This Guide on the clinical management of pandemic (H1N1) virus infection Prof. AHMED ABDELRAHMAN DEPARTMENT OF CHEST MENUFYIA UNIVERSITY HOSPITAL.

This Guide on the clinical This Guide on the clinical management of pandemic management of pandemic

(H1N1) virus infection(H1N1) virus infection

Prof. AHMED ABDELRAHMANProf. AHMED ABDELRAHMAN DEPARTMENT OF CHEST DEPARTMENT OF CHEST

MENUFYIA UNIVERSITY MENUFYIA UNIVERSITY HOSPITALHOSPITAL

INFLUENZAAcute respiratory illness caused by Acute respiratory illness caused by infection with influenza viruses.infection with influenza viruses.

Affects the upper and/or lower respiratory Affects the upper and/or lower respiratory tract and is often accompanied by systemic tract and is often accompanied by systemic signs and symptoms:signs and symptoms:– feverfever - headache- headache

– myalgiamyalgia - weakness- weakness

H1 – H16H1 – H16N1 – N9N1 – N9

N

H

Three types: A, B, CThree types: A, B, CAA epidemic flu, severe diseaseepidemic flu, severe disease

Surface proteins determine subtypeSurface proteins determine subtypeH (hemagglutinin) H (hemagglutinin) H1 – H16H1 – H16

N (neuraminidase)N (neuraminidase) N1 – N9N1 – N9

Influenza A viruses infect multipleInfluenza A viruses infect multiple species species depending on subtypedepending on subtype

HumansHumans

Birds Birds

PigsPigs

What is the Influenza A (H1N1)?What is the Influenza A (H1N1)?

Influenza A virus SubtypesInfluenza A virus Subtypes

16 different HA antigens (H1 to H16) 16 different HA antigens (H1 to H16)

9 different NA antigens (N1 to N9) 9 different NA antigens (N1 to N9)

3 subtypes of HA (H1, H2, and H3) & 3 subtypes of HA (H1, H2, and H3) &

2 subtypes of NA (N1 and N2) – caused 2 subtypes of NA (N1 and N2) – caused human disease.human disease.

found in birds & pigsfound in birds & pigs

H3N2 ("swine flu") is endemic in pigs in China, and in Vietnam. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2did when it evolved into the Hong Kong Flu strain of H3N2

H5N1  Influenza A virus  subtype it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as didH2N2 when it evolved into the Hong Kong Flu strain of H3N2.

SARS coronavirus

The SARS coronavirus, sometimes shortened

to SARS-CoV, is the RNA virus virus that causes severe

acute respiratory syndrome (SARS)

Influenza - Case DefinitionInfluenza - Case Definition

Fever Fever ≥≥ 38.00 C with 38.00 C with cough &/or sore throat cough &/or sore throat in the absence of a in the absence of a known cause other than known cause other than influenzainfluenza

Incubation periodIncubation period

Estimated incubation period 1-7 Estimated incubation period 1-7 days, (likely 1-4 days). days, (likely 1-4 days).

Infectious periodInfectious period

for a confirmed case of influenza A for a confirmed case of influenza A (H1N1) virus infection is defined (H1N1) virus infection is defined as 1 day prior to the case’s illness as 1 day prior to the case’s illness onset to 7 days after onset. onset to 7 days after onset.

CLINICAL FEATURESCLINICAL FEATURES

Clinical Features of Influenza Clinical Features of Influenza A/H1N1A/H1N1

Uncomplicated disease manifest withUncomplicated disease manifest with

feverfever

headacheheadache

upper respiratory tract symptoms upper respiratory tract symptoms (cough, sore throat, rhinorrhea),(cough, sore throat, rhinorrhea),

myalgia, fatigue, vomiting, or diarrhea.myalgia, fatigue, vomiting, or diarrhea.

ComplicationsComplications

Clinical syndromes have ranged from mild Clinical syndromes have ranged from mild respiratory illness, to lower respiratory tract respiratory illness, to lower respiratory tract illness, dehydration, or pneumonia. illness, dehydration, or pneumonia. URTIs (sinusitis, otitis media, croup)URTIs (sinusitis, otitis media, croup) LRT disease (pneumonia, bronchiolitis, status LRT disease (pneumonia, bronchiolitis, status asthmaticus), asthmaticus), cardiac (myocarditis, pericarditis),cardiac (myocarditis, pericarditis),musculoskeletal (myositis, rhabdomyolysis), musculoskeletal (myositis, rhabdomyolysis), neurologic ( encephalopathy, encephalitis, febrile neurologic ( encephalopathy, encephalitis, febrile seizures, status epilepticus), seizures, status epilepticus), In children,risk of REYE Syndrome (therefore, In children,risk of REYE Syndrome (therefore, NSAIDS contraindicated) NSAIDS contraindicated)

Symptom (%)Symptom (%)Fever* Fever* (93%) (93%) Cough Cough (83%) (83%) Shortness of breath Shortness of breath (54%) (54%) Fatigue/Weakness Fatigue/Weakness (40%)(40%) Chills Chills (37%) (37%) Myalgias Myalgias (36(36%)%)

Rhinorrhea Rhinorrhea (36%)(36%)

Sore Throat Sore Throat (31%)(31%)

Headache Headache (31%)(31%)

Vomiting Vomiting (29%)(29%)

Wheezing Wheezing (24%) (24%)

Diarrhea Diarrhea (24%)(24%)

Influenza A/H1N1 Infections in Influenza A/H1N1 Infections in ChildrenChildren

Majority are mild & self limiting Majority are mild & self limiting

Most common are Most common are

fever(100%)fever(100%) , , cough(100%)cough(100%) , , sore sore throat(66%)throat(66%) , , myalgia(44%) , vomiting & myalgia(44%) , vomiting & diarrhea(25%) diarrhea(25%)

Uncommon: altered conscious level Uncommon: altered conscious level (10%)(10%) , hypotension , hypotension

Suspected case of pandemic (H1N1) Suspected case of pandemic (H1N1) A suspected case of H1N1 infection is defined as an A suspected case of H1N1 infection is defined as an

individual with acute respiratory illness and individual with acute respiratory illness and fever and one of the followings; cough, sore fever and one of the followings; cough, sore throat, shortness of breath, difficulty in throat, shortness of breath, difficulty in breathing or chest pains with onset:breathing or chest pains with onset:Within 7 days of close contact with a person who Within 7 days of close contact with a person who is probable or confirmed case of H1N1infection, is probable or confirmed case of H1N1infection, ORORWithin 7 days of travel to a country/community Within 7 days of travel to a country/community where there has been one or more confirmed where there has been one or more confirmed cases of H1N1 infection; cases of H1N1 infection; OR OR Resident in a community where there is one or Resident in a community where there is one or more confirmed cases of H1N1 infection.more confirmed cases of H1N1 infection.

Probable case of (H1N1)Probable case of (H1N1)

A probable case of H1N1 infection is A probable case of H1N1 infection is defined as an individual with an defined as an individual with an influenza-like illness who is positive for influenza-like illness who is positive for influenza A that is confirmed by real-influenza A that is confirmed by real-time PCR, ORtime PCR, OR

an individual with a clinically an individual with a clinically compatible illness or died of an acute compatible illness or died of an acute respiratory illness who is linked to a respiratory illness who is linked to a probable or confirmed case.probable or confirmed case.

Case DefinitionsCase DefinitionsConfirmed Case of pandemic (H1N1)Confirmed Case of pandemic (H1N1)

A confirmed case of H1N1 infection is A confirmed case of H1N1 infection is defined as an individual with an influenza-defined as an individual with an influenza-like illness with laboratory confirmed like illness with laboratory confirmed pandemic (H1N1) 2009 virus infection by pandemic (H1N1) 2009 virus infection by one or more of the following test:one or more of the following test:

Real-time RT-PCRReal-time RT-PCR

Viral cultureViral culture

Influenza like illness (ILI)Influenza like illness (ILI)A person with A person with sudden onset of fever of >38 °C sudden onset of fever of >38 °C and at-least one of the following and at-least one of the following two respiratory symptoms in two respiratory symptoms in the absence of other known the absence of other known causes:causes:

dry cough & sore throat  dry cough & sore throat 

Severe acute respiratory illness (SARI)Severe acute respiratory illness (SARI)

A person meeting the case definition of A person meeting the case definition of influenza-like illness (sudden onset of influenza-like illness (sudden onset of fever > 38 0C with at-least one of the fever > 38 0C with at-least one of the following two respiratory symptoms- following two respiratory symptoms- dry cough, sore throat in the absence of dry cough, sore throat in the absence of other diagnosis) other diagnosis)

AND shortness of breath OR difficulty AND shortness of breath OR difficulty in breathing requiring hospital in breathing requiring hospital admissionadmission

Acute Respiratory Infection (ARI)Acute Respiratory Infection (ARI)For the purposes of this interim guidance, For the purposes of this interim guidance, Acute Respiratory Infection (ARI) is Acute Respiratory Infection (ARI) is defined as an acute respiratory tract illness defined as an acute respiratory tract illness that is caused by an infectious agent that is caused by an infectious agent transmitted from person to person. The transmitted from person to person. The onset of symptoms is typically rapid, over a onset of symptoms is typically rapid, over a period of hours to several days. Symptoms period of hours to several days. Symptoms include fever, cough, and often sore throat, include fever, cough, and often sore throat, coryza, shortness of breath, wheezing, or coryza, shortness of breath, wheezing, or difficulty breathing. difficulty breathing.

Complications of Influenza: Complications of Influenza: Respiratory complications are the most common Respiratory complications are the most common ones (esp secondary infections). ones (esp secondary infections). At times these complications, eg. an exacerbation At times these complications, eg. an exacerbation of COPD, may be the presenting symptom. of COPD, may be the presenting symptom. Cardiac events are not uncommon. Cardiac events are not uncommon. Complications of influenza Complications of influenza Major clinical Major clinical category category Respiratory Respiratory Pneumonia: primary viral, Pneumonia: primary viral, secondary bacterial, combined secondary bacterial, combined Upper respiratory: otitis media, sinusitis, Upper respiratory: otitis media, sinusitis, conjunctivitis conjunctivitis Acute laryngotracheo-bronchitis (croup) Acute laryngotracheo-bronchitis (croup) Bronchiolitis Bronchiolitis Complication of pre-existing disease Complication of pre-existing disease

Cardiovascular Cardiovascular Myocarditis & Pericarditis Myocarditis & Pericarditis

Muscular Muscular Rhabdomyositis Rhabdomyositis Rhabdomyolysis with myoglobinuria and Rhabdomyolysis with myoglobinuria and

renal failure renal failure Neurological Neurological Encephalitis Encephalitis

Reye’s syndrome Reye’s syndrome Guillain-Barré syndrome Guillain-Barré syndrome Transverse myelitis Transverse myelitis

Systemic Systemic Toxic shock syndrome Toxic shock syndrome Sudden death Sudden death

DIAGNOSIS

The CXR shows bilateral alveolar The CXR shows bilateral alveolar opacities in the base of both lungs.opacities in the base of both lungs. The specimen (H&E stain) showsThe specimen (H&E stain) shows

necrosis of bronchiolar walls, necrosis of bronchiolar walls, neutrophilic infiltrate and diffuse neutrophilic infiltrate and diffuse

alveolar damage with prominent alveolar damage with prominent hyaline membranes.hyaline membranes. Bacterial cultures were negative on Bacterial cultures were negative on admission, and no evidence of bacterial admission, and no evidence of bacterial infection of the lungs. infection of the lungs.

The CXR shows bilateral alveolar opacities in the base The CXR shows bilateral alveolar opacities in the base of both lungs.of both lungs.

The specimen (H&E stain) shows necrosis of bronchiolar walls, The specimen (H&E stain) shows necrosis of bronchiolar walls, neutrophilic infiltrate and diffuse alveolar damage.neutrophilic infiltrate and diffuse alveolar damage.

Real-Time Reverse Transcription-Real-Time Reverse Transcription-Polymerase Chain Reaction (rRT-Polymerase Chain Reaction (rRT-PCR) DetectionPCR) Detection– Qualitative for Qualitative for Influenza A, B, H1, and Influenza A, B, H1, and

H3 H3

– positive for influenza A and negative for positive for influenza A and negative for H1 and H3H1 and H3

– If reactivity of real-time RT-PCR for If reactivity of real-time RT-PCR for influenza A is strong (eg, Ct influenza A is strong (eg, Ct <<30), it is 30), it is more suggestive of a novel influenza A more suggestive of a novel influenza A virus. virus.

Risk factors in adults include the following: Risk factors in adults include the following:

1.1. Chronic respiratory conditions, eg asthma, Chronic respiratory conditions, eg asthma, COPD, OSA COPD, OSA

2.2. Pregnant women, esp. in second or third Pregnant women, esp. in second or third trimester trimester

3.3. Obesity (BMI > 30)Obesity (BMI > 30)

4.4. Other predisposing conditions, such Other predisposing conditions, such cardiac disease and diabetes mellitus, cardiac disease and diabetes mellitus, renal failure, immunosuppression. renal failure, immunosuppression.

5.5. Adults > 65 years of age esp. Adults > 65 years of age esp.

Risk factor for children with ILI Risk factor for children with ILI 1.1. Cardiac disease : congenital heart dis. Cardiac disease : congenital heart dis.

2.2. Chr. resp. disease : asthma Chr. resp. disease : asthma

3.3. Chronic renal failure Chronic renal failure

4.4. Diabetes mellitus or other metabolic diseases Diabetes mellitus or other metabolic diseases

5.5. Chr. neurological disease : ms. Dystrophy Chr. neurological disease : ms. Dystrophy

6.6. Impaired immunity:HIV,malignancyImpaired immunity:HIV,malignancy

7.7. Malnutrition or obesity Malnutrition or obesity

8.8. Children < 5 yrs : Higher risk of severe disease Children < 5 yrs : Higher risk of severe disease & mortality & mortality

Recognition of deterioration of Pts with Recognition of deterioration of Pts with moderate / severe illness need to be admitted moderate / severe illness need to be admitted and provided with antiviral therapy. and provided with antiviral therapy.

Severe illness following influenza occurs in at Severe illness following influenza occurs in at least 3 ways: least 3 ways:

1. severe viral infection with ARDS occurring 1. severe viral infection with ARDS occurring relatively early in illness related to viral relatively early in illness related to viral pneumonia (within 1st 4 days) pneumonia (within 1st 4 days)

2. bacterial pneumonia, complicating initial 2. bacterial pneumonia, complicating initial bronchitis caused by influenza, or following bronchitis caused by influenza, or following apparent recovery from initial illnessapparent recovery from initial illness

Abnormal pulse oximetry – Significant Abnormal pulse oximetry – Significant ↓↓in SpO2 (<92%) in SpO2 (<92%)

low SpO2 can detect severe or low SpO2 can detect severe or complicated influenza in some cases. complicated influenza in some cases.

In people with normal pre-existing In people with normal pre-existing respiratory and cardiac function, SpO2 respiratory and cardiac function, SpO2 < mid 90’s is abnormal and < low 90s is < mid 90’s is abnormal and < low 90s is very abnormal and indicates severe very abnormal and indicates severe disease. disease.

Severe Disease in Children Severe Disease in Children

Apnea Apnea

Tachypnea Tachypnea

Dyspnea Dyspnea

Cyanosis Cyanosis

Dehydration Dehydration

Altered mental status Altered mental status

Extreme irritability Extreme irritability

Lower chest wall indrawing Lower chest wall indrawing

Sternal recession Sternal recession

Grunting Grunting

Noisy breathing when calm Noisy breathing when calm

Increased Respiratory Rate in Children Increased Respiratory Rate in Children

≥≥ 50 breaths per min if under 1 yr old 50 breaths per min if under 1 yr old

≥≥ 40 breaths per min if 40 breaths per min if ≥≥ 1 year old 1 year old

Severe Clinical Dehydration or Clinical Shock in Severe Clinical Dehydration or Clinical Shock in childrenchildren

Reduced skin turgor Reduced skin turgor

Sunken eyes or fontanelle Sunken eyes or fontanelle

CNS Involvement in childrenCNS Involvement in children

Irritable Irritable

Unconscious Unconscious

Drowsiness Drowsiness

Confusion Confusion

Seizures Seizures

Weakness or paralysis Weakness or paralysis

Floppy infant Floppy infant

Patients to be hospitalized: Patients to be hospitalized:

All patients fulfilling criteria of All patients fulfilling criteria of ILI with any of the parameters ILI with any of the parameters for moderate to severe influenzafor moderate to severe influenza

Patient Home Assessment Patient Home Assessment

1 Respiratory Difficulties: Shortness of breath, rapid 1 Respiratory Difficulties: Shortness of breath, rapid breathing & blue discoloration of lips breathing & blue discoloration of lips

2 2 Coughing of blood or blood streaked sputum Coughing of blood or blood streaked sputum

3 3 Persistent chest pains Persistent chest pains

4 4 Persistent diarrhea and / or vomiting Persistent diarrhea and / or vomiting

5 5 Fever persisting beyond 2 days or recurring after 2 Fever persisting beyond 2 days or recurring after 2 days days

6 6 Abnormal behavior , confusion, less responsive , Abnormal behavior , confusion, less responsive , convulsion convulsion

7 7 Dizziness when standing and/or reduced urine Dizziness when standing and/or reduced urine productionproduction

Home Assessment Tool for pediatric Home Assessment Tool for pediatric 1.1. Lethargy or poor oral intake Lethargy or poor oral intake

2.2. Change in mental status Change in mental status

3.3. Signs of dehydration Signs of dehydration

4.4. Signs of respiratory distress Signs of respiratory distress

5.5. Fits Fits

6.6. Cyanosis Cyanosis

7.7. Persistent fever > 2 days Persistent fever > 2 days

Confirmed Case of Influenza Confirmed Case of Influenza A/H1N1 Infection A/H1N1 Infection

Individuals with ILI and +ve Individuals with ILI and +ve laboratory test , either by laboratory test , either by

a) PCR a) PCR

b) Viral culture b) Viral culture

Antiviral Treatment for Influenza A / Antiviral Treatment for Influenza A / H1N1 RECOMMENDATION: H1N1 RECOMMENDATION:

All hospitalized patients (ie. those with All hospitalized patients (ie. those with moderate to severe disease) with confirmed or moderate to severe disease) with confirmed or suspected novel influenza A H1N1.suspected novel influenza A H1N1.

Empirical therapy for suspected patients with Empirical therapy for suspected patients with severe disease should be considered if the time severe disease should be considered if the time for H1N1 confirmation is prolonged. The for H1N1 confirmation is prolonged. The antiviral treatment may be stopped if the antiviral treatment may be stopped if the results are negative. results are negative.

All individual with co-morbid factors whether All individual with co-morbid factors whether they are admitted or not. they are admitted or not.

Antiviral Therapy Antiviral Therapy Oseltamivir Oseltamivir (Tamiflu)(Tamiflu) dosage: Duration 5 days dosage: Duration 5 days

Adults & adolescents > 13 yrs: 75 mg bd Adults & adolescents > 13 yrs: 75 mg bd

(in severe cases, dosage can be doubled to 150 mg bd) (in severe cases, dosage can be doubled to 150 mg bd)

For children (according to weight): For children (according to weight):

1.1. <15kg: 30mg bd <15kg: 30mg bd

2.2. 15-23kg: 45mg bd 15-23kg: 45mg bd

3.3. 23-40kg: 60mg bd 23-40kg: 60mg bd

4.4. > 40kg: 75mg bd > 40kg: 75mg bd

Renal adjustments: patients with a serum creatinine Renal adjustments: patients with a serum creatinine clearance between 10 - 30 ml/min: treated with 75 mg clearance between 10 - 30 ml/min: treated with 75 mg daily for 5 days daily for 5 days

Oseltamivir Side EffectsOseltamivir Side Effects

Gastrointestinal(40%) : nausea , Gastrointestinal(40%) : nausea , vomiting , abd. pain/cramps, diarrhea vomiting , abd. pain/cramps, diarrhea

Neuropsychiatric(18%) : sleep Neuropsychiatric(18%) : sleep problems , insomnia , poor problems , insomnia , poor concentration , delirium , feeling concentration , delirium , feeling confused , hallucinations , bad dreams confused , hallucinations , bad dreams , nightmares , abnormal behavior , nightmares , abnormal behavior

ZanamivirZanamivir (Relenza)(Relenza) dosage: dosage:

10mg (2 puffs) bd for 5days (Adults & children) 10mg (2 puffs) bd for 5days (Adults & children)

In patients with bronchospasm: Zanamivir is In patients with bronchospasm: Zanamivir is not recommended for the treatment of not recommended for the treatment of patients with underlying airways disease (eg. patients with underlying airways disease (eg. asthma or COPD). Patients with pulmonary asthma or COPD). Patients with pulmonary dysfunction should always have a fast-acting dysfunction should always have a fast-acting bronchodilator available and discontinue bronchodilator available and discontinue zanamivir if respiratory difficulty develops. zanamivir if respiratory difficulty develops.

No dosage adjustment is required in patients No dosage adjustment is required in patients with renal impairment with renal impairment

Conclusions Conclusions Careful clinical assessment of the Careful clinical assessment of the individual with ILI in primary individual with ILI in primary healthcare setting is important healthcare setting is important Admission is needed for individual Admission is needed for individual with moderate to severe diseases of any with moderate to severe diseases of any age. age. Treatment with antiviral is needed Treatment with antiviral is needed only for admitted individuals and those only for admitted individuals and those with co-morbid factors whether with co-morbid factors whether admitted or not. admitted or not.

The single best way to protect against the The single best way to protect against the flu is to get vaccinated each year.flu is to get vaccinated each year.

flu shotflu shot— — an inactivated an inactivated

vaccine (containing vaccine (containing killed virus). - for killed virus). - for use in people older use in people older than 6 months, than 6 months, including healthy including healthy people and people people and people with chronic with chronic medical conditions.medical conditions.

The nasal-spray flu The nasal-spray flu vaccine vaccine ——made with live, made with live, weakened flu viruses weakened flu viruses that do not cause the that do not cause the flu . flu . - approved for use in - approved for use in healthy people, 2-49 healthy people, 2-49 y.o. who are not y.o. who are not pregnant.pregnant.

Thank You !Thank You !