Important differential diagnosis of influenza During a community-wide outbreak, a clinical diagnosis of

influenza can be made with a high degree of certainty with

typical illness.

In the absence of an outbreak (i.e., in sporadic or isolated

cases),influenza may be difficult to differentiate on clinical

grounds alone from an acute respiratory illness caused by any

of a variety of respiratory viruses or by Mycoplasma

pneumoniae.

BACTERIAL PNEUMONIA-classical association between pleuritic chest pain and productive cough.

Notes-bact. Pneumonia can occur with concurrent viral pneumonia or can be occurred upto 2wks post influenza.

Bacterial pneumonias generally do not run a self-limited course

d/d continued: COMMODN COLD-upper respiratory symptoms dominated with rhinitis. Fever is usually absent or mild.

Notes-fever is a negative predictor rhinovirus infection in adult.

STREPTOCOCCAL PHARYNGITIS: presence of tender unilateral adenopathy with exudates is typical of strep pharyngitis.

Notes-severe sore throat is not evidence of influenza.

BACTERIAL MENINGITIS OR ENCEPHALITIS:in general present with clouded sensorium, headache, neck stiffness.

Notes- early presentation may be confused with influenza. Most of the patients with influenza should have some improvement within 48 hrs. influenza often associate with invasive cns pathology.

OTHERS-febrile seizure, inhalational anthrax

DIAGNOSIS OF INFLUENZA: The diagnosis of influenza depends on epidemiologic,

clinical and laboratory considerations.

LAB DIAGNOSIS-

• Clinical lab test are nonspecific for diagnosis of influenza.

• Relative LEUCOPENIA is frequently seen ,though it is variable.

• If there is leucocytosis with count >15000,raised suspicion of secondary bacterial infections.

• Chest X ray show evidence of atelectasis or infiltrate in 10% of children

• In case of severe disease and bird flu there may be elevated transaminase and LDH level

Specific diagnostic test for influenza:

PREFERRED SAMPLES

a) Nasopharyngeal swab

b) Nasal wash, aspirate or swab

c) Endotracheal aspirate

d) Bronchoalveolar lavage[BAL]

e) Oropharyngeal swab

f) Combined nasopharyngeal or nasal swab with oropharyngeal swab.[IF COLLECT IN A SAME VIAL INCREASES VIRAL YIELD]

NB:BEFORE COLLECTING SAMPLES PPE SHOULD BE WEAR.

Case definitions of swine flu[h1n1] SUSPECTED CASE: A person with acute febrile illness with

onset within 7 days close contact with a person with confirmed swine flu OR reside in a community/within 7 days of travel in areas where ≥ 1 confirmed cases.

PROBABLE CASE : A probable case of swine influenza A (H1N1) virus infection is defined as a person with an acute febrile respiratory illness who: is positive for influenza A, but unsubtypable for H1 and H3 by influenza RT-PCR or reagents used to detect seasonal influenza virus infection, or is positive for influenza A by an influenza rapid test or an influenza immunofluorescence assay (IFA) plus meets criteria for a suspected case, or individual with a clinically compatible illness who died of an unexplained acute respiratory illness who is considered to be epidemiologically linked to a probable or confirmed case.

Confirmed case: A confirmed case of swine influenza A (H1N1)

virus infection is defined as a person with an acute febrile respiratory illness with laboratory confirmed swine influenza A (H1N1) virus infection at WHO approved laboratories by one or more of the following tests:

Real Time PCR

Viral culture

Four-fold rise in swine influenza A (H1N1) virus specific neutralizing antibodies

Storage and transport of samples How to Store Specimens

Store specimens at 4 °C before and during transportation within 48 hours

Store specimens at -70 °C beyond 48 hours

Do not store in standard freezer – keep on ice or in refrigerator

Avoid freeze-thaw cycles

Better to keep on ice for a week than to have repeat freeze and thaw

Transport:

While transportation cold chain should be maintained.

Follow local regulations on the transportation of infectious material

Coordinate with the laboratory .

Samples are send to NICED for diagnosis.[in Kolkata]

CHOICEOF SAMPLE WITH CLINICAL COURSE

TESTS:

RAPID INFLUENZA DIAGNOSTIC TESTS [RIDT]mechanism:

Algorithm to assist in the interpretation of RIDT results during periods when influenza viruses are circulating in the community

A test report[RT-PCR] from NICED

Advantages and Disadvantages of RIDTs Advantages:

Produce quick result in 15 minutes or less, simple to perform

Some RIDTs are approved for office/bedside use

Disadvantages:

Sub-optimal test sensitivity, false negative results are common, especially when influenza activity is high

Although specificity is high, false positive results can also occur, especially during times when influenza activity is low

Some RIDTs distinguish between influenza A or B virus infection while others do not.

RT PCR

Reverse Transcription-Polymerase Chain Reaction (RT-PCR) Advantages: Molecular assays are more sensitive and specific for detecting influenza

viruses than other influenza tests (e.g., rapid influenza diagnostic tests, immunofluorescence, and viral culture)

The likelihood of a false positive or false negative result is low and therefore, the interpretation of the result is less impacted by the level of influenza activity in the community

Some, but not all molecular assays can distinguish between specific influenza A virus subtypes

Disadvantages: Results of RT-PCR and other molecular assays may not be available in a

clinically relevant time frame to inform clinical management decisions. RT-PCR generally not available for outpatient or emergency room

settings. For hospitalized patients, these assays are not always available on-site.

Respiratory specimens may need to be sent to a state public health laboratory or commercial laboratory for RTPCR.

Therefore, although the test can yield 3-8 hours, the actual time to receive results may be substantially longer.

RT-PCR and other molecular assays are generally more expensive .

Laboratory diagnosis of avian flu

Samples

Live bird

Tracheal swab

Cloacal swab

Dead bird

Organs

Faeces of bird

Identification Procedures

Inoculation of 9-11day old embryonated chicken eggs followed by

Haemagglutination immunodiffusion test

Confirm presence of influenza virus

Subtype determination with nonspecific antisera

Strain virulence evaluation of intravinouspathogencity index (IVPI) in 4-8 week old chicken

Serology Tests available ELISA Detect antibodies to AI virus Doesn’t distinguish subtypes Agar gel diffusion Both within 1 week of infection

haemagglutination inhibition test: Serotype specific test Available for each H subtype HI titres are positive a few days later than ELISADIAGNOSIS OF HUMAN AVIAN FLU SAME AS

OTHER INFLUENZA

ALWAYS MONITOR FOR FEATURES OF COMPLICATIONS; Complications of influenza occur most frequently in patients

>64 years old and in those with certain disorders;

including cardiac or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and immunosuppression. neurospychiatric problems

Pregnancy in the second or third trimester and postpartum also predisposes to complications with influenza.

Children <2 years old (especially infants)are also at high risk for complications.

People on long term aspirin therapy.

Morbidly obese.

MANAGEMENTSupportive and treatment of uncomplicated cases in hospital- Plenty of oral fluids, good nutritional support.

Antibiotics for secondary infection. Suspected case not having pneumonia do not require antibiotic therapy .

Paracetamol or ibuprofen is prescribed for fever, myalgia and headache. Aspirin is avoided for risk of Reye’s syndrome.

For sore throat, short course of topical decongestants, saline nasal drops, throat lozenges and steam inhalation may be beneficial.

Constantly monitored for clinical / radiological evidence of LRTI.

If the laboratory reports are negative, the patient would be discharged after giving full course of oseltamivir

Antiviral medications Influenza antiviral medications should be started

as soon as possible after symptom onset These medications have not been shown to be

effective if administered more than 48 hours after onset

They can reduce illness severity and shorten duration of illness

They may also prevent serious influenza-related complications (e.g., pneumonia or exacerbation of chronic diseases)

Antiviral Drugs[mechanism]Drug Virus Target

Amantadine /

Rimantadine (high

level of resistance

cases,not

recommended

now)

Influenza A strains Matrix protein /

haemagglutinin

Oseltamivir[oral],

Zanamivir[nasal]

PERAMIVIR[ IV

prep approved by

CDC in 2014]

Influenza strains A

and B

Neuraminidase

Inhibitor

Antiviral treatments:Agents use recommd

forC/I Adverse effect

Oseltamivir(Tamiflu®)

treatment

Any age no nausea, vomiting, serious skin reactions and sporadic, transient neuropsychiatric events (self injuryor delirium; mainly reported amongJapanese adolescents andadults

chemoproph

>3mont[if needed>14days]

Zanamivir(Relenza®)

treatment

7 yrs or more

Copdasthma,allergy.

bronchitis, cough,headache,dizziness, and ear,nose and throat Infections

Peramivir(Rapivab®)

trtmnt 18yrs or more

NA DIARRHEA, others as TAMIFLU

chemoprophyls NA

Recommended dose and durationsAntiviral In children In adult

OseltamivirTreatmnt:5days

<1 yr-3 mg/kg/dose twice daily[ <3m-12mg;3-5m-20mg:5m-25 mg BD>1yr-15 kg or less, the dose is 30 mg BD>15 to 23 kg, the dose is 45 mg BD>23 to 40 kg, the dose is 60 mg BD>40 kg, the dose is 75 mg BD

75mg BD [DOSE ADJUSTMENT NEEDED IN RENAL FAILURE PATIENTS]

75mg OD

Prophylaxis:7days[mohfw 10days

If child is> 3 months <1yr old3 mg/kg/dose once dailyIf> 1 yr dose by child’s weight:15 kg or less, the dose is 30 mg once a day>15 to 23 kg, the dose is 45 mg once a day>23 to 40 kg, the dose is 60 mg once a day>40 kg, the dose is 75 mg once a day

Zanamivir(Relenza®)TREATMENT 5DAYS

10 mg (two 5mg inhalations) twice daily(FDA approved and recommended>7 yrs

SAME

Prophylaxis 7days10 mg once for>5yrs

Peramivir;for treatmnt(Rapivab®)

N/A IN CHILD; IN >18YRS.600 mg IV SINGLE DOSE ONLY ONCE.

Pharmacological treatment and prophylaxis of avian flu[WHO]

Some evidence suggests that some antiviral drugs, notably oseltamivir, can reduce the duration of viral replication and improve prospects of survival.

Dose and duration of the drug for treatment is same as above.

Chemoprophylaxis: for 7-10 days of last known exposure

No recommendation of prophylaxis in children below one year.

Chemoprophylaxis is given to high and moderate risk individuals who are close contacts with the case, professionals handling the patients and persons who are having contact with infected materials.

Management of complicated influenza Maintain airway, breathing and circulation (ABC) IV Fluids. Parentral nutrition. Oxygen therapy-Patients with signs of tachypnea, dyspnea,

respiratory distress and oxygen saturation less than 90 per cent should be supplemented with oxygen therapy

ventilatory support- Patients with severe pneumonia and acute respiratory failure (SpO2 < 90% and PaO2 <60 mmHg with oxygen therapy) must be supported with mechanical ventilation.

Invasive ventilation is preferred. To reduce spread of infectious aerosols, use of HEPA filters on expiratory ports of the ventilator circuit / high flow oxygen masks is recommended.

Antibiotics for secondary infection. Patient on mechanical ventilation should be administered

antibiotics prophylactically to prevent hospital associated infections .

Vasopressors for shock.

Management cont.

Immunomodulating drugs has not been found to be beneficial in treatment of ARDS or sepsis associated multi organ failure. High dose corticosteroids in particular have no evidence of benefit and there is potential for harm.

Low dose corticosteroids (Hydrocortisone 200-400 mg/ day) may be useful in persisting septic shock (SBP < 90).

For patients who continue to be symptomatic even after 10 days of treatment or those cases with respiratory distress and in whom secondary infection is taken care of, and if patient continue to shed virus, then resistance of the patients to anti viral would be tested. The dose of anti viral may be adjusted on case to case basis.

Complications of avian flu is very fatal;people often die with multi organ failure

Discharge criteria: It has been observed that some of the patients even though

asymptomatic, continue to test positive for influenza A H1N1. A treated and recovered patient, even though testing positive, has very little possibility of infecting others ;

Patients who responded to treatment after two to three days and become totally asymptomatic should be discharged after 5 days of treatment. There is no need for a repeat test.

Patients who continue to have symptoms of fever, sore throat etc. even on the 5th day should continue treatment for 5 more days. If the patient become asymptomatic during the course of treatment there is no need to test further.

Chemoprophylaxis (i) Chemoprophylaxis for health care workers at high risk: The

treating physicians and other paramedical personnel at the isolation facility would be put on chemoprophylaxis.

(ii) Chemoprophylaxis for contacts :Chemoprophylaxis is advised for those contacts with high risk (with under lying systemic diseases; extremes of age[< 5 years and 65> years]

In phase-5, if the clusters are reported for the first time, and given that those exposed are known and can be traced easily, then family, social and community contacts should be given Chemoprophylaxis.

(iii) Mass Chemoprophylaxis: The strategy of containment by geographic approach by giving oseltamivir to every individual in a prescribed geographic limit of 5 km from the epicenter(The village/city where the cluster is reported) would be applied:

1. If the virus is lethal and causing severe morbidity and high mortality 2. If the cluster is limited by natural geographic boundaries. This decision by State Health Department/MOHFW.

All close contacts of suspected, probable and confirmed cases. Close contacts include household /social contacts, family members, workplace or school contacts, fellow travellers etc.

All health care personnel coming in contact with suspected, probable or confirmed cases

Oseltamivir is the drug of choice

Influenza Vaccine,who should receive it[HIGH RISK GROUPS]

Persons 65 yrs or older

Persons with heart, pulmonary, renal and metabolic diseases.

Persons in nursing homes and other long-term care facilities

Persons 6 mos-18 yrs old receiving aspirin therapy

Influenza vaccine recipients--continued

Women in 2nd or 3rd trimester of pregnancy during flu season.

Household members of persons in high-risk groups

Health care workers and others providing essential community services.

Vaccination for Children Children under 6 months old are the paediatric group at

highest risk of influenza complications, but they are too young to get an influenza vaccine. The best way to protect young children is to make sure members of their household and their caregivers are vaccinated.

Influenza vaccination is recommended for all children 6 months of age and older every year.

Primarily two doses required at least four weeks apart for upto 8 years.

9 year onward single dose is recommended.

Avian influenza vaccine for birds

Convential vaccine

Inactivated oil emulsion vaccine used world wide

Recominant vaccine

Vector I LT vaccine or pox

Heteroglogous vaccine

In avian influenza contain the same agglutinin

A different Neuraminidase

THERE IS NO AVAILBLE VACCINE FOR HUMAN AGAINST AVIAN FLU.

STORAGE AND STABILITY Store at 2° to 8°C (35° to 46°F). Do not freeze. Discard product if exposed to freezing. Protect from light. Do not use vaccine after expiration date

When should vaccination occur?

Flu vaccination should begin soon after vaccine becomes available, ideally by October. However, as long as flu viruses are circulating, vaccination should continue to be offered throughout the flu season, even in January or later.

While seasonal influenza outbreaks can happen as early as October, most of the time influenza activity peaks in January or later. Since it takes about two weeks after vaccination for antibodies to develop in the body that protect against influenza virus infection, it is best that people get vaccinated so they are protected before influenza begins in the community.

Vaccine Recommendations

• Ideally, all

individuals

should have the

opportunity to be

vaccinated

against

influenza.

• Priority should

be given to high

risk population

• All those

aged over 6

months in a

clinical at-

risk group

• Only in all

high risk

children >6

months

• Universal

Vaccination

of all

children from

the age of 6

months.

• Special

attention for

children upto

60 months

• Routine

influenza

vaccination is

recommended

for all persons

aged ≥6 months

*CEVAG: Central European Advisory Grouphttp://www.who.int/docstore/wer/pdf/2002/wer7728.pdfhttp://www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0729a1.htm?s_cid=rr59e0729a1_ehttp://www.sehd.scot.nhs.uk/cmo/CMO(2010)14.pdfhttp://www.biomedcentral.com/content/pdf/1471-2334-10-168.pdf

*

WHO determines influenza vaccine contents annually

Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year .

Production of new vaccine is often difficult due to frequent changes of strains due to drifting/shifting

Mechanism of influenza vaccine

INTERNATIONAL SURVEILLANCE NETWORK

VACCINE MANUFACTURER

M A M J J A S O N D J FF M

Process of Influenza Recommendations and Vaccine Availability

WHO(Northern hemisphere)

PRODUCTION

WHO(Southern hemisphere)

PRODUCTION

Chalumeau HP. Vaccine manufacture at the time of a pandemic influenza. European journal of epidemiology1994;10: 487-490

Influenza Vaccine Composition for the 2014–15 Season [ACIP ]

Trivalent influenza vaccines contain-hemagglutinin (HA) derived from an A/California/7/2009 (H1N1)like virus, an A/Texas/50/2012 (H3N2)like virus and a B/Massachusetts/2/2012like(Yamagata lineage) virus.

Quadrivalent influenza vaccines will contain these antigens, and also a B/Brisbane/60/2008like(Victoria lineage) virus.

Both LAIV and IIV have been demonstrated to be effective in children and adults. In adults, most comparative studies have demonstrated either similar efficacy or that IIV was more efficacious. However, several studies have demonstrated superior efficacy of LAIV in children.

Recombinant IV prepared from purified HA protiens of first 3 viruses.

Influenza vaccination should not be delayed to procure a specific vaccine preparation if an appropriate one is already available.

‘Made in India’ H1N1 vaccine

Swine flu vaccine in India was launched

by Health department

Given by I/M or intranasal route.

Vaccines manufactured by

Zydus Cadila

Serum institute of india

Panacea biotech

Bharat biotech

Vaccine available in INDIABrand names manufacturer combinations type

VAXIGRIP Sanofi Pasteur Influenza [A&B] swine flu

IIV[splitvirion]trival /inj

INFLUVAC Solvay Pharma India PvtLtd

same same

INFLUGEN Lupin Laboratories Ltd. Same same

FLUARIX Glaxo SmithklinePharmaceuticals

same same

NASOVAC Serum Institute of India Ltd

same same

AGRIPAL Chiron Panacea same same

VaxiFlu S Zydus Cadila Health Care Ltd.

same same

NASOVAC-S Serum Institute of India Ltd

Same[USED>2 YRS] LAIV[trivalent]Intranasal spray

Active Ingredients:

VAXIGRIP have been prepared on eggs and are made from inactivated parts of the

following Influenza virus strains:

A/California/7/2009 NYMC X-179A(A/California/7/2009 [H1N1]pdm09 - like),

A/Texas/50/2012 NYMC X-223A (A/Texas/50/2012 [H3N2] – like)

B/Massachusetts/2/2012 NYMC BX-51B (B/Massachusetts/2/2012-like)

Nasovac-S

Live, attenuated, trivalent seasonal influenzavaccine for administration by intranasal spray

Supplied along with sterile water for inhalation as adiluent, syringe, needle, intranasal spray device anddose divider.

Each vial of the vaccine contains following strains:

Advantages of LAIV

Ref: MMWR Morb Mortal Wkly Rep. 2014 Aug 15;63(32):691-7.

Adv.

Serum antibodies

Nasal

Specific intranasal

IgA

Cell mediated immune responseProtection

against drifted virus

Mimic natural

route of inf

Painless

Herd immunity

Head to Head comparison of LAIV & IIV

LAIV IIV

Grows in nasopharaynx Not grow

Nasal spray Injection

Grows in cooler areas of nasal tract but stop growing in LRTI

Not grow

Mimic natural infection and induce double layer immunity

Serves only as a dose of antigen to the immune system

Induce local, systemic and cell mediated immunity

May not induce local immunity, good systemic response

Provide local immunity No local immunity

More effective Effectiveness less than LAIV

Painless Painful

Negligible side effect Reported side effects

Cost effective Comparatively expensive

Provide herd immunity Not possible

Preferred in children Children afraid of needles

Contraindications and precautionsIIV3/4:C/I- Severe allergic reaction to any component of the vaccine,

including egg protein, or after previous dose of vaccine.Precautions: Moderate to severe illness with or without fever; history

of GB syndrome within 6 weeks of receipt of influenza vaccine.LAIV:C/I- severe allergic reactions as above and Concomitant use of aspirin or aspirin containing medications in children

and adolescents. In addition, ACIP recommends LAIV4 not be used for pregnant women,

immunosuppressed persons, persons with egg allergy, and children aged 2–4 years who have asthma or who have had a wheezing episode noted in the medical record within the past 12 month.

LAIV should not be administered to persons who have taken influenza antiviral medications within the previous 48 hours.

Persons who care for severely immunosuppressed persons who require a protective environment should not receive LAIV, or should avoid contact with such persons for 7 days after receipt.

Precautions: As of IIV and Asthma in persons aged 5 years and older. Medical conditions which might predispose to higher risk for

complications attributable to influenza

Side effects: Mild side effects usually begin soon after you get the

vaccine and last one to two days.

Possible mild side effects of the flu shot include:

Soreness, redness, and swelling at the injection site

Fainting, mainly in adolescents

Headaches

Fever

Nausea

Possible mild side effects of the nasal spray include:

Runny nose

Wheezing

Headache

Vomiting

Muscle aches

Fever

Serious side effects:Serious side effects usually begin within a few minutes to a few hours after receiving the shot. Possible serious side effects of vaccination include:

Difficulty breathing

Hoarseness

Swelling around the eyes or lips

Hives

Paleness

Weakness

Racing heart

Dizziness

Behaviour changes

High fever

Influenza vaccine dosing algorithm for children aged 6 months through 8yrs[ACIP] for 2014-15

Recommendations regarding influenza vaccination of persons who report allergy to eggs [ACIP]

Indian Scenario:Reality

Limited data in public domain on annual Influenza casesand deaths in Indian scenario

Influenza vaccine is in Indian market since 2004

There is not much of published data on safety, tolerabilityand effectiveness of Influenza vaccine in Indian children

70

*India to compile database for influenza. Available from: URL:

http://www.livemint.com/2009/05/31215156/India-to-compile-database-on-s.html. Accessed on 22 May, 2010.

**Joseph L Mathew. Influenza vaccination for children in India. Indian Pediatrics. 2009 ;46:304-307.