به نام خدا

INFLUENZA

دكتر محمد اماميفوق تخصص ريه و

مراقبتهاي ويژهعضو هيات علمي

دانشگاه

INFLUENZA

DefinitionEtiologic AgentEpidemiologyPathogenesis and ImmunityClinical ManifestationsComplicationsLaboratory Findings and

DiagnosisDifferential DiagnosisTreatmentProphylaxis

DEFINITIONInfluenza is an acute respiratory illness caused by infection with influenza viruses

ETIOLOGIC AGENT

Orthomyxoviridae familysingle-stranded RNA genomeclassified into three distinct types:

influenza A influenza B influenza C virus based on major antigenic

differenceshost cell–derived envelope

NN

H

Influenza Type A SubtypesInfluenza Type A Subtypes

Virus Structure

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.

EPIDEMIOLOGY 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.

HISTORY: KNOWN FLU PANDEMICS

Name of pandemic

Date Deaths

Asiatic Flu 1889-1890 1 million

Spanish Flu 1918-1920 40 -100 million

Asian Flu 1957-1958 1 - 1.5 million

Hong Kong Flu 1968-1969 0.75 - 1 million

Information taken from en.wikipedia.org/wiki/influenza

1918 FLU PANDEMIC

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

ANTIGENIC 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.

ANTIGENIC 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

PATHOGENESIS AND IMMUNITY

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.

METHOD OF INFECTION AND REPLICATION:

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

CLINICAL MANIFESTATIONS

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

PERSONS AT HIGHER RISK FOR COMPLICATIONS OF INFLUENZA

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

COMPLICATIONS

Pulmonary ComplicationsExtrapulmonary Complications

PULMONARY COMPLICATIONS

Pneumonia The most significant complication of

influenza is pneumonia 1-primary" influenza viral pneumonia 2- secondary bacterial pneumonia 3- mixed viral and bacterial pneumonia

PRIMARY INFLUENZA VIRAL PNEUMONIA

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

SECONDARY BACTERIAL PNEUMONIA

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.

MIXED VIRAL AND BACTERIAL PNEUMONIA

Many patients present with mixed viral and bacterial pneumonia

Mixed viral and bacterial pneumonia occurs primarily in patients with chronic cardiovascular and pulmonary diseases

OTHER PULMONARY COMPLICATIONS

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.

EXTRAPULMONARY COMPLICATIONS

Reye's syndrome Myositis rhabdomyolysis myoglobinuria Myocarditis pericarditis Encephalitis transverse myelitis Guillain-Barré syndrome

LABORATORY FINDINGS AND DIAGNOSIS

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.

DIFFERENTIAL DIAGNOSIS

variety of respiratory viruses Mycoplasma pneumoniaeSevere streptococcal pharyngitis early bacterial pneumonia

TREATMENTTwo 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.

TARGET 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

OSELTAMIVIR 

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.

ZANAMIVIR

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

PERAMIVIR

intravenous form of zanamivir.

not approved by the FDA and can be considered for patients unable to take oral or inhaled medications

AMANTADINE

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

RIMANTADINE

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.

PREGNANCY

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