Influenza has also been associated with acute encephalitis and encephalopathy,158 which have a wide variety of manifestations.159 Most cases occur in children, but associated morbidity is higher in adults.160 The specific pathogenesis of influenza-associated encephalitis is unclear but may be related to the cytokine response

Reye syndrome is associated with many viral infections, prominently including influenza and varicella in children

The classic manifestation is a change in mental status occurring several days after a typical respiratory illness. Manifestations range from lethargy to delirium, obtundation, seizures, and respiratory arrest.

Reye syndrome is almost exclusively seen in children who have been given aspirin for treatment of febrile illnesses due to influenza and other viruses

Children who require continuous aspirin therapy are an important target group for influenza vaccination to reduce the risks of Reye syndrome

Influenza is an acute, febrile illness caused by infection with influenza type A or B virus that occurs in outbreaks of varying severity almost every winter in temperate climates, and year-round in tropical climates.

Influenza virus has been causing recurrent epidemics of febrile respiratory disease every 1 to 3 years for at least the past 400 years.

The greatest pandemic in recorded history occurred in 1918–1919 when, during three “waves” of influenza, 21 million deaths were recorded worldwide, among them 549,000 in the United States.2

The phenomenon of hemagglutination, which was discovered by Hirst in 1941, led to simple and inexpensive methods for the measurement of virus and specific antibody.8

The modern understanding of influenza was ushered in with the isolation by Smith and associates of influenza A virus in ferrets in 1933.3

into three distinct types: influenza A, influenza B, and influenza C virus. There are significant differences in genetic organization, structure, host range, epidemiology, and clinical characteristics among the three influenza virus types (Table 16 5.3)

However, all three viruses share certain features, including the presence of a host-cell–derived envelope, envelope gly- coproteins of critical importance in virus entry and egress from cells, and a segmented genome of negative-sense (i.e., opposite of message sense), single-stranded RNA.

The standard nomenclature for influenza viruses includes the influenza type, place of initial isolation, strain designation, and year of isolation. For example, the influenza A virus isolated by Francis from a patient in Puerto Rico in 1934 is given the strain designation A/Puerto Rico/8/34, sometimes referred to as PR8 virus. Influenza A viruses are further divided into subtypes based on the hemagglutinin (H, or HA) and neuraminidase (N, or NA) antigens (e.g., H1N1 or H3N2)

Although influenza B viruses have a similar structure, they do not exhibit the same type of antigenic and genetic variation in the HA and NA, and therefore do not have subtypes. However, since 2001, two antigenically distinct lineages of influenza B viruses, termed the “Victoria” lineage and the “Yamagata” lineage, have cocirculated in humans.18

Influenza viruses enter the cell by attachment of the viral hemag- glutinin to sialic acid–containing receptors on the cell membrane, followed by internalization of the virus into an acidic endosome. In the acidic environment of the endosome, the HA undergoes a conformational change that liberates a fusion peptide and results in fusion of the viral envelope with the endosomal membrane. At the same time, the third envelope protein, the M2 protein, acts as an ion channel allowing H+ ions to enter the virion from the endosome. This in turn allows the viral gene segments to leave the virion and enter the cytoplasm, a process known as uncoating

Viral gene segments are transported to the nucleus, where the viral polymerase complex, composed of the proteins PB1, PB2, and PA, directs the synthesis of the plus-sense messenger RNA and synthesis of negative- sense copies that will serve as progeny genomic RNA

Because the genome of influenza virus is segmented, segments can be exchanged between viruses infecting the same cell, a process referred to as reassortment. Genetic reassortment plays an important role in the generation of pandemic influenza A viruses, and has also been taken advantage of for the construction of attenuated live influenza vaccines

It has been estimated that a typical case of influenza, on average, is associated with 5 to 6 days of restricted activity, 3 to 4 days of bed disability, and about 3 days lost from work or school.28

Direct medical costs of illness account for only about 20% of the total expenses of a case of influenza, with a major proportion (30%–50%) of the economic impact due to loss of productivity.29

Influenza-related death rates in nursing home residents with comorbid conditions are as high as 2.8% per year.35

The increased risk of influenza during pregnancy was dramatically demonstrated during the 2009 pandemic.36 Previous studies had identified an increased risk of hospitalization associated with influenza epidemics during pregnancy, especially in the second and third trimesters and in the immediate postpartum period.37

The mechanism(s) by which pregnancy enhances the risk of influenza are not clear but might include the increased cardiovascular demands of pregnancy, and hormonally mediated changes to the innate and adaptive immune response.40

Obesity also emerged as a risk factor for influenza morbidity and mortality during the 2009 pandemic that had not been recognized in previous seasonal epidemics or pandemics.41,42 Although compromise to respiratory mechanics as a direct result of extreme obesity undoubtedly plays a role, there is also evidence to support a detrimental role of adipose tissue in the inflammatory response that might also enhance the influenza disease process