Pandemic Influenza

Information

Definitions

Influenza is an illness caused by influenza type A or B virus
Pandemic influenza is when there is a global disease outbreak due to a new strain of influenza virus for which there is little or no immunity and no vaccine. The new strain must also cause serious illness and be easily transmitted from person to person. Other factors include a shift to highest death rates in younger individuals, successive pandemic waves, higher transmissibility than that of typical seasonal influenza and impacts in geographic regions not typical of seasonal influenza
A pandemic is present when there is a global disease outbreak with increased and sustained transmission of a pandemic strain of influenza in the general population
Typical symptoms of influenza include fever, sore throat, cough, rhinorrhea, lethargy, myalgias
Other symptoms can include anorexia, nausea, vomiting, diarrhea, conjunctivitis
Most deaths and severe cases are the result of pneumonia (either due to influenza or secondary bacterial)

Pathogenesis

Transmitted by inhalation

Transmission is fairly easy between humans for typical influenza strains
Avian influenza is endemic and easily spread between birds and are influenza A viruses (many strains possible, but pathogenic in humans has mostly been H5N1, more rarely H7N3, H7N7 and H9N2)
Swine influenza is endemic among swine world wide and are either influenza C viruses or influenza A viruses (strains H1N1, H1N2, H3N1, H3N2 and H2N3)
Transmission from animals to humans is not common and often results in no clinical illness

Virus binds to cells in respiratory tract

Hemagglutinin may have some role in initial binding
Enters cell and converts genomic RNAs into messenger RNAs
As virus forms inside a cell, buds from host wall
Neuraminidase is required for viral budding

M2 Protein

Matrix protein, functions as a proton channel
Facillitates pH dependent dissociation of matrix proteins from influenza RNA

Influenza viruses destroy ciliated epithelium lining trachea and bronchi

This leads to denudation of upper respiratory tract
Inflammatory response ensues
Acute neutrophil infiltration, then mononuclear cells

Macrophage Stimulation

Influenza viruses infect macrophages, stimulate cytokine production
TNFa, IL6, IL1ß, interferons (IFNa and IFNß), chemokines
Viral NS1 gene products linked to levels of cytokine (particularly TNFa) production
Avian H5N1 influenza particularly virulent, stimulates very high TNFa and IFNß levels
Level of cytokine stimulation linked to clinical severity

Secretions may fill bronchioles

Viral interstitial pneumonia may develop
Severe illness unusual in normal hosts except for H5N1 strains
Other avian-transmitted strains H9N2 and H7N7 usually associated with chickens, ducks
More common in elderly, cystic fibrosis, pregnant, and immunocompromised patients

Secondary bacterial pneumonia common (especially H. influenzae and S. aureus)
Antibodies do not appear until 3-4 weeks post infection
Cell immunity and interferon are initial responses (day 4)
Antibodies arising from infection or vaccination are serotype specific and neutralilzing

Description

Influenza A

Influenza A is generally more pathogenic than influenza B

All pandemics of the 20th century, and that of 2009 were due to Influenza A strains
Infects humans, pigs, horses, marine mammals, and birds

All known influenza strains infect birds
H1-H3, H5, H7, H9 strains infect humans
Avian influenza H5N1 strain has epidemic potential

Avian Influenza Virus (H5N1)

Highly pathogenic strains entrenched among poultry
Most patients with H5N1 disease have direct contact with poultry
Wild birds can also carry H5N1 strains and may mediate spreading to other geographies
Human to human transmission of avian H5N1 in two family clusters reported
Human to human transmission is extremely inefficient; extensive unprotected contact appears to be required
H5N1 is highly pathogenic, has infected 400 people (as of mid 2009) with a fatality rate >50%
Avian H7N7 influenza A transmission from chickens to humans
Rapid antigenic changes result in large number of "clades" of H5N1
Clades 2.2 are increasing; clade 2.3 is most common
Clades 2.1 and 1 (and uncommonly clades 0 and 7) also infect humans

In contrast to the regular seasonal epidemics of influenza, pandemics occur irregularly and cause high levels of mortality. Four Influenza pandemics have emerged in the last 300 years.

The 1918-1919 Spanish Flu (20-40 million people died), caused by influenza A, H1N1
1957 Asian Flu (1-1.5 million people died ), caused by influenza A, H2N2
1968 Hongkong Flu ( 3/4 to1 million people died ), caused by influenza A, H3N2
2009, Swine Flu, caused by H1N1 with pandemic declared on 11 June 2009

In 2009, cases of influenza like illness were first reported in Mexico on March 18; the outbreak was subsequently confirmed as H1N1 influenza A.

The first novel H1N1 patient in the United States was confirmed by laboratory testing at CDC on April 15, 2009. The second patient was confirmed on April 17, 2009. Manifestations of 2009 H1N1 novel influenza A are similar to those of the seasonal influenza
Patients present with symptoms of acute respiratory illness along with 2 of the following symptoms- fever, malaise, chills, fatigue, sore throat, diarrhea and vomiting
On 11 June 2009 WHO raised the pandemic alert level to its highest level, level six in response to ongoing global spread of the novel influenza A virus (H1N1)
27,737 people in 74 countries have been infected with 141 confirmed deaths as of 10^th June 2009
By mid June 2009, vaccine manufacturers report that mass production of H1N1 vaccine is ongoing

Epidemiology

Influenza is a very common cause of upper respiratory tract infection (URTI) in all ages
Underlies ~51,000 deaths per year in USA; 90% aged >64 years
Influenza A(H3N2) > Influenza B > Influenza A(H1N1) most common causes of death
Higher incidence in young and school-aged children (3 mo-16 years), although children are less prone to develop pulmonary complications
Hospitalization rates higher in infants, elderly, and persons with chronic medical illnesses
Occurs more commonly in winter
Women in 3rd trimester of pregnancy and elderly people with chronic illness are at higher risks of complications of influenza
RSV infection often incorrectly diagnosed as influenza
Vaccination against influenza reduces antibiotic use, lost worktime, and mortality

2009 Novel H1N1 influenza outbreak (Swine flu)

Has globally affected 27,737 people with 13217 confirmed cases in the United states alone (as of June 10, 2009)
141 confirmed deaths globally with 27 deaths in the US (as of June 10, 2009)

Etiology

Results from infection with the 3 basic types of influenza virus A, B or C from the family orthomyroviridae.
Transmitted by small-particle aerosols and deposited on the respiratory tract epithelium. If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells. Then cellular dysfunction and degeneration occurs, along with viral replication
The most common subtypes affecting Humans are H1N1 and H3N2

2009 H1N1 Influenza A

Human to human transmission
Transmission mainly through secretions of infected people
May be transmitted by touching infected objects and then touching nose or mouth

History & Physical Findings

History

Does the patient have recent travel to a country where epidemics have been reported?
Does the patient have history of contact with an infected person?
If spread from animals to humans, does the patient have a history of contact with that type of animal in a region of outbreak?
Does the patient have symptoms that might be influenza?

The presentation of influenza virus infection varies largely, however, it usually includes many of the symptoms described below. The incubation period ranges from 1 to 4 days with an average of about 2 days. Ask about the following symptoms:

Fever
Cough
Sore throat
Dyspnea
Headache (prominent)
Myalgias
Rhinorrhea
Conjunctivits
Sinusitis
Photophobia
Chest discomfort/pleurisy
Nasuea or vomiting ~12% (increased incidence in children)

Physical findings on examination

Physical examination may have the following findings

Fever
Rhinorrhea
Injection of pharynx and/or conjunctiva
Chest exam may have rales or wheezing
Hypoxia/Tachypnea (if significant pneumonia)
Hypotension (if septic usually from secondary bacterial infection)
Dehydration (if significant illness or gastroenteritis/anorexia)

Laboratory/Diagnostic Testing/Findings

Hematology test findings

Serological diagnoses (paired sera) involves comparison of acute and convalescent serum antibody titers: Takes > 2wks to report results
The leuckocyte count may be elevated, low or normal (not useful for diagnosis)

Chemistry test findings

Creatinine phosphokinase (CPK) may be elevated in acute viral myositis
Electrolyte, urea and creatinine testing may be indicated in cases of significant gastroenteritis or dehydration

Laboratory (Usually from nasal swab)

Laboratory confirmation is required for diagnosis

Viral culture: Detects influenza A and B. Provides results in 2-10 days
Detection of viral proteins - Point of care diagnostic test available
Detection of viral nucleic acid
Immunofluorescence DFA antibody staining: Results obtained in 2-4 hrs
Enzyme immunoassay: Results obtained in 2 hrs

Rapid Diagnostic Test: Results are obtained within 15 minutes.

Quickvue Influenza (A and B) - immunoassay, sensitivity >75%, specificity >95%
3 M rapid detection Flu A+B test
Directigen Flu A: Identifies influenza A
Directigen Flu A+ B : Identifies influenza A and B
BinaxNOW Influenza A & B: Identifies influenza A and B
OSOM Influenza A & B: Identifies influenza A and B
SAS FluAlert: Identifies influenza A and B
TRU FLU: Identifies influenza A and B
XPECT FLU: Identifies influenza A and B
Quickvue is probably the easiest, most rapid, and most accurate overall
For H5N1, real time polymerase chain reaction (PCR) is likely to be best test
Due to lower sensitivity of rapid tests, negative tests should be confirmed by viral culture and other means if necessary

Radiographic findings

CXR

Usually unnecessary unless hypoxia, tachypnea (out of proportion to fever) or abnormal lung examination
CXR will be normal in most cases, with infiltrates most commonly being due to a secondary bacterial pneumonia
With influenza pneumonia, will most typically see a diffuse interstitial infiltrate (clinically the patient will have ARDS)
In cases of avian influenza, bilateral infiltrates, lobar collapse, and/or focal consolidation have been reported

Differential Diagnosis

Definitive diagnosis requires cell culture of nasopharyngeal swabs or aspirate or acute and convalescent antibody titers.

Differential diagnoses to consider are

Respiratory syncytial virus
Adenovirus
Corovirus
Parainfluenza virus infection
Secondary bacterial pneumonia
Mixed bacterial-viral pneumonia

Respiratory Syncitial Virus (RSV)

Both influenza and RSV are common in children
Influenza most common November through February
RSV most common January through March

Herpes virus

Varicella zoster virus - particularly in adults with first time chicken pox
Cytomegalovirus - particularly in transplant patients
Herpes simplex virus

Differentiation from Common cold

Comparison of Typical Cold Virus Versus Influenza

Sign/Symptom	Influenza	Cold
Onset	Sudden	Gradual
Fever	Common, High grade	Rare
Cough	Nonproductive	Hacking
Headache	Prominent	Rare
Myalgia	Common, often severe	Slight
Fatigue	Up to 2-3 wks	Mild
Exhaustion	Early, prominent	Very rare
Chest pain	Common	Mild to moderate
Rhinorrhea	Sometimes	Common
Sore throat	Sometimes	Common
Sneezing	Sometimes	Common

General treatment measures

Rest
Hydration
Antipyretics- Usually ibuprofen or acetaminophen (avoid aspirin in children)
Antibiotics: If pneumonia is present
Neuraminidase inhibititors: Zanamivir (Relenza) or oseltamivir (Tamiflu) are currently the only recommended drugs. It is important to review viral sensitivities for a given season as resistance can be widely present, or very little resistance may be present in a given strain of influenza
Amantadines (adamantanes) block early viral replication: amantadine and rimantadine are the two drugs in this group. Amantadines are no longer recommended due to resistance and low effectiveness
Chemoprophylaxis with amantadines may be recommended for institutional outbreaks
Inhalation of zanamivir may cause bronchospasm, and should not be prescribed to asthmatics. Oseltamivir may cause nausea or vomiting
Vaccination - strongly preferred in order to minimize outbreaks
Vaccination and antiviral therapy are both cost-effective in healthy working adults

Medications indicated with specific doses

Oseltamivir (TamiFlu)

Third generation neuraminidase inhibitor with 80% bioavailability
Approved for both treatment and prevention of influenza infection
Oseltamivir reduces viral shedding and respiratory illness >75%
Reduced symptom scores: both duration and severity
Effective for acute influenza infection when initiated within 36 hours
May reduce incidence of secondary complications of influenza
Reduces new influenza ~ 90% in household contacts of cases used within 48 hours
Good activity against Avian Influenza H5N1
Neuraminidase mutations confer resistance to oseltamivir and can arise within 5 days
Side effects were only transient mild nausea and some vomiting
Adult dose (treatment): 75 mg PO bid x 5 day [renal insufficient CrCl 10-30 mL/min: 75 mg PO qd x 5 days]
Adult dose (prophylaxis): 75 mg PO qd throughout exposure period (with H1N1, recommended to continue for 10 days after last known exposure) [renal insufficient CrCl 10-30 mL/min: 75 mg PO q48 hrs]
Pediatric dose (treatment):

< 3 mos: 12 mg PO bid x 5 days
3-5 mos: 20 mg PO bid x 5 days
6-11 mos: 25 mg PO bid x 5 days
>1 yr, < 15 kg: 30 mg PO bid x 5 days
>1 yr, 15-23 kg: 45 mg PO bid x 5 days
>1 yr, 23-40 kg: 60 mg PO bid x 5 days
>1 yr, > 40 kg: 75 mg PO bid x 5 days

Pediatric dose (prophylaxis): Similar to adult prophylaxis protocols, doses given as in treatment dosing listed above by age/weight, but given qd (not bid). For example, a 25 kg child would receive 60 mg PO qd for prophylaxis
Prophylaxis for 6 weeks in frail persons > 64 years old reduces influenza complications 85% and is well tolerated
Cost effective treatment (without definitive diagnosis) in unvaccinated and high-risk vaccinated patients > 65 years old

Zanamivir (Relenza)

Sialic acid analogue which inhibits influenza A and B virus neuraminidases
Active against both Types A and B influenza (unlike amantadine/rimantadine)
Inhaled version is approved for treatment of all influenza types
Zanamivir has poor oral bioavailability (~10%)
Improves influenza symptoms when started after onset of symptoms
Also highly protective in prophylactic setting
Prevents flu-like symptoms when given prophylactically or 1-2 days after infection
50-90% reduction in symptoms of influenza infection and earlier return to work
Reduced requirements for antibiotics in high risk patients with influenza
Effective (80%) for prophylaxis of family members exposed to influenza
Adult/Pediatric > 7 yrs (Treatment): 10 mg (2 blisters) inhaled q12 hrs x 5 days (on first day, make sure to get 2 doses in, may be as close as 2 hrs apart)
Adult/Pediatric > 7 yrs (Prophylaxis): 10 mg (2 blisters) inhaled q24 hrs (with H1N1, recommended to continue for 10 days after last known exposure)

Rimantadine (Flumadine)

Methyl amantadine with same mechanism of action as amantadine
Increasing incidence of rimantidine resistant influenza A and influenza B
92% of isolates in 2005-6 showed mutations conferring amantadine resistance
Much improved side effect profile (less neurotoxicity) compared with amantadine
Decrease for renal insufficiency only if creatinine clearance <10mL/min
Excellent for prophylaxis, 70-90% prevention rate
Adults (Treatment): 100 mg PO bid x 3-5 days
Adults (Prophylaxis): 100 mg PO bid (for period of exposure)
Children (Prophylaxis)

1-10 yrs: 5 mg/kg/day divided qd/bid to max 150 mg/day
>10 yrs: 100 mg PO bid

Amantadine (Symmetrel)

Amantadine ~80% effective in preventing illness; reduces symptoms duration
Binds to M2 protein of influenza A blocking function of M2 protein
No effect on influenza B or parainfluenza viruses and increasing resistant influenza A
Side effects: neurotoxicity (anxiety, agitation), insomnia, dizziness, hallucination,
Coma has been reported in the elderly, especially with renal insufficiency
Teratogenic; contraindicated in pregnancy
Adults (Treatment/Prophylaxis): 100 mg PO bid (in elderly 100 mg PO qd)

Treatment is for 3-5 days, prophylaxis is for period of exposure

Children (Treatment or Prophylaxis)

1-10 yrs: 5 mg/kg/day divided qd/bid to max 150 mg/day
>10 yrs: 100 mg PO bid
Treatment is for 3-5 days, prophylaxis is for period of exposure

CDC recommendations for treatment for 2009 H1N1 Novel influenza

Oseltamivir

Adults: 75 mg PO bid for 5 days; start immediately after symptom onset
Child: Recommended doses as follows

< 3 mo: 12 mg PO bid for 5 days; start immediately after symptom onset
3-5 mo: 20 mg PO bid for 5 days; start immediately after symptom onset
6-11 mo: 25 mg PO bid for 5 days; start immediately after symptom onset
1 yr, 15 kgs: 30 mg PO bid for 5 days; start immediately after symptom onset
15-23 kgs: 45 mg PO bid for 5 days; start immediately after symptom onset
24-40 kgs: 60 mg PO bid for 5 days; start immediately after symptom onset
> 40 kgs: 75 mg PO bid for 5 days; start immediately after symptom onset

Zanamivir

Adult/Pediatric > 7 yrs: 10 mg (2 blisters) inhaled q12 hrs x 5 days (on first day, make sure to get 2 doses in, may be as close as 2 hrs apart)

Dietary or Activity restrictions

Patients should be advised to

Stay at home for at least 7 days after symptoms begin or until they have been symptom-free for 24 hours, whichever is longer (for pandemic influenza)
Get plenty of rest
Drink clear fluids (such as water, sports drinks, electrolyte beverages for infants) to keep from being dehydrated
Cover mouth when coughing or sneezing.
Clean hands with soap and water or an alcohol-based hand rub often and especially after using tissues and after coughing or sneezing into hands
Educate high-risk patients about prevention and strict hand-washing procedures
Avoid close contact with others
Do not go to work or school while they are infected
Be watchful for emergency warning signs that might indicate need to seek medical attention

Disposition

Patients are hospitalized in the event of serious illness; usually respiratory compromise due to either viral or bacterial pneumonia
Home quarantine and in some situations, admission for quarantine may be necessary

Follow-up

Monitoring

Monitor for signs of secondary bacterial infection
Monitor for signs of worsening respiratory status
Monitor for deteriorating mental status
Monitor for myoglobinuria if muscle pain is present

Assessment of therapy

Influenza A infection usually lasts longer than Influenza B or C infection.
Fever may last for 5-7 days and may recur if bacterial superinfection is present
Cough, lethargy, malaise may last up to 2 weeks

Complications

Major complications are bacterial superinfections

Streptococcus pneumoniae
Haemophilus influenzae
Staph. aureus most common
Pneumonia, otitis media, and sinusitis can occur
Influenza may also present with croup in young children

Acute Necrotizing Encephalopathy

Very uncommon severe complication of influenza
Vasogenic and cytotoxic edema in the brain
Leukocytosis in periphery
Cerebrospinal fluid may show no cells and unremarkable chemistry
Severe encephalopathic picture requiring intensive care
Treatment with oseltamivir and methylprednisolone

Rare Complications

Reye Syndrome

Usually Influenza B in young children on aspirin
May cause fulminant hepatic failure

Severe and/or recurrent pneumonitis
Encephalitis
Acute myositis, pericarditis, myocarditis
Guillain-Barre Syndrome
Multiorgan dysfunction syndrome (sepsis syndrome) may occur with severe infections

Prevention

Vaccine Types

Parenteral inactivated - Alfluria, Fluarix, Fluvirin, Fluzone, FluLaval
Fluzone Preservative free available for those with possible allergies
Live attenuated Intranasal vaccine - FluMist
Both inactivated and live attenuated vaccines are effective against influenza virus strains that have shown significant drift from vaccine strain
Avian influenza vaccine has been licensed but is not generally available

Egg Allergies and Inactivated Parenteral Vaccine

Caution in patients with egg allergies
If vaccine egg protein content is < 1.2µg/mL, patients with egg allergies may safely receive vaccine

Efficacy of Inactivated Parenteral Vaccine

At least 50% effective in reducing hospitalizations for flu and related disease
Influenza vaccination in elderly persons reduces their risk of hospitalizations for cardiac disease + stroke ~20%, respiratory infection ~30%, and any-cause death ~50%
Vaccination associated with 27-45% reduction in hospitalizations in elderly
Vaccinating healthcare workers reduces overall hospital mortality rates
Vaccinating children in day care settings reduced febrile respiratory illness 42%
Vaccinating children in day care also reduced febrile respiratory illness in contacts 80%
Vaccinations of children in Japan reduces mortality in older persons
Vaccinating elementary school students associated with reduced influenza symptoms in students and their households
Vaccinating healthy working adults <65 years reduces lost workdays, influenza- like illness, physician visits
Vaccinating healthy working adults is cost-effective when viral strains and vaccine strains are the same
Cost effective in healthcare professionals: efficacy ~90% for Influenza A and B

Safety of Inactivated Parenteral Vaccine

Inactivated influenza vaccine is safe and beneficial overall
Asthmatics should receive vaccine
Minimal local side effects of vaccine, with no increase in systemic symptoms
Do not give to persons wtih severe allergy to hens' eggs
Do not give to persons with history of Guillain-Barre sydnrome within 6 weeks after receiving vaccine

Live Intranasal Vaccine (FluMist)

Three strains (2 influenza A, 1 B) attenuated by reassortment with mutant virus
Efficacy ~90% in children 15-71 months and 12-59 months old
Reduced febrile respiratory illness, workdays lost, physician visits in adults 18-64
Efficacy likely 10-15% better than inactivated virus including in young children
Increase in runny nose, nasal congestion, headache versus placebo
FDA approved for healthy people 5-49 years old, 0.25mL per nostril annually
Safe in children without history of wheezing/asthma 12-59 months old

Live, Attenuated Influenza Virus Vaccine

Trivalent type A(H3N2) influenza vaccine attenuated given with intranasal inhaler
Tested in healthy, working adults against placebo
Vaccine reduced febrile illnesses 18-28% and antibiotic use
Vaccine reduced days of work lost by 17-27%
Vaccine conferred cross-protection since it was not an exact match with common flu

Baculovirus-Hemagglutinin Influenza Vaccine

Pure HA expression from insect (baculovirus) cells
Trivalent vaccine safe and immunogenic in humans
Evidence of protection against influenza, inncluded drifted virus

CDC Prophylaxis Recommendations for 2009 Novel H1N1 Influenza outbreak

Oseltamivir

Adults: 75 mg PO qd (continuinue throughout exposure period and for additional 10 days after last known exposure to confirmed case )
Child: Recommended doses as follows (continuinue throughout exposure period and for additional 10 days after last known exposure to confirmed case )

3-5 mo: 20 mg PO qd
6-11 mo: 25 mg PO qd
1 yr, 15 kgs: 30 mg PO qd
15-23 kgs: 45 mg PO qd
24-40 kgs: 60 mg PO qd
> 40 kgs: 75 mg PO qd

Zanamivir

Adults: Two 5 mg inhalations bid
Child ( 5 years): Two 5 mg inhalations bid

Prognosis

Prognosis depends on the severity of infection, immunity and the time when the therapy was started after the start of symptoms
Most patients recover fully, unless there are complications
Recovery takes 1- 2 weeks
Influenza related pneumonia is an important cause of death in elderly and in high risk patients with chronic illness
Appropriate antibacterial therapy reduces mortality rate
Secondary complications can lengthen the course of illness and worsen the chances of a full recovery
Poor outcomes usually occur in the elderly, often due to dehydration, exacerbations of comorbid condition, secondary complications

Associated conditions

Pharyngitis
Conjunctivitis
Pneumonia
Laryngotracheitis (croup)
Bronchitis/bronchiolitis
Gastroenteritis

ICD-9-CM

487.0 Influenza with pneumonia
487.1 Influenza with other respiratory manifestations
487.8 Influenza with other manifestations

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