Definition Etiologic Agent Epidemiology Pathogenesis and Immunity Clinical Manifestations Complications Laboratory Findings and Diagnosis Differential Diagnosis Treatment Prophylaxis
D EFINITION Influenza is an acute respiratory illness caused by infection with influenza viruses
E TIOLOGIC A GENT Orthomyxoviridae family single-stranded RNA genome classified into three distinct types: influenza A influenza B influenza C virus based on major antigenic differences host cell–derived envelope
The standard nomenclature for influenza viruses includes : the influenza type place of initial isolation strain designation year of isolation
For example, an influenza A virus isolated 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 subdivided (subtyped) on the basis of the surface hemagglutinin (H) and neuraminidase (N) antigens Influenza A has 16 distinct H subtypes and 9 distinct N subtypes only H1, H2, H3, N1, and N2 have been associated with epidemics of disease in humans
Influenza A and B viruses are major human pathogens Type A and type B viruses are morphologically similar The hemagglutinin is the site by which the virus binds to sialic acid cell receptors, whereas the neuraminidase degrades the receptor and plays a role in the release of the virus from infected cells after replication has taken place
Immune responses to the H antigen are the major determinants of protection against infection with influenza virus, while those to the N antigen limit viral spread and contribute to reduction of the infection.
Infection with influenza virus results in long-lived resistance to reinfection with the homologous virus. Infection induces both systemic and local antibody, as well as cytotoxic T- cell responses, each of which plays a role in recovery from infection and resistance to reinfection.
E PIDEMIOLOGY Influenza outbreaks are recorded virtually every year, although their extent and severity vary widely Localized outbreaks take place at variable intervals, usually every 1–3 years. Global pandemics have occurred at variable intervals, but much less frequently than interpandemic outbreaks
Influenza A outbreaks typically begin abruptly, peak over a two to three week period, and last for two to three months. In most outbreaks, the earliest indication of influenza activity is an increase in febrile respiratory illnesses in children, followed by increases in influenza-like illnesses in adults. Increases in absenteeism from work and school are usually later manifestations of outbreaks
Most outbreaks have attack rates of 10 to 20 percent in the general population, but rates can exceed 50 percent in pandemics Extraordinarily high attack rates have been reported in institutionalized and semiclosed populations.
H ISTORY : K NOWN F LU P ANDEMICS Name of pandemic DateDeaths Asiatic Flu1889-18901 million Spanish Flu1918-192040 -100 million Asian Flu1957-19581 - 1.5 million Hong Kong Flu1968-19690.75 - 1 million Information taken from en.wikipedia.org/wiki/influenza
1918 F LU P ANDEMIC http://en.wikipedia.org/wiki/Image:1918_flu_in_Oakland.jpg American Red Cross nurses tend to flu patients in temporary wards set up inside the Oakland municipal Auditorium.
Influenza virus infection is acquired by transfer of virus-containing respiratory secretions. Both small- particle aerosols and droplets probably play a role in this transmission, but for infection control purposes influenza is generally considered to be transmitted by droplets
In temperate climates in either hemisphere, epidemics occur almost exclusively in the winter months (generally October to April in the Northern hemisphere and May to September in the Southern hemisphere), while influenza may be seen year round in the tropics.
Influenza epidemics are regularly associated with excess morbidity and mortality, usually expressed in the form of excess rates of pneumonia and influenza-associated hospitalizations and deaths
Attack rates are generally highest in the young, whereas mortality is generally highest in the elderly Excess morbidity and mortality are particularly high in those with medical conditions including pulmonary conditions such as asthma or COPD. Rates of influenza-related hospitalizations are particularly high in healthy children under 2 years of age.
A high frequency of antigenic variation is a unique feature of influenza virus that helps to explain why this virus continues to cause epidemic disease
A NTIGENIC DRIFT relatively minor antigenic changes that result from amino acid changes in one or more of the five identified major antigenic sites on the HA molecule.
A NTIGENIC SHIFT complete replacement of the HA or NA with a novel HA or NA. These viruses are “new” viruses to which the population has no immunity antigenic shifts, are seen only with influenza A viruses and may be associated with pandemics.
Influenza B virus causes outbreaks that are generally less extensive and are associated with less severe disease than those caused by influenza A virus. The hemagglutinin and neuraminidase of influenza B virus undergo less frequent and less extensive variation than those of influenza A viruses
Influenza B outbreaks are seen most frequently in schools and military camps, although outbreaks in institutions in which elderly individuals reside have also been noted on occasion. The most serious complication of influenza B virus infection is Reye's syndrome.
In contrast to influenza A and B viruses, influenza C virus appears to be a relatively minor cause of disease in humans. It has been associated with common cold–like symptoms and occasionally with lower respiratory tract illness
P ATHOGENESIS AND I MMUNITY Infection with influenza virus in humans is generally limited to the respiratory tract. After inoculation, the incubation period is thought to be from 18 to 72 hours, depending in part on the inoculum dose. Virus shedding is maximal at the onset of illness and may continue for 5 to 7 days or longer in children.
diffuse inflammation of the larynx, trachea, and bronchi, and a range of histologic findings Initially, viral infection involves the ciliated columnar epithelial cells Generally, the tissue response becomes more prominent as one moves distally in the airway. Recovery is associated with rapid regeneration of the epithelial cell layer, and pseudometaplasia.
M ETHOD OF I NFECTION AND R EPLICATION : The flu virus binds onto sugars on the surfaces of epithelial cells such as nose, throat, and lungs of mammals and intestines of birds. http://en.wikipedia.org/wiki/Image:Virus_Replication_large.svg
The host response to influenza infections involves a complex interplay of humoral antibody, local antibody, cell-mediated immunity, interferon, and other host defenses. Serum antibody responses, which can be detected by the second week after primary infection Antibodies to the hemagglutinin appear to be the most important mediators of immunity Virus shedding generally stops within 2–5 days after symptoms first appear
C LINICAL M ANIFESTATIONS incubation period of 1 to 2 days an abrupt onset of symptoms Systemic symptoms include feverishness, chilliness or frank shaking chills, headaches, myalgia, malaise, and anorexia. dry cough, severe pharyngeal pain, and nasal obstruction and discharge Elderly individuals may simply present with fever, lassitude, and confusion without the characteristic respiratory complaints, which may not occur at all.
the spectrum of clinical presentations is wide, ranging from a mild, afebrile respiratory illness similar to the common cold (with either a gradual or an abrupt onset) to severe prostration with relatively few respiratory signs and symptoms
In most of the cases that come to a physician's attention, the patient has a fever, with temperatures of 38°–41°C (100.4°–105.8°F). A rapid temperature rise within the first 24 h of illness is generally followed by gradual defervescence over 2–3 days, although, on occasion, fever may last as long as 1 week. Patients report a feverish feeling and chilliness, but true rigors are rare. Headache, either generalized or frontal, is often particularly troublesome Myalgias may involve any part of the body but are most common in the legs and lumbosacral area. Arthralgias may also develop.
Respiratory symptoms often become more prominent as systemic symptoms subside Examination of the pharynx may yield surprisingly unremarkable results despite a severe sore throat Mild cervical lymphadenopathy may be noted, especially in younger individuals
In uncomplicated influenza, the acute illness generally resolves over 2–5 days, and most patients have largely recovered in 1 week cough may persist 1–2 weeks longer. symptoms of weakness or lassitude (postinfluenza asthenia) may persist for several weeks
P ERSONS AT H IGHER R ISK FOR C OMPLICATIONS OF I NFLUENZA Children from birth to 4 years old Pregnant women Persons 65 years old Children and adolescents (6 months to 18 years old) who are receiving long-term aspirin therapy and therefore may be at risk for developing Reye's syndrome after influenza Adults and children who have chronic disorders of the pulmonary or cardiovascular system, including asthma Adults and children who have chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunodeficiency (including immunodeficiency caused by medications or by HIV) Adults and children who have any condition that can compromise respiratory function or compromise the handling of respiratory secretions or can increase the risk of aspiration Residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions
C OMPLICATIONS Pulmonary Complications Extrapulmonary Complications
P ULMONARY C OMPLICATIONS Pneumonia The most significant complication of influenza is pneumonia 1-primary" influenza viral pneumonia 2- secondary bacterial pneumonia 3- mixed viral and bacterial pneumonia
P RIMARY I NFLUENZA V IRAL P NEUMONIA least common but most severe of the pneumonic complications Primary influenza viral pneumonia has a predilection for individuals with cardiac disease, particularly those with mitral stenosis, but has also been reported in otherwise-healthy young adults as well as in older individuals with chronic pulmonary disorders. In some pandemics of influenza pregnancy increased the risk of primary influenza pneumonia
S ECONDARY B ACTERIAL P NEUMONIA The most common bacterial pathogens in this setting are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae Secondary bacterial pneumonia occurs most frequently in high-risk individuals with chronic pulmonary and cardiac disease and in elderly individuals.
M IXED V IRAL AND B ACTERIAL P NEUMONIA Many patients present with mixed viral and bacterial pneumonia Mixed viral and bacterial pneumonia occurs primarily in patients with chronic cardiovascular and pulmonary diseases
O THER P ULMONARY C OMPLICATIONS worsening of chronic obstructive pulmonary disease exacerbation of chronic bronchitis and asthma. In children, influenza infection may present as croup Sinusitis as well as otitis media (the latter occurring particularly often in children) may also be associated with influenza.
E XTRAPULMONARY C OMPLICATIONS Reye's syndrome Myositis rhabdomyolysis myoglobinuria Myocarditis pericarditis Encephalitis transverse myelitis Guillain-Barré syndrome
L ABORATORY F INDINGS AND D IAGNOSIS During acute influenza, virus may be detected in throat swabs, nasopharyngeal swabs or washes, or sputum. The virus can be isolated by use of tissue culture—or, less commonly, chick embryos within 48–72 h after inoculation. Most commonly, the laboratory diagnosis is established with rapid tests that detect viral antigens by means of immunologic or enzymatic techniques.
The tests are relatively specific but are of variable sensitivity depending on the technique and the virus to be detected The most sensitive and specific in vitro test for influenza virus is reverse-transcriptase polymerase chain reaction
sensitivities in adults and elderly patients tend to be lower than those reported in young children sensitivity is likely to be higher early in the course of illness
Serologic methods for diagnosis require comparison of antibody titers in sera obtained during the acute illness with those in sera obtained 10–14 days after the onset of illness and are useful primarily in retrospect. Fourfold or greater titer rises as detected by HI or CF or significant rises as measured by ELISA are diagnostic of acute infection.
D IFFERENTIAL D IAGNOSIS variety of respiratory viruses Mycoplasma pneumoniae Severe streptococcal pharyngitis early bacterial pneumonia
T REATMENT Two classes of antiviral agents are currently available for the treatment and prevention of influenza the M2 inhibitors (M2Is) amantadine and rimantadine the neuraminidase inhibitors (NIs) oseltamivir and zanamivir
The M2Is are active against all strains of influenza A virus. However, these drugs have no activity against influenza B viruses and resistance to their antiviral effects emerges readily. The NIs are active against both influenza A and B viruses.
T ARGET POPULATIONS FOR TREATMENT The decision of whom to treat with antivirals should be made on a case-by-case basis based on the patient's individual risk for influenza complications, the severity of illness, and the time since onset of symptoms (in uncomplicated cases). Preference should be given to those at highest risk for influenza complications (eg, lung transplant recipients, individuals with advanced HIV infection [CD4<200 cells/microL], hematopoietic stem cell transplant recipients).
Pregnant women are also at increased risk for influenza complications, but the decision of whether to offer treatment should be weighed against the lack of data regarding the safety of neuraminidase inhibitors during pregnancy The risk of complicated influenza during pregnancy increases by trimester and with associated comorbidities. Conversely, the risk of the antivirals probably is greatest in the first trimester
O SELTAMIVIR A 5-day course of oseltamivir or zanamivir reduces the duration of signs and symptoms of uncomplicated influenza by 1–1.5 days if treatment is started within 2 days of the onset of illness. Treatment, influenza A and B-75 mg PO bid Prophylaxis, influenza A and B-75 PO qd nausea and vomiting, neuropsychiatric side effects in children
available as a capsule or powder for liquid suspension. It has good bioavailability and is widely distributed in the body.
Z ANAMIVIR Treatment, influenza A and B-10 mg bid by inhalation Prophylaxis, influenza A and B-10 mg qd by inhalation Zanamivir may exacerbate bronchospasm in asthmatic patients
P ERAMIVIR intravenous form of zanamivir. not approved by the FDA and can be considered for patients unable to take oral or inhaled medications
A MANTADINE Treatment, influenza A- Age 1–9, 5 mg/kg in 2 divided doses, up to 150 mg/d Age 10 to 65 -100 mg PO bid Age>65-100 mg/d Prophylaxis, influenza A Age 1–9, 5 mg/kg in 2 divided doses, up to 150 mg/d Age 10 to65 -100 mg PO bid Age>65-100 mg/d
Amantadine or rimantadine treatment of illness caused by sensitive strains of influenza A virus similarly reduces the duration of symptoms of uncomplicated influenza by ~50% if begun within 48 h of onset of illness. The most common side effects of amantadine are minor and reversible central nervous system (CNS) side effects such as insomnia, dizziness, or difficulty in concentrating These dose-related side effects may be more troublesome in the elderly, in whom confusion is noted in about 18% of recipients
amantadine use has been associated with seizures in individuals with prior seizure disorder The CNS effects of amantadine are increased when these drugs are coadministered with anticholinergics or antihistamines, or drugs such as trimethoprim-sulfamethoxazole that inhibit tubular secretion of amantadine and increase the potential for CNS toxicity
R IMANTADINE Treatment, influenza A Age 1-12-Not approved Age 12-65 100 mg PO bid Age>65-100–200 mg/d Prophylaxis, influenza A Age 1–9, 5 mg/kg in 2 divided doses, up to 150 mg/d Age 10 to 65, 100 mg PO bid Age>65 100–200 mg/d
Rimantadine is associated with a considerably reduced rate of CNS side effects. There are no known drug interactions that significantly affect the levels or metabolism of rimantadine.
The therapeutic efficacy of antiviral compounds in influenza has been demonstrated primarily in studies of young adults with uncomplicated disease The effectiveness of these drugs in the treatment or prevention of complications of influenza is unclear
For uncomplicated influenza in individuals at low risk for complications, symptom-based rather than antiviral therapy may be considered. Acetaminophen or nonsteroidal anti- inflammatory agents can be used for relief of headache, myalgia, and fever, but salicylates should be avoided in children <18 years of age because of the possible association with Reye's syndrome. Since cough is ordinarily self-limited, treatment with cough suppressants generally is not indicated; codeine-containing compounds may be employed if the cough is particularly troublesome. Patients should be advised to rest and maintain hydration during acute illness and to return to full activity only gradually after illness has resolved, especially if it has been severe.
P REGNANCY All four drugs (oseltamivir, zanamivir, amantadine, rimantadine) are classified as FDA Pregnancy Category C, indicating that their effects in pregnant women and their fetuses have not been well defined. Thus, they should be used during pregnancy only if the perceived benefit justifies the potential risk to the embryo or fetus